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Contributions of the anterior cingulate cortex and amygdala to pain- and fear-conditioned place avoidance in rats
Abstract
The pain experience includes a sensory-discriminative and an affective-emotional component. The sensory component of pain has been extensively studied, while data about the negative affective component of pain are quite limited. The anterior cingulate cortex (ACC), and amygdala are thought to be key neural substrates underlying emotional responses. Using formalin-induced conditioned place avoidance (F-CPA) and electric foot-shock conditioned place avoidance (S-CPA) models, the present study observed the effects of bilateral excitotoxic (quinolinic acid 200 nmol/microl) lesions of the ACC and amygdala on pain and fear induced negative emotion, as well as on sensory component of pain. In the place-conditioning paradigm, both intraplantar (i.pl.) injection of formalin and electric foot-shock produced conditioned place avoidance. Excitotoxin-induced lesion of either the ACC or amygdala significantly reduced the magnitude of F-CPA. However, the decrease in the magnitude of S-CPA occurred only in the amygdala, but not ACC lesioned animals. Neither ACC nor amygdala lesion significantly changed formalin-induced acute nociceptive behaviors. These results suggest that the amygdala is involved in both pain- and fear-related negative emotion, and the ACC might play a critical role in the expression of pain-related negative emotion.
... These include the rostral ACC (rACC), also referred to as the pregenual ACC, which is distinct from the subdivisions of MCC and the posterior cingulate cortex in the dorsal and caudal ACC, respectively 7 . How this anatomical diversity is translated into functional differences has not been considered in pain and may underlie the diverse putative functions described for the cingulate cortex in pain modulation [8][9][10][11][12][13][14][15][16] . ...
... Rodent studies on the functions of the ACC in pain describe either an exclusive role in pain-related negative affect but not in the sensory component of pain [8][9][10] or pronociceptive sensory functions [11][12][13][14][15][16] . Most studies addressing the impact of cingulate function on nociception have targeted the pregenual ACC (rACC) 9,14,16,[27][28][29][30] , whereas we focused exclusively on the MCC, which is a cytoarchitecturally and functionally distinct subdomain of the cingulate across several species, including mouse, rat and human 7 . ...
... A normal distribution of the data was tested with the Kolmogorov-Smirnov test if the sample size allowed. No statistical methods were used to predetermine sample sizes, but our sample sizes are similar to those reported in previous publications 8,9,14,28,30 . If the equal-variance assumptions were not valid, statistical significance was evaluated using the Mann-Whitney test. ...
The identity of cortical circuits mediating nociception and pain is largely unclear. The cingulate cortex is consistently activated during pain, but the functional specificity of cingulate divisions, the roles at distinct temporal phases of central plasticity and the underlying circuitry are unknown. Here we show in mice that the midcingulate division of the cingulate cortex (MCC) does not mediate acute pain sensation and pain affect, but gates sensory hypersensitivity by acting in a wide cortical and subcortical network. Within this complex network, we identified an afferent MCC–posterior insula pathway that can induce and maintain nociceptive hypersensitivity in the absence of conditioned peripheral noxious drive. This facilitation of nociception is brought about by recruitment of descending serotonergic facilitatory projections to the spinal cord. These results have implications for our understanding of neuronal mechanisms facilitating the transition from acute to long-lasting pain.
... Utilization of an electrical shock as a negative reinforcer might seem counterintuitive, as the ACC has been established as a structure important for processing affective aspects of pain (Fuchs, Peng, Boyette-Davis, & Uhelski, 2014). However, Gao, Ren, Zhang, and Zhao (2004) specifically evaluated reactivity to electrical shocks and did not find any effect after an ACC lesion, while they reported significant reductions in responses to formalininduced pain. Furthermore an ACC lesion does not prevent rats from developing conditioned freezing after application of a shock (Cardinal et al., 2003). ...
... The current results suggest that ACC might be a key structure in computing predatory imminence (Fanselow & Lester, 1988) and selecting the appropriate mode of defensive response (eg., fleeing vs. freezing) under threat. Since ACC-amygdala connectivity is required for affective aspect of pain (Gao et al., 2004) and perhaps other forms of defensive response regulation, this pathway may be also significantly involved in the avoidance of fast-moving robot. ...
... The spinal cord is responsible for receiving information from nociceptors and projecting to the brain and plays a major role in integrating and modulating nociceptive signals (Kuner, 2010). Studies have reported that brain regions anterior cingulate cortex (ACC) and amygdala (AMY) are important areas in pain sensation and involved in the interpretation and assessment of the affective and emotional components of pain (Gao et al., 2004;Phelps and LeDoux, 2005;Cao et al., 2009;Navratilova et al., 2015;Neugebauer, 2015). The lesion of ACC and AMY was documented to inhibit the conditioned place aversion of formalin (Gao et al., 2004;Cao et al., 2009). ...
... Studies have reported that brain regions anterior cingulate cortex (ACC) and amygdala (AMY) are important areas in pain sensation and involved in the interpretation and assessment of the affective and emotional components of pain (Gao et al., 2004;Phelps and LeDoux, 2005;Cao et al., 2009;Navratilova et al., 2015;Neugebauer, 2015). The lesion of ACC and AMY was documented to inhibit the conditioned place aversion of formalin (Gao et al., 2004;Cao et al., 2009). Increasing evidence indicates that cellular and molecular adaptations within these two regions appear under chronic stress and chronic pain conditions (Simons et al., 2014;Ji et al., 2017;Sellmeijer et al., 2018;Navratilova et al., 2019). ...
Chronic neuropathic pain caused by nerve damage is a most common clinical symptom, often accompanied by anxiety- and depression-like symptoms. Current treatments are very limited at least in part due to incompletely understanding mechanisms underlying this disorder. Changes in gene expression in the dorsal root ganglion (DRG) have been acknowledged to implicate in neuropathic pain genesis, but how peripheral nerve injury alters the gene expression in other pain-associated regions remains elusive. The present study carried out strand-specific next-generation RNA sequencing with a higher sequencing depth and observed the changes in whole transcriptomes in the spinal cord (SC), anterior cingulate cortex (ACC), and amygdala (AMY) following unilateral fourth lumbar spinal nerve ligation (SNL). In addition to providing novel transcriptome profiles of long non-coding RNAs (lncRNAs) and mRNAs, we identified pain- and emotion-related differentially expressed genes (DEGs) and revealed that numbers of these DEGs displayed a high correlation to neuroinflammation and apoptosis. Consistently, functional analyses showed that the most significant enriched biological processes of the upregulated mRNAs were involved in the immune system process, apoptotic process, defense response, inflammation response, and sensory perception of pain across three regions. Moreover, the comparisons of pain-, anxiety-, and depression-related DEGs among three regions present a particular molecular map among the spinal cord and supraspinal structures and indicate the region-dependent and region-independent alterations of gene expression after nerve injury. Our study provides a resource for gene transcript expression patterns in three distinct pain-related regions after peripheral nerve injury. Our findings suggest that neuroinflammation and apoptosis are important pathogenic mechanisms underlying neuropathic pain and that some DEGs might be promising therapeutic targets.
... Although the neuronal pathways and brain areas involved in the affective component of pain remain elusive, accumulating evidence has implicated the anterior cingulate cortex (ACC) as a critical brain region for the emotional processing of pain [2][3][4][5][6]. Neuroimaging studies indicate that ACC activity increases during the presentation of a noxious stimulus and during chronic pain conditions [7,8]. ...
... Neuroimaging studies indicate that ACC activity increases during the presentation of a noxious stimulus and during chronic pain conditions [7,8]. In animals, lesioning of the ACC abolishes formalininduced conditioned place avoidance (pain-related aversion) without affecting formalin-induced spontaneous pain behavior (pain sensation) [3,6,9]. Microinjection of an Xiao-Bo Wu and Li-Na He contributed equally to this work. ...
Pain consists of sensory-discriminative and emotional-affective components. The anterior cingulate cortex (ACC) is a critical brain area in mediating the affective pain. However, the molecular mechanisms involved remain largely unknown. Our recent study indicated that C-X-C motif chemokine 13 (CXCL13) and its sole receptor CXCR5 are involved in sensory sensitization in the spinal cord after spinal nerve ligation (SNL). Whether CXCL13/CXCR5 signaling in the ACC contributes to the pathogenesis of pain-related aversion remains unknown. Here, we showed that SNL increased the CXCL13 level and CXCR5 expression in the ACC after SNL. Knockdown of CXCR5 by microinjection of Cxcr5 shRNA into the ACC did not affect SNL-induced mechanical allodynia but effectively alleviated neuropathic pain-related place avoidance behavior. Furthermore, electrophysiological recording from layer II–III neurons in the ACC showed that SNL increased the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs), decreased the EPSC paired-pulse ratio, and increased the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor/N-methyl-D-aspartate receptor ratio, indicating enhanced glutamatergic synaptic transmission. Finally, superfusion of CXCL13 onto ACC slices increased the frequency and amplitude of spontaneous EPSCs. Pre-injection of Cxcr5 shRNA into the ACC reduced the increase in glutamatergic synaptic transmission induced by SNL. Collectively, these results suggest that CXCL13/CXCR5 signaling in the ACC is involved in neuropathic pain-related aversion via synaptic potentiation.
... For example, CPA can be induced by pairing a context with electric foot-shocks [16][17][18] . However, foot-shocks are non-ethological, noxious stimuli 19,20 . ...
... However, the interpretation of LiCl-CPA data can be inconclusive, as LiCl per se was shown to interfere with neuronal mechanisms involved in memory processing, such as NMDA receptor 11 and glycogen synthase kinase 3β (GSK3β) 48 signaling. As a non-pharmacological alternative, CPA can be induced by pairing one of the spaces of a 2-or 3-compartments chamber with footshocks [16][17][18] . However, such non-ethological, noxious stimuli 19,20 might not implicate neural systems that underlie responses to natural threats 21 . ...
The place conditioning paradigm is an efficient, widely-used method to study mechanisms that underlie appetitive or aversive learning and memory processes. However, pharmacological agents used to induce conditioned place preference (CPP) or aversion (CPA) can per se interfere with learning and memory processing, hence confounding the results. Therefore, non-pharmacological place conditioning procedures are of high importance. Here, we introduce a novel procedure for induction of CPA in mice, by water flooding. We found that pairing a context with immersion in moderately cold shallow water resulted in aversion and avoidance of that context during a place preference test. Importantly, place aversion emerged only when mice experienced the onset of flood during conditioning training, but not when mice were placed in a compartment pre-filled with water. We also found that warm water was not sufficiently aversive to induce CPA. Moreover, CPA was observed after two or three context-flood pairings but not after one or four pairings, suggesting that moderate conditioning intensity produces optimal CPA expression. Thus, flood-induced CPA is a simple, cheap, and efficient procedure to form and measure place aversion memories in mice, using an ethologically-relevant threat.
... unpleasantness, pain-related emotions, avoidance-goals) features of pain. For instance, the somatosensory cortex 110 and the posterior portion of the insula were associated with the sensory processing of pain 111 , whereas the anterior part of the insula, the amygdala, and the cingulate cortex might be associated with affective processing of pain [112][113][114][115][116][117] . ...
... (Under review). 115 ...
Although expectancy effects have been described before (e.g. placebo effect), no one ever
questioned their specificity. After all, it might be that when people anticipate pain, they form a representation of the approaching event, which could be shared with other aversive
experiences, such as the case of disgust. In the present thesis, I examined the nature and
specificity of expectancy of pain and disgust in the context of perceptual decisions
(Experiments 1 & 2) and higher cognitive (moral) decisions (Experiments 3 & 4). I conducted four experiments to analyze behavioral, physiological and neural measures (using fMRI) from healthy human volunteers, which were all engaged in a new experimental set-up, specifically developed for testing the following experimental questions: (1) to which degree pain and disgust expectations recruit similar/dissociated representations of the upcoming event? (2) to which extent pain and disgust expectations affect high-level decisions, such as those involving morally-questionable behavior?
... Since then, an endless variety of correlates have been reported. In rodents, mPFC neurons have been found to respond to (among other things); actions, action sequences, action planning, movements of individual limbs, body positions, allocentric locations, contexts, present and future choices, effort, movement trajectory, stopping, stranger approach, pup interaction, errors, prediction errors, post-error slowing, conflict, cost-benefit ratio, timing, spatial goals, progress towards a goal, rewards, anticipated reward, reward consumption, reward-related feedback, drug-related cues/stimuli, valence, Burgos-Robles, Vidal-Gonzalez, & Quirk, 2009;Dejean, Courtin, Karalis, et al., 2016;Gao, Ren, Zhang, & Zhao, 2004;Powell, Buchanan, & Gibbs, 1990;Powell & Ginsberg, 2005;Powell, Maxwell, & Penney, 1996;Yang, Tan, Cheng, et al., 2018). When tested in the same animal, individual ACC neurons can be activated by both pain and sexual attraction (Lu, Chen, Zhou, Inokuchi, & Zhuo, 2018). ...
... Rats typically exhibit the defensive behavior of freezing in response to a footshock or a cue previously paired with a footshock and in some studies the activity of mPFC neurons was correlated with these freezing responses (Burgos-Robles et al., 2009;Dejean et al., 2016). Yet, ACC lesions do not always eliminate freezing behavior (Bissière, Plachta, Hoyer, et al., 2008;Gao et al., 2004). Furthermore, after carefully monitoring EMG activity, Steenland, Li, and Zhuo (2012) were unable to find a positive correlation between the activity of ACC neurons and freezing responses. ...
In spite of being an intensive area of research focus, the anterior cingulate cortex (ACC) remains somewhat of an enigma. Many theories have focused on its role in various aspects of cognition yet surgically precise lesions of the ACC, used to treat severe emotional disorders in human patients, typically have no lasting effects on cognition. An alternative view is that the ACC has a prominent role in regulating autonomic states. This view is consistent with anatomical data showing that a main target of the ACC are regions involved in autonomic control and with the observation that stimulation of the ACC evokes changes in autonomic states in both animals and humans. From an electrophysiological perspective, ACC neurons appear able to represent virtually any event or internal state, even though there is not always a strong link between these representations and behavior. Ensembles of neurons form robust contextual representations that strongly influence how specific events are encoded. The activity patterns associated with these contextually-based event representations presumably impact activity in downstream regions that control autonomic state. As a result, the ACC may regulate the autonomic and perhaps emotional reactions to events it is representing. This event-based control of autonomic tone by the ACC would likely arise during all types of cognitive and affective processes, without necessarily being critical for any of them.
... 12,51 Conversely, chronic pain is frequently accompanied by anhedonia-like symptoms, including fatigue and reduced involvement in formerly pleasurable activities. 66 From previous findings, we know that the amygdala plays a key role in the emotional evaluation of sensory stimuli, 17,19,50 including pain, 21,48 and even seems to tag the incoming nociceptive signal as aversive before it is being further processed by cortical brain areas. 15 Moreover, activation of the amygdala has been shown to be correlated with the modulation of pain perception 58 and behavioural responses to pain 64 after the presentation of positively and negatively valenced stimuli. ...
... In this study, we focussed specifically on the neural mechanisms that characterize individuals who are prone to emotional facilitation of pain. More specifically, we investigated individual differences in the connectivity of the amygdala, because of its role in the emotional evaluation of pain, 15,21,48 and pain chronification. 15,26 Historically, it has been suggested that the intensity and location of nociceptive input is encoded in brain areas including S1, S2/operculum, and posterior insular cortex. ...
The amygdala is central to emotional processing of sensory stimuli, including pain. Because recent findings suggest that individual differences in emotional processes play a part in the development of chronic pain, a better understanding of the individual patterns of functional connectivity that make individuals susceptible to emotionally modulated facilitation of pain is needed. We therefore investigated the neural correlates of individual differences in emotional pain facilitation using resting-state functional magnetic resonance imaging (rs-fMRI) with amygdala seed.Thirty-seven participants took part in 3 separate sessions, during which pain sensitivity was tested (session 1), participants underwent rs-fMRI (session 2), and emotional pain modulation was assessed (session 3). Amygdala served as seed for the rs-fMRI analysis and whole-brain voxelwise connectivity was tested. Pain modulatory scores were entered as regressor for the group analysis.Stronger connectivity of the amygdala to S1/M1, S2/operculum, and posterior parietal cortex at rest characterized individuals who showed greater pain facilitation by negative emotions. When comparing the amygdala networks associated with pain unpleasantness and with pain intensity modulation, most of the identified areas were equally related to either pain rating type; only amygdala connectivity to S1/M1 was found to predict pain intensity modulation specifically.We demonstrate that trait-like patterns of functional connectivity between amygdala and cortical regions involved in sensory and motor responses are associated with the individual amplitude of pain facilitation by negative emotional states. Our results are an early step towards improved understanding of the mechanisms that give rise to individual differences in emotional pain modulation.
... En ce qui concerne la composante affective, les régions les plus impliquées sont l'ACC et l'amygdale (Gao et al., 2004). Les études électrophysiologiques menées sur les animaux et les humains valident l'implication de l'ACC dans la composante affective (Davis et al., 1997;Koga et al., 2010;Yamamura et al., 1996). ...
... La nature GABAergique des neurones Rxfp-3 positifs a été mise en évidence au niveau du complexe médial septal, par contre dans cette région, les neurones Rxfp-3 positifs sont des neurones PV (Albert-Gascó et al., 2018).Dans un deuxième temps on s'est intéressé à étudier l'effet du système relaxine-3/RXFP-3 au niveau de l'ACC. Notre choix s'est porté sur l'ACC, puisque c'est une région riche en fibre relaxine-3, c'est une région cérébrale impliquée dans la composante affective de la douleur et c'est une région qui émet et reçoit des projections de la BLA(Gao et al., 2004;Neugebauer et al., 2004Neugebauer et al., , 2009).Nos résultats montrent que l'injection du peptide 5 induit une analgésie mécanique et non thermique chez les souris CFA, qui est annulée par l'ajout de R3 (B1-22) R. Cependant l'injection de R3 (B1-22) R a induit une proalgie chez les souris NaCl. Aucune étude à ce jour ne s'est penchée sur l'implication la relaxine -3 et ses analogues au niveau de l'ACC. ...
La douleur chronique souvent accompagnée d’anxiété et de dépression est un fléau mondial. La modulation de la douleur par les neuropeptides (NP) est bien connu au niveau des afférences primaires et de la moelle épinière. Peu de données sont toutefois disponibles sur leur rôle dans la douleur dans le cerveau. La famille relaxine comprend la relaxine, présente dans le système nerveux central (SNC) et qui possède des propriétés antifibrotiques, et la relaxine-3, strictement exprimée dans le SNC et qui présente des effets anxiolytiques et antidépressifs. Notre objectif est d’étudier la modulation de la douleur par les neuropeptides relaxine et relaxine-3 dans un modèle de douleur inflammatoire persistante chez la souris.Nos résultats démontrent que non seulement le système relaxine-3 / RXFP3, mais aussi le système relaxine / RXFP1 encore très peu exploré dans le SNC, ont des effets analgésiques en conditions de douleur inflammatoire. Les sites d'action de ces systèmes peptidergiques comprennent des régions corticales (cortex cingulaire, claustrum) et sous-corticales (amygdale) qui régulent les voies descendantes et l'intégration sensorielle dans la moelle épinière. Nos données mettent en évidence le potentiel thérapeutique de cette famille peptidergique dont les rôles dans la douleur n'avaient jamais été testés.
... A large body of evidence, including both clinical and experimental research, indicates that the anterior cingulate cortex (ACC) plays a role in the processing of noxious stimuli and in pain-related depression and anxiety [15][16][17][18][19][20][21][22]. Protein kinase Mzeta (PKMzeta), an isoform of protein kinase C with persistent activity, is involved in the neural plasticity associated with pain and anxiety disorders [23,24]. ...
... We also assessed the effect of ZIP microinjection into the ACC on anxiety-like behaviors in the open-field test and the elevated zero maze. ZIP PKMzeta has been reported to interact with GluR1 to maintain LTP in the ACC [27], a key brain region involved in the affective components of pain [15,45]. The blockade of PKMzeta significantly reduces the postsynaptic GluR1 insertion in ACC neurons following a peripheral nerve injury [25,44,46]. ...
Chronic inflammatory pain can induce emotional diseases. Electroacupuncture (EA) has effects on chronic pain and pain-related anxiety. Protein kinase Mzeta (PKMzeta) has been proposed to be essential for the maintenance of pain and may interact with GluR1 to maintain CNS plasticity in the anterior cingulate cortex (ACC). We hypothesized that the PKMzeta-GluR1 pathway in the ACC may be involved in anxiety-like behaviors of chronic inflammatory pain and that the mechanism of EA regulation of pain emotion may involve the PKMzeta pathway in the ACC. Our results showed that chronic inflammatory pain model decreased the paw withdrawal threshold (PWT) and increased anxiety-like behaviors. The protein expression of PKCzeta, p-PKCzeta (T560), PKMzeta, p-PKMzeta (T560), and GluR1 in the ACC of the model group were remarkably enhanced. EA increased PWT and alleviated anxiety-like behaviors. EA significantly inhibited the protein expression of p-PKMzeta (T560) in the ACC, and only a downward trend effect for other substances. Further, the microinjection of ZIP remarkably reversed PWT and anxiety-like behaviors. The present study provides direct evidence that the PKCzeta/PKMzeta-GluR1 pathway is related to pain and pain-induced anxiety-like behaviors. EA treatment both increases pain-related somatosensory behavior and decreases pain-induced anxiety-like behaviors by suppressing PKMzeta activity in the ACC.
... As seen in Fig. 5d, e, there was no significant difference between the rapamycin treated group and DMSO group. Our result is in line with previous studies [3,27]. This suggests that mTOR signaling in the rACC had no effect on foot-shock induced fear-related aversion and potentially is mediated by other mechanisms. ...
The mechanistic target of rapamycin (mTOR) has been demonstrated to mediate pain-related aversion induced by formalin in the rostral anterior cingulate cortex (rACC). However, it remains unclear the signaling pathways and regulatory proteins involved. In the rACC, brain-derived neurotrophic factor (BDNF), an activity-dependent neuromodulator, has been shown to play a role in the development and persistence of chronic pain. In this study, we used a rat formalin-induced inflammatory pain model to demonstrate BDNF up-regulation in the rACC. Stimulation with exogenous BDNF up-regulated mTOR, whilst cyclotraxin B (CTX-B), a tropomyosin receptor kinase B (TrkB) antagonist, down-regulated mTOR. Our results suggest BDNF could activate an mTOR signaling pathway. Subsequently, we used formalin-induced conditioned place avoidance (F-CPA) training in rat models to investigate if mTOR activation was required for pain-related aversion. We demonstrated that BDNF/mTOR signaling could activate the NMDA receptor subunit episilon-2 (NR2B), which is required for F-CPA. Our results reveal that BDNF activates mTOR to up-regulate NR2B expression, which is required for inflammatory pain-related aversion in the rACC of rats.
... Together, these studies suggest that the mPFC plays an important role in the affective responses towards pain and the affective responses as a result of chronic pain. Relatd to pain avoidance, the ACC has been highlighted as well as critical for avoiding pain stimuli, in that ablation of ACC neurons disrupts the ability of rodents to avoid contexts, in which pain was experienced (Gao et al., 2004;Qu et al., 2011). Moreover, single-neuron recordings in the ACC reveal that specific populations of ACC neurons shift their firing rate from a pain-specific signal to encoding the anticipation of pain during conditioning of place avoidance (Urien et al., 2018). ...
Experiencing pleasure and displeasure is a fundamental part of life. Hedonics guide behavior, affect decision-making, induce learning, and much more. As the positive and negative valence of feelings, hedonics are core processes that accompany emotion, motivation, and bodily states. Here, the affective neuroscience of pleasure and displeasure that has largely focused on the investigation of reward and pain processing, is reviewed. We describe the neurobiological systems of hedonics and factors that modulate hedonic experiences (e.g., cognition, learning, sensory input). Further, we review maladaptive and adaptive pleasure and displeasure functions in mental disorders and well-being, as well as the experience of aesthetics. As a centerpiece of the Human Affectome Project, language used to express pleasure and displeasure was also analyzed, and showed that most of these
analyzed words overlap with expressions of emotions, actions, and bodily states. Our review shows that hedonics are typically investigated as processes that accompany other functions, but the mechanisms of hedonics (as core processes) have not been fully elucidated.
... Nevertheless, ACC neurons project to or receive inputs from several regions important for pain processing, such as amygdala and nucleus accumbens (for review see Neugebauer, 2015). The central and basolateral nuclei of the amygdala, also participate in both pain-and fear-related negative emotion (for review see Gao et al., 2004), and contribute to the antinociceptive effect of systemically administered morphine (Manning, 1998). Additionally, CB1-immunoreactive cell bodies and fibers were demonstrated in cortical areas, amygdala and nucleus accumbens (Tsou et al., 1998;Moldrich and Wenger, 2000). ...
Background: Pain involves different brain regions and is critically determined by emotional processing. Among other areas, the rostral anterior cingulate cortex (rACC) is implicated in the processing of affective pain. Drugs that interfere with the endocannabinoid system are alternatives for the management of clinical pain. Cannabidiol (CBD), a phytocannabinoid found in Cannabis sativa, has been utilized in preclinical and clinical studies for the treatment of pain. Herein, we evaluate the effects of CBD, injected either systemically or locally into the rACC, on mechanical allodynia in a postoperative pain model and on the negative reinforcement produced by relief of spontaneous incision pain. Additionally, we explored whether CBD underlies the reward of pain relief after systemic or rACC injection.
Methods and Results: Male Wistar rats were submitted to a model of incision pain. All rats had mechanical allodynia, which was less intense after intraperitoneal CBD (3 and 10 mg/kg). Conditioned place preference (CPP) paradigm was used to assess negative reinforcement. Intraperitoneal CBD (1 and 3 mg/kg) inverted the CPP produced by peripheral nerve block even at doses that do not change mechanical allodynia. CBD (10 to 40 nmol/0.25 μL) injected into the rACC reduced mechanical allodynia in a dose- dependent manner. CBD (5 nmol/0.25 μL) did not change mechanical allodynia, but reduced peripheral nerve block-induced CPP, and the higher doses inverted the CPP. Additionally, CBD injected systemically or into the rACC at doses that did not change the incision pain evoked by mechanical stimulation significantly produced CPP by itself. Therefore, a non-rewarding dose of CBD in sham-incised rats becomes rewarding in incised rats, presumably because of pain relief or reduction of pain aversiveness.
Conclusion: The study provides evidence that CBD influences different dimensions of the response of rats to a surgical incision, and the results establish the rACC as a brain area from which CBD evokes antinociceptive effects in a manner similar to the systemic administration of CBD. In addition, the study gives further support to the notion that the sensorial and affective dimensions of pain may be differentially modulated by CBD.
... The CeA is the output nucleus for major amygdala function and thus has widespread projections to the forebrain and brainstem (Bernard et al., 1996;Davis, 1998;LeDoux, 2000). A large number of studies have described a key role of the amygdala in modulating chronic pain in animals associated with stress, anxiety and colitis (Davis, 1992;Rosen and Schulkin, 1998;Gao et al., 2004;DeBerry et al., 2015). More specifically, hyperactivity and synaptic plasticity of CeA neurons have been linked to pain-related behaviors . ...
A non-invasive, auricular percutaneous electrical nerve field stimulation (PENFS) has been suggested to modulate central pain pathways. We investigated the effects of BRIDGE® device on the responses of amygdala and lumbar spinal neurons and the development of post-colitis hyperalgesia. Male Sprague-Dawley rats received intracolonic trinitrobenzene sulfonic acid (TNBS) and PENFS on the same day. Control rats had sham devices. The visceromotor response (VMR) to colon distension and paw withdrawal threshold (PWT) was recorded after 7 days. A different group of rats had VMR and PWT at baseline, after TNBS and following PENFS. Extracellular recordings were made from neurons in central nucleus of the amygdala (CeA) or lumbar spinal cord. Baseline firing and responses to compression of the paw were recorded before and after PENFS. Sham treated rats exhibited a much higher VMR (>30mmHg) and lower PWT compared to PENFS treated rats (p<0.05). PENFS decreased the VMR to colon distension and increased the PWT compared to pre-stimulation (p<0.05). PENFS resulted in a 57% decrease in spontaneous firing of the CeA neurons (0.59 ±0.16 vs control: 1.71±0.32imp/sec). Similarly, the response to somatic stimulation was decreased by 56% (3.6 ± 0.52 vs control: 1.71 ± 0.32 imps/s, p<0.05). Spinal neurons showed a 47% decrease in mean spontaneous firing (4.05 ±0.65 vs control: 7.7±0.87 imp/sec) and response to somatic stimulation (7.62±1.7 vs control: 14.8± 2.28 imp/sec, p<0.05). PENFS attenuated baseline firing of CeA and spinal neurons which may account for the modulation of pain responses in this model of post-inflammatory visceral and somatic hyperalgesia.
... In healthy individuals, acute pain stimuli activate the ACC, where it encodes affective, but not sensory, aspects of pain (Duerden and Albanese, 2013;Rainville et al., 1997). Lesions of the ACC attenuate the affective components of pain without impacting nociceptive behaviors (Gao et al., 2004;Johansen and Fields, 2004;Johansen et al., 2001;Qu et al., 2011). Unsurprisingly, given its involvement in acute pain processing, much has been described in this brain region in chronic pain. ...
The transition from acute to chronic pain is accompanied by increased engagement of emotional and motivational circuits. Adaptations within this corticolimbic circuitry contribute to the cellular and behavioral maladaptations associated with chronic pain. Central regions within the corticolimbic brain include the mesolimbic dopamine system, the amygdala, and the medial prefrontal cortex. The evidence reviewed herein supports the notion that chronic pain induces significant changes within these corticolimbic regions that contribute to the chronicity and intractability of pain. In addition, pain-induced changes in corticolimbic circuitry are poised to impact motivated behavior and reward responsiveness to environmental stimuli, and may modulate the addiction liability of drugs of abuse, such as opioids.
... Functional brain imaging studies in human and primates have revealed that the ACC is activated when subjects observe conspecifics experiencing fear [5,8,9,11]. Additionally, previous studies have suggested that in rodents, ACC contributes to negative emotional behaviors or affective pain [15][16][17][18] and fear [19]. For example, lidocaine inactivation or electric activation of ACC respectively depresses or enhances observer's freezing during OF [20][21][22]. ...
The ability to detect conspecific's distress is crucial for animal survival. In rodent models, observational fear (OF) occurs when one animal perceives another fear related negative emotions, which may model certain behaviors caused by witnessing traumatic experiences in humans. Anterior cingulate cortex (ACC) has been showed to play a crucial role in OF. However, cellular and neural circuit basis relating to ACC governing OF is poorly understood. Here, we used Designer Receptor Exclusively Activated by a Designer Drug (DREADD) system to investigate the cell type specific circuit mechanism of ACC in OF. Firstly, inhibitory hM4D (Gi) designer receptor together with clozapine N-oxide (CNO) injection was applied to inactivate ACC neurons in the observer mice. We found that, chemogenetic inhibition of ACC resulted in a decreased freezing response in the observer mice. Next, combining PV-ires-Cre mice and Cre-dependent DREADD system, we selectively targeted the ACC parvalbumin (PV) interneurons with the excitatory hM3D (Gq) designer receptor. Activation of ACC PV interneurons following CNO injection reduced freezing response in the observer mice, while had no effect on freezing response in the demonstrator mice. Finally, monosynaptic rabies retrograde tracing revealed that ACC PV interneurons receive inputs from the mediodorsal thalamic nucleus (MD) and the ventromedial thalamic nucleus (VM), both known for their roles in OF. Taken together, these findings reveal that ACC activation is important for OF, during which PV interneurons in ACC play an important regulatory role. Abnormal function of ACC PV interneurons might contribute to the pathology of empathy- deficits related diseases, such as autism and schizophrenia.
... The ACC is often conceptualised as a nexus for the processing of external salient stimuli, autonomic response regulation, and subsequent affective learning (Gao et al., 2004;Vogt, 2005). For example, fear learning in mice through observing other mice receiving painful foot shocks has been demonstrated to involve the ACC (Jeon et al., 2010). ...
A cardinal feature of persistent pain that follows injury is a general suppression of behaviour, in which motivation is inhibited in a way that promotes energy conservation and recuperation. Across species, the anterior cingulate cortex is associated with the motivational aspects of phasic pain, but whether it mediates motivational functions in persistent pain is less clear. Using burrowing behaviour as an marker of non-specific motivated behaviour in rodents, we studied the suppression of burrowing following painful confirmatory factor analysis or control injection into the right knee joint of 30 rats (14 with pain) and examined associated neural connectivity with ultra-high-field resting state functional magnetic resonance imaging. We found that connectivity between anterior cingulate cortex and subcortical structures including hypothalamic/preoptic nuclei and the bed nucleus of the stria terminalis correlated with the reduction in burrowing behaviour observed following the pain manipulation. In summary, the findings implicate anterior cingulate cortex connectivity as a correlate of the motivational aspect of persistent pain in rodents.
... It is interesting in this respect that the cingulate cortex and the amygdala are both part of the limbic system and as such, do not strictly process sensory information but are rather important for coding the emotional content of a sensory stimulus. Intriguingly, painful stimuli trigger different neuronal activity patterns in the somatosensory and cingulate cortex [39,40]. ...
Somatostatin-expressing (SOM⁺), inhibitory interneurons represent a heterogeneous group of cells and given their remarkable diversity, classification of SOM⁺ interneurons remains a challenging task. Electrophysiological, morphological and neurochemical classes of SOM⁺ interneurons have been proposed in the past but it remains unclear as to what extent these classes are congruent. We performed whole-cell patch-clamp recordings from 127 GFP-labeled SOM⁺ interneurons ('GIN') of the superficial cingulate cortex with subsequent biocytin-filling and immunocytochemical labeling. Principal component analysis followed by k-means clustering predicted two putative subtypes of SOM⁺ interneurons, which we designated as group I and group II GIN. A key finding of our study is the fact that these electrophysiologically and morphologically distinct groups of SOM⁺ interneurons can be correlated with two neurochemical subtypes of SOM⁺ interneurons described recently in our laboratory. In particular, all SOM⁺ interneurons expressing calbindin but no calretinin could be classified as group I GIN, whereas all but one neuropeptide Y- and calretinin-positive interneurons were found in group II.
... Increased cortical activation of the areas discovered in our ACLR participants have also been associated with higher levels of fear and the expression of fear and painrelated avoidance behaviors and negative emotion (Gao et al. 2004). Given that the ACLR participants in the current study all reported some level of pain (as denoted via KOOS pain and symptom scores; Table 1) and fear of movement (as denoted via TSK scores; Table 1), we chose to further explore this relationship by performing correlation analyses between KOOS pain, KOOS symptoms, TSK, and the ensemble mean brain activation of the four frontal lobe clusters observed to be statistically different in individuals with ACLR (as visually depicted in Fig. 2b). ...
Quadriceps muscle dysfunction is common following anterior cruciate ligament reconstruction (ACLR). Data considering the diversity of neural changes, in-concert with morphological adaptations of the quadriceps muscle, are lacking. We investigated bilateral differences in neural and morphological characteristics of the quadriceps muscle in ACLR participants (n = 11, month post-surgery: 69.4 ± 22.4) compared to controls matched by sex, age, height, weight, limb dominance, and activity level. Spinal reflex excitability was assessed using Hoffmann reflexes (H:M); corticospinal excitability was quantified via active motor thresholds (AMT) and motor-evoked potentials (MEP) using transcranial magnetic stimulation. Cortical activation was assessed using a knee flexion/extension task with functional magnetic resonance imaging (fMRI). Muscle volume was quantified using structural MRI. Muscle strength and patient-reported outcomes were also collected. 2 × 2 RM ANOVAs were used to evaluate group differences. Smaller quadriceps muscle volume (total volume, rectus femoris, vastus medialis, and intermedius) and lower strength were detected compared to contralateral and control limbs. Individuals with ACLR reported higher levels of pain and fear and lower levels of knee function compared to controls. No differences were observed for H:M. ACLR individuals demonstrated higher AMT bilaterally and smaller MEPs in the injured limb, compared to the controls. ACLR participants demonstrated greater activation in frontal lobe areas responsible for motor and pain processing compared to controls, which were associated with self-reported pain. Our results suggest that individuals with ACLR demonstrate systemic neural differences compared to controls, which are observed concurrently with smaller quadriceps muscle volume, quadriceps muscle weakness, and self-reported dysfunction.
... The BLA has been heavily implicated in aversive learning and pain-related aversion (Helmstetter and Bellgowan, 1993;Le-Doux, 2000). Similar to ACC lesions, lesions of the BLA abolish the conditioned aversion to intraplantar formalin and noxious footshock (Gao et al., 2004;Tanimoto et al., 2003). Infusion of an N-methyl-D-aspartate (NMDA) antagonist or morphine into the BLA also reduces formalin-induced conditioned place aversion (Deyama et al., 2007). ...
Hyperexcitability of the anterior cingulate cortex (ACC) is thought to drive aversion associated with chronic neuropathic pain. Here, we studied the contribution of input from the mediodorsal thalamus (MD) to ACC, using sciatic nerve injury and chemotherapy-induced mouse models of neuropathic pain. Activating MD inputs elicited pain-related aversion in both models. Unexpectedly, excitatory responses of layer V ACC neurons to MD inputs were significantly weaker in pain models compared to controls. This caused the ratio between excitation and feedforward inhibition elicited by MD input to shift toward inhibition, specifically for subcortically projecting (SC) layer V neurons. Furthermore, direct inhibition of SC neurons reproduced the pain-related aversion elicited by activating MD inputs. Finally, both the ability to elicit pain-related aversion and the decrease in excitation were specific to MD inputs; activating basolateral amygdala inputs produced opposite effects. Thus, chronic pain-related aversion may reflect activity changes in specific pathways, rather than generalized ACC hyperactivity.
... ACC is an important limbic structure which involves the processing of aversive components of pain. 4,35,36 As shown in Figure 8, when compared to vehicle group, capsaicin injection evoked a robust increase of c-Fos immunoreactivity in the contralateral ACC derived from PKG-I fl/fl mice (Figure 8(a), upper panels). Similar c-Fos expression profile was seen after intramuscular injection of acidic saline in PKG-I fl/fl mice (Figure 8(a), upper panels). ...
Chronic pain represents a frequent and poorly understood public health issue. Numerous studies have documented the key
significance of plastic changes along the somatosensory pain pathways in chronic pain states. Our recent study demonstrated
that the cGMP-dependent protein kinase I (PKG-I) specifically localized in nociceptors constitutes a key mediator of
hyperexcitability of primary sensory neurons and spinal synaptic plasticity after inflammation. However, whether PKG-I in
nociceptors further affects the cortical plasticity in the ascending pain pathways under pathological states has remained
elusive. The immediate-early gene c-fos and phosphorylated ERK1/2 (pERK1/2) are considered reliable indicators for the
neuronal activation status and it permits a comprehensive and large-scale observation of nociceptive neuronal activity along
the ascending pain pathways subjected to tissue injury. In the present study, we systemically demonstrated that peripheral
injury in PKG-Ifl/fl mice produced a significant upregulation of c-Fos or pERK1/2 over from the periphery to the cortex along
the pain pathways, including dorsal root ganglion, spinal dorsal horn, ventral posterolateral thalamus, primary somatosensory
hindlimb cortex, anterior cingulate cortex, basolateral amygdala, periaqueductal gray, and parabrachial nucleus. In contrast,
very few cells in the above regions showed c-Fos or pERK1/2 induction in nociceptor-specific knockout mice lacking PKG-I
(SNS-PKG-I/ mice). Our results indicate that PKG-I expressed in nociceptors is not only a key determinant of dorsal root
ganglion hyperexcitability and spinal synaptic plasticity but also an important modulator of cortical neuronal activity in
pathological pain states and represent what we believe to be novel targets in the periphery for pain therapeutics.
... While the somatosensory cortex responds faster to dimensional features of noxious stimuli, and is more engaged when larger body surfaces are exposed to pain, the ACC as part of the limbic system is thought to be modulated by the affective relevance pertinent to a change in motivational tone or response selection (Peyron, Laurent, and Garcia-Larrea, 2000;Ploner et al., 2002). The ACC is often conceptualized as a nexus for the processing of external salient stimuli, autonomic response regulation and subsequent affective learning (Gao et al., 2004;Vogt, 2005). For example, fear learning in mice through observing other mice receiving painful foot shocks has been demonstrated to involve the ACC (Jeon et al., 2010). ...
A cardinal feature of persistent pain that follows injury is a general suppression of behavior, in which motivation is inhibited in a way that promotes energy conservation and recuperation. Across species, the anterior cingulate cortex (ACC) is associated with the motivational aspects of phasic pain, but whether it mediates motivational functions in persistent pain is less clear. Using burrowing behavior as an marker of non-specific motivated behavior in rodents, we studied the suppression of burrowing following painful CFA or control injection into the right knee-joint of 37 rats (18 with pain), and examined associated neural connectivity with ultra-high-field resting state functional MRI. We found that connectivity between ACC and the subcortex correlated with the reduction in burrowing behavior observed following the pain manipulation. In a full replication study we confirmed these findings in a group of 44 rats (23 with pain). Across both datasets, reduced burrowing was associated with increased connectivity between ACC and subcortical structures including hypothalamic/preoptic nuclei and the bed nucleus of the stria terminalis. Together, the findings implicate ACC connectivity as a robust correlate of the motivational aspect of persistent pain in rodents.
... Ablation of the ACC regions alleviates the emotional suffering of patients with chronic pain, but it does not affect their ability to evaluate the intensity of their own pain (Yen et al., 2005). Similarly, chemical and electrolytic lesions of the ACC in rodents attenuate the affective component of the pain state, as shown by the reduction in conditioned place avoidance induced by a noxious stimulus (Gao et al., 2004;Johansen and Fields, 2004;Johansen et al., 2001;Qu et al., 2011). ...
Observational fear learning in rodents is a type of context-dependent fear conditioning in which an unconditioned stimulus (US) is provided vicariously by observing conspecific others receiving foot shocks. This suggests the involvement of affective empathy, with several recent studies showing many similarities between this behavior and human empathy. Neurobiologically, it is important to understand the neural mechanisms by which the vicarious US activates the fear circuit via the affective pain system, obviating the sensory pain pathway and eventually leading to fear memory formation. This paper reviews current studies on the neural mechanisms underlying observational fear learning and provides a perspective on future research on this subject.
... Examples include stress-induced and attentional analgesia, in which stress or a shift in attentional focus reduces responsiveness to noxious stimulation (Baker et al., 2019). Perhaps even more compelling are tests of associative learning and memory, in which animals are asked to demonstrate their unpleasant experience of a noxious event or condition through their subsequent responses to places or signals associated with that event/condition or its relief (Gao et al., 2004;Dunlop et al., 2006;Elwood, 2011;Gerber et al., 2014;Sneddon et al., 2014). ...
Pain is an aversive experience with sensory and emotional components which functions to protect animals from current and future tissue damage. Understanding pain is important because it can negatively affect animal welfare, productive function, and behavior. Here, we present a brief summary of the evidence that birds are capable of both the sensory and emotional components of pain. We consider the presence and activation of structures and pathways necessary to process nociceptive inputs (i.e., those with the potential to damage tissues) as well as the animal's observable responses that reflect different levels of processing, e.g., withdrawal reflexes, physiological and behavioral responses and their mitigation, learning. The available evidence indicates that birds are likely to experience all aspects of pain. However, few avian species have been studied and little is known about processing of nociceptive inputs in the avian forebrain. More research is needed to improve our understanding of pain in birds.
... Whether decreased consumption of a sweet solution reflects a depressive state in response to persistent pain cannot be concluded from this study, however, since we did not assess hedonic drinking in adolescent THC-treated rats that were not in pain. Inclusion of this additional control in future studies, plus use of other affect-related measures of pain such as place avoidance (e.g., Gao et al. 2004), are needed to address this issue. ...
Rationale
Adolescent cannabinoid exposure has been shown to alter cognitive, reward-related, and motor behaviors as well as mesocorticolimbic dopamine (DA) function in adult animals. Pain is also influenced by mesocorticolimbic DA function, but it is not known whether pain or cannabinoid analgesia in adults is altered by early exposure to cannabinoids.
Objective
To determine whether adolescent Δ⁹-tetrahydrocannabinol (THC) exposure alters pain-related behaviors before and after induction of persistent inflammatory pain, and whether it influences antinociceptive of THC, in adult rats, and to compare the impact of adolescent THC exposure on pain to its effects on known DA-dependent behaviors such as exploration and consumption of a sweet solution.
Methods
Vehicle or THC (2.5 to 10 mg/kg s.c.) was administered daily to male and female rats on post-natal day (PND) 30–43. In adulthood (PND 80–88), sensitivity to mechanical and thermal stimuli before and after intraplantar injection of complete Freund’s adjuvant (CFA) was determined. Antinociceptive, exploratory, and consummatory effects of 2.0 mg/kg THC were then examined.
Results
Adolescent THC exposure did not significantly alter adult sensitivity to non-noxious or noxious stimuli either before or after CFA injection, nor did it alter the antinociceptive effect of THC. In contrast, adolescent THC exposure altered adult exploratory and consummatory behaviors in a sex-dependent manner: when tested as adults, adolescent THC-treated males showed less hedonic drinking than adolescent vehicle-treated males, and females but not males that had been THC-exposed as adolescents showed reduced sensitivity to THC-induced suppression of activity and THC-induced hedonic drinking as adults.
Conclusions
Adolescent THC exposure that altered both exploratory and consummatory behaviors in adults did not alter pain-related behaviors either before or after induction of inflammatory pain, suggesting that cannabinoid exposure during adolescence is not likely to substantially alter pain or cannabinoid analgesia in adulthood.
... The anterior cingulate cortex has a key role in pain processing and pain-related emotion 5,6 and widely connects with regions of the descending control system including the rostral ventromedial medulla. 7 This brainstem modulatory circuit exerts excitatory and inhibitory influences over spinal nociceptive processing. ...
What we already know about this topic:
Descending control from supraspinal neuronal networks onto spinal cord neurons can modulate nociceptionEndogenous opioids in these brain circuits participate in pain modulationA differential opioidergic role for brain nuclei involved in supraspinal pain modulation has not been previously reported WHAT THIS ARTICLE TELLS US THAT IS NEW: In vivo electrophysiologic recordings from the dorsal horn of the spinal cord in male rats reveal differential effects of morphine at the anterior cingulate cortex, right amygdala, and the ventromedial medulla on evoked pain responsesThese data differentiate supraspinal opioid circuit regulation of spinal nociceptive processing and suggest that the regulation of sensory and affective components of pain are likely separate BACKGROUND:: The anterior cingulate cortex and central nucleus of the amygdala connect widely with brainstem nuclei involved in descending modulation, including the rostral ventromedial medulla. Endogenous opioids in these circuits participate in pain modulation. The hypothesis was that a differential opioidergic role for the brain nuclei listed in regulation of spinal neuronal responses because separable effects on pain behaviors in awake animals were previously observed.
Methods:
This study utilized in vivo electrophysiology to determine the effects of morphine microinjection into the anterior cingulate cortex, right or left central nucleus of the amygdala, or the rostral ventromedial medulla on spinal wide dynamic range neuronal responses in isoflurane-anesthetized, male Sprague-Dawley rats. Ongoing activity in the ventrobasal thalamus was also measured. In total, 33 spinal nerve ligated and 26 control age- and weight-matched control rats were used.
Results:
Brainstem morphine reduced neuronal firing to 60-g von Frey stimulation in control rats (to 65 ± 12% of control response (means ± 95% CI), P < 0.001) with a greater inhibition in neuropathic rats (to 53 ± 17% of control response, P < 0.001). Contrasting anterior cingulate cortex morphine had only marginal modulatory effects on spinal neuronal responses with limited variance in effect between control and neuropathic rats. The inhibitory effects of morphine in the central nucleus of the amygdala were dependent on pain state and laterality; only right-side morphine reduced neuronal firing to 60-g stimulation in neuropathic rats (to 65 ± 14% of control response, P = 0.001). In addition, in neuropathic rats elevated ongoing neuronal activity in the ventral posterolateral thalamus was not inhibited by anterior cingulate cortex morphine, in contrast to evoked responses.
Conclusions:
Cumulatively the data support opioid modulation of evoked responses predominately through a lateralized output from the right amygdala, as well as from the brainstem that is enhanced in injured conditions. Minimal modulation of dorsal horn responses was observed after anterior cingulate cortex opioid administration regardless of injury state.
... High densities of opioid receptors are found in higher "affective" brain centers [10,12]. The anterior cingulate cortex (ACC) has a key role in pain processing and pain-related emotion [13,14] and widely connects with brainstem and midbrain loci, including the RVM [15]. Endogenous opioid signaling in the ACC modulates pain aversiveness and, upon chronicity, the amygdala is a key player in affective pain. ...
While the acute sensation of pain is protective, signaling the presence of actual or potential bodily harm, its persistence is unpleasant. When pain becomes chronic, it has limited evolutionarily advantage. Despite the differing nature of acute and chronic pain, a common theme is that sufferers seek pain relief. The possibility to medicate pain types as varied as a toothache or postsurgical pain reflects the diverse range of mechanism(s) by which pain-relieving “analgesic” therapies may reduce, eliminate, or prevent pain. Systemic application of an analgesic able to cross the blood–brain barrier can result in pain modulation via interaction with targets at different sites in the central nervous system. A so-called supraspinal mechanism of action indicates manipulation of a brain-defined circuitry. Pre-clinical studies demonstrate that, according to the brain circuitry targeted, varying therapeutic pain-relieving effects may be observed that relate to an impact on, for example, sensory and/or affective qualities of pain. In many cases, this translates to the clinic. Regardless of the brain circuitry manipulated, modulation of brain processing often directly impacts multiple aspects of nociceptive transmission, including spinal neuronal signaling. Consideration of supraspinal mechanisms of analgesia and ensuing pain relief must take into account nonbrain-mediated effects; therefore, in this review, the supraspinally mediated analgesic actions of opioidergic, anti-convulsant, and anti-depressant drugs are discussed. The persistence of poor treatment outcomes and/or side effect profiles of currently used analgesics highlight the need for the development of novel therapeutics or more precise use of available agents. Fully uncovering the complex biology of nociception, as well as currently used analgesic mechanism(s) and site(s) of action, will expedite this process.
... The anterior cingulate cortex (ACC) is a key brain region in the affective-motivational component of pain (Price, 2000). It has been found that lesion of the ACC reduces both formalin-induced conditioned place aversion (F-CPA) and visceral pain-induced CPA, pre-clinical behavioral paradigms used to investigate the affective component of pain, without affecting nociceptive responding (Johansen et al., 2001;Gao et al., 2004;Yan et al., 2012). Glutamatergic transmission and the expression of glutamatergic receptors in the ACC are increased in animal models of pain (Xu et al., 2008;Chen et al., 2014;Li W. et al., 2014;Yi et al., 2014;Hubbard et al., 2015;Liu et al., 2015), as well as clinically in patients with chronic pain conditions (Kameda et al., 2017;Lv et al., 2018). ...
Pain is comprised of both sensory and affective components. The anterior cingulate cortex (ACC) is a key brain region involved in the emotional processing of pain. Specifically, glutamatergic transmission within the ACC has been shown to modulate pain-related aversion. In the present study, we use in vivo optogenetics to activate or silence, using channelrhodopsin (ChR2) and archaerhodopsin (ArchT) respectively, calmodulin-kinase IIα (CaMKIIα)-expressing excitatory glutamatergic neurons of the ACC during a formalin-induced conditioned place aversion (F-CPA) behavioral paradigm in both female and male adult Sprague-Dawley rats. Expression of c-Fos, a marker of neuronal activity, was assessed within the ACC using immunohistochemistry. Optogenetic inhibition of glutamatergic neurons of the ACC abolished F-CPA without affecting formalin-induced nociceptive behavior during conditioning. In male rats, optogenetic activation of ACC glutamatergic neurons decreased formalin-induced nociceptive behavior during conditioning without affecting F-CPA. Interestingly, the opposite effect was seen in females, where optogenetic activation of glutamatergic neurons of the ACC increased formalin-induced nociceptive behavior during conditioning. The abolition of F-CPA following optogenetic inhibition of glutamatergic neurons of the ACC was associated with a reduction in c-Fos immunoreactivity in the ACC in male rats, but not female rats. These results suggest that excitatory glutamatergic neurons of the ACC play differential and sex-dependent roles in the aversion learning and acute sensory components of pain.
... This affective pain response likely has specific neuroanatomic substrates, such as limbic and subcortical structures, including the mediodorsal thalamus, hypothalamus, anterior cingulate cortex, amygdala, and insular cortex. [56][57][58] Specifically, mouse grimace may involve activation of the insular cortex. In one study, ablation of anterior cingulate cortex or amygdala had no effect on visceral pain related grimace, whereas ablation of the rostral anterior insula reduced mouse grimace. ...
Objective:
Cortical spreading depression (SD) is an intense depolarization underlying migraine aura. Despite the weight of evidence linking SD to the pain phase of migraine, controversy remains over a causal role of SD in cephalgia because of the invasive nature of previous SD induction methods. To overcome this problem, we used a novel minimally invasive optogenetic SD induction method and examined the effect of SD on behavior.
Methods:
Optogenetic SD was induced as a single event or repeatedly every other day for 2 weeks. End points, including periorbital and hindpaw mechanical allodynia, mouse grimace, anxiety, and working memory, were examined in male and female mice.
Results:
A single SD produced bilateral periorbital mechanical allodynia that developed within 1 hour and resolved within 2 days. Sumatriptan prevented periorbital allodynia when administered immediately after SD. Repeated SDs also produced bilateral periorbital allodynia that lasted 4 days and resolved within 2 weeks after the last SD. In contrast, the hindpaw withdrawal thresholds did not change after repeated SDs suggesting that SD-induced allodynia was limited to the trigeminal region. Moreover, repeated SDs increased mouse grimace scores 2 days after the last SD, whereas a single SD did not. Repeated SDs also increased thigmotaxis scores as a measure of anxiety. In contrast, neither single nor repeated SDs affected visuospatial working memory. We did not detect sexual dimorphism in any end point.
Interpretation:
Altogether, these data show a clinically congruent causal relationship among SD, trigeminal pain, and anxiety behavior, possibly reflecting SD modulation of hypothalamic, thalamic, and limbic mechanisms. ANN NEUROL 2020.
... Such a replacement has been associated with a reduced variability in experimental data, which increases statistical power, thereby reducing the number animals required for hypothesis testing (Ladu et al., 2015;Spinello et al., 2013). With specific reference to CPA paradigms, harmless robots can replace traditional noxious stimuli that are generally used to condition experimental subjects (Cain et al., 2004;Wong et al., 2014;Gao et al., 2004). Ultimately, ethorobotics may promote advancements towards the 3R's principle (replacement, reduction, and refinement) for animal welfare (Russell & Burch, 1959). ...
Background
Anxiety represents one of the most urgent health challenges in Western Countries, where it is associated with major medical and societal costs. A common therapeutic approach is the use of selective serotonin reuptake inhibitors, such as Citalopram. However, this treatment of choice is characterized by incomplete efficacy and potential side effects. Preclinical research is needed to detail the mechanisms underlying therapeutic efficacy of available treatments.
Methods
Zebrafish, a rapidly emerging model species, constitutes an excellent candidate for high-throughput studies in behavioral pharmacology. Here, we present a robotics-based experimental paradigm to investigate the effects of acute Citalopram administration on conditioned place aversion. We trained adult subjects in a three-partitioned tank, consisting of one central and two lateral compartments: the latter were associated either with a fear eliciting robotic stimulus or with an empty environment. Following training, we implemented an automated three-dimensional tracking system to assess the spatial association and detail individual phenotype in a stimulus-free test session.
Results
We observed a linear dose-response profile with respect to geotaxis, with increasing Citalopram concentrations reducing the tendency to swim near the bottom of the tank. Although control subjects failed to exhibit the predicted conditioned aversion, we found preliminary evidence that Citalopram may affect sexes differentially, with male subjects showing increased conditioned aversion at low Citalopram concentration.
Conclusions
Experimental paradigms based on robotics and three-dimensional tracking can contribute methodological advancements in zebrafish behavioral psychopharmacology.
... In an animal model of migraine pain induced by application of inflammatory mediators to the dural membrane, lesions of the ACC prevented the acquisition for place preference produced by injection of lidocaine into the rostral ventral medulla [46] . The important role of the ACC in the integration of the aversive component of pain was also demonstrated by the evidence that a CPA to formalin-induced pain was absent following the lesion of the ACC [47,48] . Migraineurs were identified to have structural and functional cerebral abnormalities (e.g., reduced cortical thickness) in the prefrontal cortex, the rostral ACC, the somatosensory cortex, the orbitofrontal cortex, and insular cortex [45] . ...
Clinical studies have suggested that internal and/or external aversive cues may produce a negative affective-motivational component whereby maladaptive responses (plasticity) of dural afferent neurons are initiated contributing to migraine chronification. However, pathophysiological processes and neural circuitry involved in aversion (unpleasantness)-producing migraine chronification are still evolving. An interdisciplinary team conducted this narrative review aimed at reviewing neuronal plasticity for developing migraine chronicity and its relevant neurocircuits and providing the most cutting-edge information on neuronal mechanisms involved in the processing of affective aspects of pain and the role of unpleasantness evoked by internal and/or external cues in facilitating the chronification process of migraine headache. Thus, information presented in this review promotes the understanding of the pathophysiology of chronic migraine and contribution of unpleasantness (aversion) to migraine chronification. We hope that it will bring clinicians' attention to how the maladaptive neuroplasticity of the emotion brain in the aversive environment produces a significant impact on the chronification of migraine headache, which will in turn lead to new therapeutic strategies for this type of pain.
The amygdala is a key subcortical region thought to contribute to emotional components of pain. As opioid receptors are found in both the central (CeA) and basolateral (BLA) nuclei of the amygdala, we investigated the effects of morphine microinjection on evoked pain responses, pain motivated behaviors, dopamine release in the nucleus accumbens (NAc), and descending modulation in rats with left side spinal nerve ligation (SNL). Morphine administered into the right or left CeA had no effect on nerve injury induced tactile allodynia or mechanical hyperalgesia. Right, but not left, CeA morphine produced conditioned place preference (CPP) and increased extracellular dopamine in the NAc selectively in SNL rats, suggesting relief of aversive qualities of ongoing pain. In SNL rats, CPP and NAc dopamine release following right CeA morphine was abolished by blocking mu opioid receptor (MOR) signaling in the rostral anterior cingulate cortex (rACC). Right CeA morphine also significantly restored SNL-induced loss of the diffuse noxious inhibitory controls (DNIC), a spino-bulbo-spinal pain modulatory mechanism, termed conditioned pain modulation in humans. Microinjection of morphine into the BLA had no effects on evoked behaviors and did not produce CPP in nerve injured rats. These findings demonstrate that the amygdalar action of morphine is specific to the right CeA contralateral to the side of injury and results in enhancement of net descending inhibition. Additionally, engagement of MORs in the right CeA modulates affective qualities of ongoing pain through endogenous opioid neurotransmission within the rACC, revealing opioid-dependent functional connections from the CeA to the rACC.
Somatosensory afferents are traditionally classified by soma size, myelination, and their response specificity to external and internal stimuli. Here, we propose the functional subdivision of the nociceptive somatosensory system into two branches. The exteroceptive branch detects external threats and drives reflexive-defensive reactions to prevent or limit injury. The interoceptive branch senses the disruption of body integrity, produces tonic pain with strong aversive emotional components, and drives self-caring responses toward to the injured region to reduce suffering. The central thesis behind this functional subdivision comes from a reflection on the dilemma faced by the pain research field, namely, the use of reflexive-defensive behaviors as surrogate assays for interoceptive tonic pain. The interpretation of these assays is now being challenged by the discovery of distinct but interwoven circuits that drive exteroceptive versus interoceptive types of behaviors, with the conflation of these two components contributing partially to the poor translation of therapies from preclinical studies.
Pain can be ignited by noxious chemical (e.g., acid), mechanical (e.g., pressure), and thermal (e.g., heat) stimuli and generated by the activation of sensory neurons and their axonal terminals called nociceptors in the periphery. Nociceptive information transmitted from the periphery is projected to the central nervous system (thalamus, somatosensory cortex, insular, anterior cingulate cortex, amygdala, periaqueductal grey, prefrontal cortex, etc.) to generate a unified experience of pain. Local field potential (LFP) recording is one of the neurophysiological tools to investigate the combined neuronal activity, ranging from several hundred micrometers to a few millimeters (radius), located around the embedded electrode. The advantage of recording LFP is that it provides stable simultaneous activities in various brain regions in response to external stimuli. In this study, differential LFP activities from the contralateral anterior cingulate cortex (ACC), ventral tegmental area (VTA), and bilateral amygdala in response to peripheral noxious formalin injection were recorded in anesthetized male rats. The results indicated increased power of delta, theta, alpha, beta, and gamma bands in the ACC and amygdala but no change of gamma-band in the right amygdala. Within the VTA, intensities of the delta, theta, and beta bands were only enhanced significantly after formalin injection. It was found that the connectivity (i.t. the coherence) among these brain regions reduced significantly under the formalin-induced nociception, which suggests a significant interruption within the brain. With further study, it will sort out the key combination of structures that will serve as the signature for pain state.
The pain signals rise from peripheral nociceptors and travel to the physical brain (spine, brainstem, thalamus, somatosensory cortex, etc.). The physical brain analyzes these signals by means of cognitive functions. At the same time, the emotional brain (limbic system) choose the same affective memories that match the pain signals. The physical brain puts these together and creates a physical reaction named pain sensation. Once a pain sensation is stored in the mind, the sensation can easily return following some physical and/or mental stimulation. This is called pain experience. This pain experience is itself mental. The true meaning of pain may be the somatization or acting out of negative emotion that a person feels when he or she recognizes some stimulation as harmful to the body or soul. This pain experience may occur continuously if he or she recognizes it as catastrophic, or the surrounding circumstances may be felt as harmful. The main role of neurosurgeons is to modulate pain signals, still if the central pain maintenance mechanism is active, pain sensation memories may easily return. Theoretical backgrounds to comprehend the true meaning of pain is also reviewed.
Despite being an intensive area of research, the function of the anterior cingulate cortex (ACC) remains somewhat of a mystery. Human imaging studies implicate the ACC in various cognitive functions, yet surgical ACC lesions used to treat emotional disorders have minimal lasting effects on cognition. An alternative view is that ACC regulates autonomic states, consistent with its interconnectivity with autonomic control regions and that stimulation evokes changes in autonomic/emotional states. At the cellular level, ACC neurons are highly multi-modal and promiscuous, and can represent a staggering array of task events. These neurons nevertheless combine to produce highly event-specific ensemble patterns that likely alter activity in downstream regions controlling emotional and autonomic tone. Since neuromodulators regulate the strength of the ensemble activity patterns, they would regulate the impact these patterns have on downstream targets. Through these mechanisms, the ACC may determine how strongly to react to the very events its ensembles represent. Pathologies arise when specific event-related representations gain excessive control over autonomic/emotional states.
The ability to perceive pain is a basic property of humans and of all other higher order animals. The primary role of pain sensation and nociception (that is, the neuronal activity encoding pain) is to protect against potentially harmful threats arriving from the environment or the body interior. Pain can however also become dysfunctional and persist for extended periods of time without an apparent benefit, instead becoming a major burden that requires medical attention. Chronic pain is a major socio-economic challenge, which – despite scientific advances in the understanding of its causes – remains poorly responsive to the drugs available on the market today. Recent insights into the mechanisms of chronic pain states suggest that a common factor for many kinds of persistent pain states is a loss of inhibition in spinal cord circuits that normally control nociceptive input to the brain. The so- called benzodiazepines – first marketed by Hoffmann-La Roche in the 1960s – are drugs that facilitate synaptic inhibition throughout the CNS and have as such the potential to reverse pathological disinhibition. Benzodiazepines facilitate inhibition by increasing the activity of γ-aminobutyric acid (GABA) at its receptor, a heteropentameric anion permeable ion channel. Although rodent studies have shown that pathologically increased pain sensitivity can be normalized by intrathecal (spinal) injection of benzodiazepines, these drugs do not exert clinically relevant analgesia in human patients, at least not after systemic application. In this thesis, I have tested the hypothesis that benzodiazepines reverse pathological pain after systemic application if their action is restricted to well-defined subtypes of GABAA receptors. Using GABAA receptor point-mutated mice, I was able to demonstrate that selective targeting of GABAA receptors that contain the α2 subunit (α2-GABAA) receptors evoke pronounced pain relief in the absence of confounding and undesired sedation. I could also confirm previous findings that had proposed that activation of the same GABAA receptors induces anxiolysis and muscle relaxation. Importantly, selective targeting of α2- GABAA receptors avoided several unwanted effects of classical non-selective benzodiazepines including sedation, impairment of motor coordination, and the progressive loss of therapeutic efficacy over time. Using mice in which the action of classical benzodiazepine agonists was restricted to only a single GABAA receptor subtype, I could also propose a new hypothesis explaining why classical benzodiazepines lack clinically relevant analgesic properties. For two clinically used benzodiazepines (diazepam and midazolam), I could demonstrate that strong α1-GABAA receptor-mediated sedation occurs already at doses.
The rostral anterior cingulate cortex (rACC) is a key structure in mediating the negative affective component of chronic pain. Brain-derived neurotrophic factor (BDNF) is known to play a critical role in activity-dependent synaptic plasticity, learning and memory. It has been shown that BDNF signalling in the rACC might be involved in spontaneous pain-related aversion, but its underlying mechanism is still largely unknown. To address this question, we measured the mRNA and protein levels of BDNF in the rACC after nerve injury and found that BDNF expression was markedly higher in nerve-injured rats than in controls. Moreover, we found that conditioned place avoidance (CPA), a behavioural phenotype reflecting pain-related aversion, was acquired in rats with partial sciatic nerve transection. However, a local injection of a BDNF-tropomyosin receptor kinase B (TrkB) antagonist into the rACC completely suppressed this process. Importantly, we found that administration of exogenous BDNF into the rACC of intact rats was sufficient to produce CPA, while selectively blocking phosphorylated extracellular signal regulated kinase (p-ERK) with a mitogen-activated protein kinase (MAPK) inhibitor U0126 completely abolished the acquisition of BDNF-induced CPA. In conclusion, we demonstrate, for the first time, that ERK is an important downstream effector of the BDNF/TrkB-mediated signalling pathway in the rACC that contributes to the development of neuropathic pain-related aversion.
Reducing pain in animals is an ethical and sometimes legal requirement, but how do we assess pain and does it confound data collection?
Neuropathic pain is caused by peripheral nerve injury (PNI). One hallmark symptom is allodynia (pain caused by normally innocuous stimuli), but its mechanistic underpinning remains elusive. Notably, whether selective stimulation of non-nociceptive primary afferent Aβ fibers indeed evokes neuropathic pain-like sensory and emotional behaviors after PNI is unknown, because of the lack of tools to manipulate Aβ fiber function in awake, freely moving animals. In this study, we used a transgenic rat line that enables stimulation of non-nociceptive Aβ fibers by a light-activated channel (channelrhodopsin-2; ChR2). We found that illuminating light to the plantar skin of these rats with PNI elicited pain-like withdrawal behaviors that were resistant to morphine. Light illumination to the skin of PNI rats increased the number of spinal dorsal horn (SDH) Lamina I neurons positive to activity markers (c-Fos and phosphorylated extracellular signal-regulated protein kinase; pERK). Whole-cell recording revealed that optogenetic Aβ fiber stimulation after PNI caused excitation of Lamina I neurons, which were normally silent by this stimulation. Moreover, illuminating the hindpaw of PNI rats resulted in activation of central amygdaloid neurons and produced an aversion to illumination. Thus, these findings provide the first evidence that optogenetic activation of primary afferent Aβ fibers in PNI rats produces excitation of Lamina I neurons and neuropathic pain-like behaviors that were resistant to morphine treatment. This approach may provide a new path for investigating circuits and behaviors of Aβ fiber-mediated neuropathic allodynia with sensory and emotional aspects after PNI and for discovering novel drugs to treat neuropathic pain.
It has been reported that during chemotherapy treatment, some patients can experience nausea before pharmacological administration, suggesting that contextual stimuli are associated with the nauseating effects. There are attempts to reproduce with animal models the conditions under which this phenomenon is observed to provide a useful paradigm for studying contextual aversion learning and the brain structures involved. This manuscript assessed the hippocampus involvement in acquiring and maintaining long-term conditioned place avoidance (CPA) induced by a gastric malaise-inducing agent, LiCl. Our results demonstrate that a reliable induction of CPA is possible after one acquisition trial. However, CPA establishment requires a 20-min confinement in the compartment associated with LiCl administration. Interestingly, both hippocampal regions seem to be necessary for CPA establishment; nonetheless, inactivation of the ventral hippocampus results in a reversion of avoidance and turns it into preference. Moreover, we demonstrate that activation of dorsal/ventral hippocampal NMDA receptors after CS–US association is required for long-term CPA memory maintenance.
Increase in proton concentration [H⁺] or decrease in local and global extracellular pH occurs in both physiological and pathological conditions. Acid-sensing ion channels (ASICs), belonging to the ENaC/Deg superfamily, play an important role in signal transduction as proton sensor. ASICs and in particular ASIC-1a (one of the six ASICs subunits) which is permeable to Ca²⁺, are involved in many physiological processes (including synaptic plasticity) and neurodegenerative diseases. Activity-dependent long-term potentiation (LTP) is a major type of long-lasting synaptic plasticity in the CNS, associated with learning, memory, development, fear and persistent pain. Neurons in the anterior cingulate cortex (ACC) play critical roles in pain perception and chronic pain and express ASIC-1a channels. During synaptic transmission, acidification of the synaptic cleft presumably due to the co-release of neurotransmitter and H⁺ from synaptic vesicles activates postsynaptic ASIC-1a channels in ACC of mice. This generates ASIC1a synaptic currents that add to the glutamatergic excitatory postsynaptic currents (EPSCs). Here we report that modulators like histamine and corticosterone, acting through ASIC-1a regulate synaptic plasticity, reducing the threshold for LTP induction of glutamatergic EPSCs. Our findings suggest a new role for ASIC-1a mediating the neuromodulator action of histamine and corticosterone regulating specific forms of synaptic plasticity in the mouse ACC.
Increasing evidence suggests that long-term opioids and pain induce similar adaptive changes in the brain's reward circuits, however, how pain alters the addictive properties of opioids remains poorly understood. In this study using a rat model of morphine self-administration (MSA), we found that short-term pain, induced by an intraplantar injection of complete Freund's adjuvant, acutely decreased voluntary morphine intake, but not food intake, only at a morphine dose that did not affect pain itself. Pre-treatment with indomethacin, a non-opioid inhibitor of pain, before the pain induction blocked the decrease in morphine intake. In rats with steady MSA, the protein level of GluA1 subunits of glutamate AMPA receptors (AMPARs) was significantly increased, but that of GluA2 was decreased, resulting in an increased GluA1/GluA2 ratio in central nucleus of the amygdala (CeA). In contrast, pain decreased the GluA1/GluA2 ratio in the CeA of rats with MSA. Microinjection of NASPM, a selective inhibitor of homomeric GluA1-AMPARs, into CeA inhibited morphine intake. Furthermore, viral overexpression of GluA1 protein in CeA maintained morphine intake at a higher level than controls and reversed the pain-induced reduction in morphine intake. These findings suggest that CeA GluA1 promotes opioid use and its upregulation is sufficient to increase opioid consumption, which counteracts the acute inhibitory effect of pain on opioid intake. These results demonstrate that the CeA GluA1 is a shared target of opioid and pain in regulation of opioid use, which may aid in future development of therapeutic applications in opioid abuse.
The pervasive use of opioid compounds for pain relief is rooted in their utility as one of the most effective therapeutic strategies for providing analgesia. While the detrimental side effects of these compounds have significantly contributed to the current opioid epidemic, opioids still provide millions of patients with reprieve from the relentless and agonizing experience of pain. The human experience of pain has long recognized the perceived unpleasantness entangled with a unique sensation that is immediate and identifiable from the first-person subjective vantage point as “painful.” From this phenomenological perspective, how is it that opioids interfere with pain perception? Evidence from human lesion, neuroimaging, and preclinical functional neuroanatomy approaches is sculpting the view that opioids predominately alleviate the affective or inferential appraisal of nociceptive neural information. Thus, opioids weaken pain-associated unpleasantness rather than modulate perceived sensory qualities. Here, we discuss the historical theories of pain to demonstrate how modern neuroscience is revisiting these ideas to deconstruct the brain mechanisms driving the emergence of aversive pain perceptions. We further detail how targeting opioidergic signaling within affective or emotional brain circuits remains a strong avenue for developing targeted pharmacological and gene-therapy analgesic treatments that might reduce the dependence on current clinical opioid options.
Key points:
Chronic pain is disabling because sufferers form negative associations between pain and activities, such as work, leading to the sufferer limiting these activities. Pain information arriving in the amygdala is responsible for forming these associations and contributes to us feeling bad when we are in pain. Ongoing injuries enhance the delivery of pain information to the amygdala. If we want to understand why chronic pain can continue without ongoing injury, it is important to know whether this facilitation continues once the injury has healed. In the present study, we show that a 2 min noxious heat stimulus, without ongoing injury, is able to enhance delivery of pain information to the amygdala for 3 days. If the noxious heat stimulus is repeated, this enhancement persists even longer. These changes may prime this information pathway so that subsequent injuries may feel even worse and the associative learning that results in pain-related avoidance may be promoted.
Abstract:
Pain is an important defence against dangers in our environment; however, some clinical conditions produce pain that outlasts this useful role and persists even after the injury has healed. The experience of pain consists of somatosensory elements of intensity and location, negative emotional/aversive feelings and subsequent restrictions on lifestyle as a result of a learned association between certain activities and pain. The amygdala contributes negative emotional value to nociceptive sensory information and forms the association between an aversive response and the environment in which it occurs. It is able to form this association because it receives nociceptive information via the spino-parabrachio-amygdaloid pathway and polymodal sensory information via cortical and thalamic inputs. Synaptic plasticity occurs at the parabrachial-amygdala synapse and other brain regions in chronic pain conditions with ongoing injury; however, very little is known about how plasticity occurs in conditions with no ongoing injury. Using immunohistochemistry, electrophysiology and behavioural assays, we show that a brief nociceptive stimulus with no ongoing injury is able to produce long-lasting synaptic plasticity at the rat parabrachial-amygdala synapse. We show that this plasticity is caused by an increase in postsynaptic AMPA receptors with a transient change in the AMPA receptor subunit, similar to long-term potentiation. Furthermore, this synaptic potentiation primes the synapse so that a subsequent noxious stimulus causes prolonged potentiation of the nociceptive information flow into the amygdala. As a result, a second injury could have an increased negative emotional value and promote associative learning that results in pain-related avoidance.
The anterior cingulate cortex (ACC) is activated by noxious stimuli and is involved in the affective component of pain processing; but its role in the sensory component of pain remains largely unknown. Studies have verified that Chemokine (C-X-C motif) receptor 3 (CXCR3) is involved in nociceptive sensitization in the spinal cord after peripheral nerve injury; however, the expression of CXCR3 in the ACC and its role in neuropathic pain has not been reported. Here, we showed that CXCR3 co-localized with neurons in the ACC and the upregulation of CXCR3 corresponded with hypersensitive behaviors after a chronic constriction injury of the sciatic nerve. Pharmacological blockade of CXCR3 using local injection of its inhibitor, AMG487, into the ACC significantly attenuated hyperalgesia induced by chronic constriction injury and suppressed the phosphorylation of extracellular signal-regulated kinase (ERK). Collectively, these results suggest that CXCR3 in the ACC is involved in hyperalgesia induced by peripheral nerve injury and ERK may be a downstream target.
L’ADHD (Attention-deficit/hyperactivity disorder) est une maladie du développement caractérisée par l’impulsivité, l’hyperactivité, et l’inattention. Les voies neuronales impliquées dans ces déficits indiquent des dysfonctionnements dans les réseaux catécholaminergiques frontal-sous-corticaux, impliquant l'innervation dopaminergique et noradrénergique. Des études récentes ont mis en évidence une hypersensibilité à la douleur chez les patients ADHD et soulignent une possible comorbidité entre l’ADHD et la douleur. Cependant, les mécanismes et les circuits neuraux impliqués dans ces interactions sont inconnus. Afin de décrypter cette relation, nous avons généré un modèle ADHD de souris à P5 par une lésion néonatale des voies dopaminergiques centrales avec la 6-Hydroxydopamine (6-OHDA) et nous avons démontré la validité du modèle pour mimer le syndrome ADHD. Ensuite, nous avons analysé les comportements douloureux dans le modèle de souris 6-OHDA. Ces derniers présentent un abaissement des seuils de la douleur, ce qui suggère que l’ADHD induit une sensibilisation à la douleur (comorbidité ADHD-Douleur). Nous avons confirmé à l’aide d’enregistrements extracellulaires unitaires, que les modifications de la sensibilité à la douleur des souris 6-OHDA sont dues à une augmentation de l’excitabilité des neurones nociceptifs de la moelle épinière. Cette sensibilisation passe donc par une altération de l’intégration sensorielle dans la moelle épinière via la mise en jeu de contrôles descendants. La connectivité "cortex cingulaire antérieur (ACC) – insula postérieur (PI)" est la clé dans cette comorbidité ADHD-douleur, impliquée dans les fonctions exécutives, les émotions et elle envoie aussi des projections vers la corne dorsale de la moelle épinière. En effet, en combinant les analyses électrophysiologiques, optogénétiques et comportementales, nous avons démontré que les effets de l’ADHD sur la sensibilisation douloureuse passent par la mise en jeu de l’ACC et de la voie ACC – PI. En conclusion, nous montrons que les conditions ADHD induisent une hyperactivation des neurones nociceptifs de la moelle épinière et une hypersensibilité à la douleur. Nous suggérons également que le circuit ACC – PI pourrait déclencher un dysfonctionnement des neurones de la moelle épinière sur la douleur dans les conditions ADHD.
Patients with bone cancer pain (BCP) are more prone to aversion. which not only causes mental distress but also aggravates BCP. However, the mechanism of BCP-related aversion is still unclear. Previous studies have demonstrated that the brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signaling pathway of the rostral anterior cingulate cortex (rACC) plays an important role in the regulation of emotions related to chronic pain, such as neuropathic pain or inflammatory pain; however, few studies have investigated the role of this pathway in cancer pain. This study explored the role of BDNF in cancer pain-related aversion in the rACC and to determine whether N-methyl D-aspartate receptor subtype 2B (NR2B) and extracellular signal-regulated kinase (ERK)-cAMP response element-binding (CREB) signaling are involved in cancer pain-related aversion. A Sprague-Dawley rat model of BCP (one of the classic BCP models) was established, and the changes in pain aversion were detected by mechanical stimulation-induced conditioned place avoidance. Our findings confirmed that rats with BCP exhibited intense pain aversion accompanied by the up-regulated BDNF expression in the rACC. Additionally, the pain aversion of BCP rats was reduced while blocking the BDNF-TrkB. Furthermore, the expression of NR2B and phosphorylated ERK (pERK)/phosphorylated CREB (pCREB) were up-regulated with the development of pain aversion, whereas the use of NR2B blocker Ro25-6981, or ERK inhibitor U0126 could reduce the pain aversion. The expression of NR2B and pERK/pCREB were up-regulated after exogenous BDNF was injected into the rACC, whereas the expression levels of NR2B and pERK/pCREB were down-regulated after blocking the BDNF-TrkB signaling. In conclusion, the BDNF-TrkB signaling in the rACC mediates the generation of aversion in rats with BCP, which requires the involvement of NR2B and the ERK-CREB signaling pathway.
The negative emotions caused by persistent pain, called affective pain, are known to seriously affect human physical and mental health. The anterior cingulate cortex (ACC), especially the rostral ACC (rACC) plays a key role in the development of this affective pain. N-methyl-D-aspartate (NMDA) receptors, which are widely distributed in the ACC, are involved in the regulation of emotional behavior. It is well known that activation of opioid receptors can relieve pain, but whether it can alleviate affective pain is not clear. In the present study, conditioned place avoidance (CPA) responses induced by complete Freund's adjuvant (CFA) were used to represent the affective pain of place aversion. The behavioral measurements were synchronously combined with multichannel electrophysiological recordings of the discharge frequency of rACC pyramidal neurons to explore whether affective pain could be alleviated by the synthetic opioid [D-Ala2, D-Leu5]-Enkefalin (DADLE), an agonist of δ-opioid receptors. To further investigate this treatment as a mechanism for the relief of affective pain in CFA-treated animals, we used whole-cell patch recordings in slice preparations of the rACC region to determine the dose-dependent effects of DADLE on NMDA receptor-mediated currents. Then, western blot was used to determine levels of phosphorylated NMDA receptor subunits GluN1, GluN2 and GluN3 as affected by the δ-opioid receptor activation. The results showed that activation of δ-opioid receptors down-regulates the phosphorylation of NMDA receptor subunits, thereby inhibiting NMDA currents, decreasing the discharge frequency of rACC pyramidal neurons, and reversing the CPA response. Thus, δ-opioid receptor activation in the rACC region can alleviate affective pain.
It has been argued that exposure to inescapable shock produces later behavioral changes such as poor shuttle box escape learning because it leads to the conditioning of intense fear, which later transfers to the shuttle box test situation and interferes with escape. Both fear, as assessed by freezing, and escape were measured in Sprague-Dawley rats 24 hrs after exposure to inescapable shock. Lesions of the basolateral region and central nucleus of the amygdala eliminated the fear that transfers to the shuttle box after inescapable shock, as well as the fear conditioned in the shuttle box by the shuttle box shocks. However, the amygdala lesions did not reduce the learning deficit produced by inescapable shock. In contrast, dorsal raphe nucleus lesions did not reduce the fear that transfers to the shuttle box after inescapable shock, but eliminated the enhanced fear conditioning in the shuttle box as well as the escape deficit. The implications of these results for the role of fear and anxiety in mediating inescapable shock effects are discussed. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
The role of N-methyl-D-aspartate (NMDA) receptors in Pavlovian fear conditioning was examined using the NMDA antagonist DL-2-amino-5-phosphonovaleric acid (APV). Either APV (5 micrograms/rat) or saline was administered before the training phase, the testing phase, or both. APV completely blocked acquisition but not expression of fear conditioning. The L enantiomer of APV did not affect the acquisition of conditional fear. To separate encoding from consolidation processes, APV was administered either before or immediately after the footshock unconditional stimulus (US) during the training phase. The results indicate that APV must be present during the US to produce its effects on fear conditioning. The behavioral effect of the drug is not due to analgesic action because APV did not alter pain sensitivity. The data suggest that NMDA receptors are critical for the acquisition but not expression of fear conditioning. These effects on fear conditioning are parallel to the in vitro effects of APV on the acquisition but not expression of long-term potentiation (LTP) and suggest that endogenously generated NMDA-dependent LTP participates in the neural plasticity underlying fear conditioning.
Previous work has implicated projections from the acoustic thalamus to the amygdala in the classical conditioning of emotional responses to auditory stimuli. The purpose of the present studies was to determine whether the lateral amygdaloid nucleus (AL), which is a major subcortical target of projections from the acoustic thalamus, might be the sensory interface of the amygdala in emotional conditioning. Lesions were placed in AL of rats and the effects on emotional conditioning were examined. Lesions of AL, but not lesions of the striatum above or the cortex adjacent to the AL, interfered with emotional conditioning. Lesions that only partially destroyed AL or lesions placed too ventrally that completely missed AL had no effect. AL lesions did not affect the responses elicited following nonassociative (random) training. AL is thus an essential link in the circuitry through which auditory stimuli are endowed with affective properties and may function as the sensory interface of the amygdala during emotional learning.
The goal of this work was to test the involvement of the central nucleus and basolateral complex of the amygdala in fear conditioning, using auditory and visual conditioned stimuli (CSs). The acoustic startle reflex in rats was used as the behavioral index of conditioning because startle is reliably enhanced in the presence of a conditioned stimulus (CS) previously paired with a footshock. Initially, differential conditioning procedures indicated reliable discrimination between a noise CS and a visual CS. Subsequently, the effects of amygdala lesions were evaluated when both modalities were paired with shocks in the same rats. Electrolytic or ibotenic acid lesions of the central nucleus of the amygdala blocked fear-potentiated startle to both auditory and visual CSs, consistent with the idea that the central nucleus serves as a response independent, final common relay for fear conditioning. Similarly, pre- or post-training electrolytic or NMDA-induced lesions of the basolateral complex of the amygdala, which damaged the lateral nucleus, and most of the basolateral nucleus, disrupted fear-potentiated startle to both CS modalities. This finding is consistent with the suggestion that, in fear conditioning, the basolateral complex of the amygdala serves as an obligatory relay of sensory information from subcortical and cortical sensory areas to the central nucleus of the amygdala.
The effects of amygdala, hippocampus, and periaqueductal gray (PAG) lesions on contextual fear conditioning in rats were examined. Freezing behavior served as the measure of conditioning. Unlesioned control animals showed reliable conditional freezing in the testing chamber when observed both immediately and 24 hr after footshocks. In contrast, rats with amygdala or ventral PAG lesions exhibited a significant attenuation in freezing both immediately and 24 hr after the shocks. Dorsal PAG lesions had no effect on freezing at either time. Animals with hippocampal lesions displayed robust freezing behavior immediately following the shock, even though they showed a marked deficit in freezing 24 hr after the shock. These results indicate that there are anatomically dissociable short- and long-term conditional fear states.
1. To identify the forebrain and brain stem structures that are active during the perception of acute heat pain in humans, we performed H2 15O positron emission tomographic (PET) analyses of cerebral blood flow (CBF) on nine normal volunteers while they received repetitive noxious (50 degrees C) and innocuous (40 degrees C) 5 s heat pulses to the forearm (average resting temperature of 31.8 degrees C). Each subject rated the subjective intensity of each stimulation series according to a magnitude estimation procedure in which 0 = no heat sensation, 7 = barely painful, and 10 = barely tolerable. 2. Three scans were performed at each temperature. Mean CBF images were created for each experimental condition and oriented onto standardized stereotaxic coordinates. Subtraction images were created between conditions for each subject and averaged across subjects. Volumes of interest (VOI) were chosen, based on a priori hypotheses and the results of previously published PET studies. In addition, a separate statistical summation analysis of individual voxels was performed. Statistical thresholds were established with corrections for multiple comparisons. 3. Significant CBF increases to 50 degrees C stimuli were found in the contralateral thalamus, cingulate cortex, S2 and S1 cortex, and insula. The ipsilateral S2 cortex and thalamus, and the medial dorsal midbrain and cerebellar vermis also showed significant CBF increases. All subjects rated the 50 degrees C stimuli as painful (average subjective rating = 8.9 +/- 0.9 SD) and the 40 degrees C stimuli as warm, but not painful (average subjective rating = 2.1 +/- 1.0).(ABSTRACT TRUNCATED AT 250 WORDS)
Considerable evidence suggests that various discrete nuclei within the amygdala complex are critically involved in the assignment of emotional significance or value to events through associative learning. Much of this evidence comes from aversive conditioning procedures. For example, lesions of either basolateral amygdala (ABL) or the central nucleus (CN) interfere with the acquisition or expression of conditioned fear. The present study examined the effects of selective neurotoxic lesions of either ABL or CN on the acquisition of positive incentive value by a conditioned stimulus (CS) with two appetitive Pavlovian conditioning procedures. In second-order conditioning experiments, rats first received light-food pairings intended to endow the light with reinforcing power. The acquired reinforcing power of the light was then measured by examining its ability to serve as a reinforcer for second-order conditioning of a tone when tone-light pairings were given in the absence of food. Acquisition of second-order conditioning was impaired in rats with ABL lesions but not in rats with CN lesions. In reinforcer devaluation procedures, conditioned responding of rats with ABL lesions was insensitive to postconditioning changes in the value of the reinforcer, whereas rats with CN lesions, like normal rats, were able to spontaneously adjust their CRs to the current value of the reinforcer. The results of both test procedures indicate that ABL, but not CN, is part of a system involved in CSs' acquisition of positive incentive value. Together with evidence that identifies a role for CN in certain changes in attentional processing of CSs in conditioning, these results suggest that separate amygdala subsystems contribute to a variety of processes inherent in associative learning.
The amygdala is thought to play a crucial role in emotional and social behaviour. Animal studies implicate the amygdala in both fear conditioning and face perception. In humans, lesions of the amygdala can lead to selective deficits in the recognition of fearful facial expressions and impaired fear conditioning, and direct electrical stimulation evokes fearful emotional responses. Here we report direct in vivo evidence of a differential neural response in the human amygdala to facial expressions of fear and happiness. Positron-emission tomography (PET) measures of neural activity were acquired while subjects viewed photographs of fearful or happy faces, varying systematically in emotional intensity. The neuronal response in the left amygdala was significantly greater to fearful as opposed to happy expressions. Furthermore, this response showed a significant interaction with the intensity of emotion (increasing with increasing fearfulness, decreasing with increasing happiness). The findings provide direct evidence that the human amygdala is engaged in processing the emotional salience of faces, with a specificity of response to fearful facial expressions.
Three experiments examined the effects of intra-amygdaloid infusions of an N-methyl-D-aspartate (NMDA) receptor antagonist, D,L-2-amino-5-phosphonovalerate (APV), on contextual fear conditioning in rats. In Experiment 1, APV infusion into the basolateral amygdala (BLA), before training, disrupted the acquisition of contextual fear. In Experiment 2, APV produced a disruption of both the acquisition and expression of contextual fear. This blockade of contextual fear was not state dependent, not due to a shift in footshock sensitivity, and not the result of increased motor activity in APV-treated rats. In Experiment 3, fear conditioning was not affected by a posttraining APV infusion into the BLA. These results indicate that NMDA receptors in the BLA are necessary for both the acquisition and expression of Pavlovian fear conditioning to contextual cues in rats.
In the present study, startle responses during resting states as well as during the presentation of a set of emotive slides were recorded from a 32-year-old male patient with a rare localized lesion of the right amygdala. The startle reflex is a response modulated by affective states: it has been reliably used in the literature to measure the aversiveness of emotive stimuli. The animal literature has shown that the circuit of this reflex is directly influenced by amygdala projections. The startle responses of the patient were compared with those of eight age-matched normal subjects. The patient's startle amplitudes showed an overall impaired response and an inhibited reflex contralateral to the lesion. In addition, he failed to show the typical startle potentiation induced by an aversive emotive background. The data confirm, in the human, previous results from the literature in other species on amygdala involvement in startle and emotional responses. Furthermore, the observation of the importance of the right amygdala in the modulation of emotion is consistent with the hypothesis of right hemisphere specialization for aversive emotions. The results are discussed in the context of the literature on human amygdala lesions.
Transneuronal tracing of a nociceptive pathway, the spino-(trigemino)-parabrachio-amygdaloid pathway, was performed using an alpha-herpes virus, the Bartha strain of pseudorabies virus (PRV). Microinjection of PRV into the central nucleus of the amygdala (Ce) resulted in progressive retrograde and transneuronal infection of a multisynaptic circuit involving neurons in the brainstem and spinal cord as detected immunocytochemically. At short survival (26 hr), retrogradely labeled neurons were concentrated in the external lateral nucleus of the parabrachial complex (elPB) but were absent from both the trigeminal nucleus caudalis (TNC) and the spinal cord. At longer survivals (52 hr), labeled cells were present in lamina I of both the TNC and spinal dorsal horn. Retrograde labeling from the Ce with Fluoro-gold demonstrated that elPB neurons have long dendrites extending laterally into the terminal field of spinal and trigeminal afferents, where transneuronal passage of PRV to these afferents could occur. Even longer survivals (76 hr) resulted in a columnar pattern of cell labeling in the TNC and spinal dorsal horn that extended from lamina I into lamina II. At this longest survival, primary sensory neurons became infected. Bilateral excitotoxic lesions of the elPB blocked almost all viral passage from the Ce to superficial laminae of the TNC and spinal dorsal horn. These results demonstrate that nociceptive input to the amygdala is relayed from neurons in lamina I through the elPB. We propose that this modular arrangement of lamina I and II neurons may provide the basis for spinal processing of peripheral input to the amygdala.
Previous work has implicated projections from the acoustic thalamus to the amygdala in the classical conditioning of emotional responses to auditory stimuli. The purpose of the present studies was to determine whether the lateral amygdaloid nucleus (AL), which is a major subcortical target of projections from the acoustic thalamus, might be the sensory interface of the amygdala in emotional conditioning. Lesions were placed in AL of rats and the effects on emotional conditioning were examined. Lesions of AL, but not lesions of the striatum above or the cortex adjacent to the AL, interfered with emotional conditioning. Lesions that only partially destroyed AL or lesions placed too ventrally that completely missed AL had no effect. AL lesions did not affect the responses elicited following nonassociative (random) training. AL is thus an essential link in the circuitry through which auditory stimuli are endowed with affective properties and may function as the sensory interface of the amygdala during emotional learning.
1. Neurons were recorded in the parabrachial (PB) area, located in the dorsolateral region of the pons (with the use of extracellular micropipette), in the anesthetized rat. Parabrachioamygdaloid (PA) neurons (n = 67) were antidromically identified after stimulation in the centralis nucleus of the amygdala (Ce). The axons of these neurons exhibit a very slow conduction velocity, between 0.26 and 1.1 m/s, i.e., in the unmyelinated range. 2. These PA neurons were located in a restricted region of the PB area: the subnuclei external lateral (PBel) and external medial (PBem). A relative somatotopic organization was found in this region. 3. These units were separated into two groups: 1) a group of nociceptive-specific (NS) neurons (69%), which responded exclusively to noxious stimuli, and 2) a group of nonresponsive (NR) neurons (31%). 4. The NS neurons exhibited low or lacked spontaneous activity. They responded exclusively to mechanical (pinch or squeeze) and/or thermal (waterbath or waterjet greater than 44 degrees C) noxious stimuli with a marked and sustained activation with a rapid onset and generally without afterdischarge. Noxious thermal stimuli generally induced a stronger response than the noxious mechanical stimuli. These neurons exhibited a clear capacity to encode thermal stimuli in the noxious range: 1) the stimulus-response function was always positive and monotonic; 2) the slope of the curve progressively increased up to a maximum where it was very steep, then the steepness of the slope decreased close to the maximum response; and 3) the mean threshold was 44.1 +/- 2 degrees C, and the point of steepest slope of the mean curve was around 47 degrees C. 5. The excitatory receptive fields of the NS neurons were large in the majority (70%) of the cases and included several areas of the body. A more marked activation was often obtained from stimuli applied to one part of the body, denoted as the preferential receptive field (PRF). In the other cases (30%), the excitatory receptive field was relatively small (SRF) and restricted to one part of the body (the tail, a paw, a hemiface, or the tongue). Both the PRF and SRF were more often located on the contralateral side. In addition, noxious stimuli applied outside the excitatory receptive field were found to strongly inhibit the responses of NS neurons. 6. All the NS neurons responded to intense transcutaneous electrical stimulation applied to the PRF or SRF with two peaks of activation.(ABSTRACT TRUNCATED AT 400 WORDS)
The role of N-methyl-D-aspartate (NMDA) receptors in Pavlovian fear conditioning was examined using the NMDA antagonist DL-2-amino-5-phosphonovaleric acid (APV). Either APV (5-mu-g/rat) or saline was administered before the training phase, the testing phase, or both. APV completely blocked acquisition but not expression of fear conditioning. The L enantiomer of APV did not affect the acquisition of conditional fear. To separate encoding from consolidation processes, APV was administered either before or immediately after the footshock unconditional stimulus (US) during the training phase. The results indicate that APV must be present during the US to produce its effects on fear conditioning. The behavioral effect of the drug is not due to analgesic action because APV did not alter pain sensitivity. The data suggest that NMDA receptors are critical for the acquisition but not expression of fear conditioning. These effects on fear conditioning are parallel to the in vitro effects of APV on the acquisition but not expression of long-term potentiation (LTP) and suggest that endogenously generated NMDA-dependent LTP participates in the neural plasticity underlying fear conditioning.
Patients with chronic pain suffer from much more affective emotional disturbance than pain sensation. The present study examined Fos expression associated with pain-related aversion in rats, using formalin-induced conditioned place avoidance (F-CPA) test, which could distinguish pain emotion from pain sensation. When pain experience was retrieved, the rats with F-CPA produced rigorous emotion-like behaviors. As a result, more Fos-Ll neurons were observed in anterior cingulate cortex, retrosplenial cortex, insular cortex, parietal cortex area 2, frontal cortex area 1-3, claustrum, lateral septal area, amygdala, dorsomedial hypothalamic nucleus, central medial nucleus, paraventricular nucleus, superior colliculus, inferior colliculus and periaqueductal gray. The results for the first time mapped the brain regions associated with processing of pain affect and emotion in rats.
The PET H2 15O-bolus method was used to image regional brain activity in normal human subjects during intense pain induced by intradermal injection of capsaicin and during post-capsaicin mechanical allodynia (the perception of pain from a normally non-painful stimulus). Images of regional cerebral blood flow were acquired during six conditions: (i) rest; (ii) light brushing of the forearm; (iii) forearm intradermal injection of capsaicin, (iv) and (v) the waning phases of capsaicin pain; and (vi) allodynia. Allodynia was produced by light brushing adjacent to the capsaicin injection site after ongoing pain from the capsaicin injection had completely subsided. Capsaicin treatment produced activation in many discrete brain regions which we classified as subserving four main functions: sensation-perception (primary somatosensory cortex, thalamus and insula); attention (anterior cingulate cortex); descending pain control (periaqueductal grey); and an extensive network related to sensory-motor integration (supplementary motor cortex, bilateral putamen and insula, anterior lobe and vermis of the cerebellum and superior colliculus). Comparison of the noxious and non-noxious stimuli yielded several new insights into neural organization of pain and tactile sensations. Capsaicin pain, which had no concomitant tactile component, produced little or no activation in secondary somatosensory cortex (SII), whereas light brushing produced a prominent activation of SII, suggesting a differential sensitivity of SII to tactile versus painful stimuli. The cerebellar vermis was strongly activated by capsaicin, whereas light brush and experimental allodynia produced little or no activation, suggesting a selective association with C-fibre stimulation and nociceptive second-order spinal neurons. The experimental allodynia activated a network that partially overlapped those activated by both pain and light brush alone. Unlike capsaicin-induced pain, allodynia was characterized by bilateral activation of inferior prefrontal cortex, suggesting that prefrontal responses to pain are context dependent.
Only recently have neuroimaging studies moved away from describing regions activated by noxious stimuli and started to disentangle subprocesses within the nociceptive system. One approach to characterizing the role of individual regions is to record brain responses evoked by different stimulus intensities. We used such a parametric single‐trial functional MRI design in combination with a thulium:yttrium–aluminium–granate infrared laser and investigated pain, stimulus intensity and stimulus awareness (i.e. pain‐unrelated) responses in nine healthy volunteers. Four stimulus intensities, ranging from warm to painful (300–600 mJ), were applied in a randomized order and rated by the subjects on a five‐point scale (P0–4). Regions in the dorsolateral prefrontal cortex and the intraparietal sulcus differentiated between P0 (not perceived) and P1 but exhibited no further signal increase with P2, and were related to stimulus perception and subsequent cognitive processing. Signal changes in the primary somatosensory cortex discriminated between non‐painful trials (P0 and P1), linking this region to basic sensory processing. Pain‐related regions in the secondary somatosensory cortex and insular cortex showed a response that did not distinguish between innocuous trials (P0 and P1) but showed a positive linear relationship with signal changes for painful trials (P2–4). This was also true for the amygdala, with the exception that, in P0 trials in which the stimulus was not perceived (i.e. ‘uncertain’ trials), the evoked signal changes were as great as in P3 trials, indicating that the amygdala is involved in coding ‘uncertainty’, as has been suggested previously in relation to classical conditioning.
Brain imaging with positron emission tomography has identified some of the principal cerebral structures of a central network activated by pain. To discover whether the different cortical and subcortical areas process different components of the multidimensional nature of pain, we performed a regression analysis between noxious heat-related regional blood flow increases and experimental pain parameters reflecting detection of pain, encoding of pain intensity, as well as pain unpleasantness. The results of our activation study indicate that different functions in pain processing can be attributed to different brain regions; ie, the gating function reflected by the pain threshold appeared to be related to anterior cingulate cortex, the frontal inferior cortex, and the thalamus, the coding of pain intensity to the periventricular gray as well as to the posterior cingulate cortex, and the encoding of pain unpleasantness to the posterior sector of the anterior cingulate cortex. Ann Neurol 1999;45:40–47
The effect of graded inflammatory stimuli (intraplantar-carrageenan, 0.2, 1, and 6 mg/150 μl) on paw edema and c-Fos protein expression at two levels of the spinoparabrachial pathway, the spinal cord and parabrachial area (PB), were studied. The present study, in awake rats, is an extension of previous study (Bester et al. [1997] J. Comp. Neurol. 383:439–458) which evaluated, in anesthetized rats, the effect of graded cutaneous heat stimulation on c-Fos-expression at the same levels.At the spinal level, the c-Fos-protein-like-immunoreactive (c-Fos-LI) neurons were located primarily in superficial laminae ipsilateral to intraplantar carrageenan. The number of c-Fos-LI neurons increased dose dependently (r = 0.973, n = 24) for carrageenan, from a number close to zero for the saline injection. At the PB level, c-Fos was predominantly expressed contralateral to intraplantar carrageenan. c-Fos-LI neurons were located primarily around the pontomesencephalic junction in (i) a restricted pontine area, centered in the lateral crescent, and including an adjacent part of the outer portion of the external lateral subnucleus, and (ii) the mesencephalic superior lateral subnuclei. The number of c-Fos-LI neurons in the PB area was correlated with that in the superficial laminae (r = 0.935, n = 24) and with the paw edema (r = 0.931, n = 24). No significant changes in c-Fos expression were observed in the nucleus of the solitary tract and ventrolateral medulla.The close correlation between c-Fos expression at both the spinal and PB levels and inflammatory edema provides further evidence for the involvement of spinoparabrachial pathway in inflammatory nociceptive processes. The present results are congruent with the existence of electrophysiologically demonstrated spinoparabrachio-amygdaloid and -hypothalamic nociceptive pathways. J. Comp. Neurol. 397:10–28, 1998. © 1998 Wiley-Liss, Inc.
A method for assessing pain and analgesia in rats and cats is described. The procedure involves subcutaneous injection of dilute formalin into the forepaw, after which the animal's responses are rated according to objective behavioral criteria. The formalin test is a statistically valid technique which has two advantages over other pain tests: (1) little or no restraint is necessary, permitting unhindered observation of the complete range of behavioral responses; and (2) the pain stimulus is continuous rather than transient, thus bearing greater resemblance to most clinical pain. The analgesic effects of morphine, meperidine, and stimulation of the periaqueductal grey matter are evaluated using this test.
1. Single-unit responses in area 24 of cingulate cortex were examined in halothane-anesthetized rabbits during stimulation of the skin with transcutaneous electrical (TCES, 3-10 mA), mechanical (smooth or serrated forceps to the dorsal body surface or graded pressures of 100-1,500 g to the stabilized ear) and thermal (> 25 degrees C) stimulation. 2. Of 542 units tested in cingulate cortex, 150 responded to noxious TCES (> or = 6 mA), 93 of 221 units tested responded to noxious mechanical (serrated forceps) and 9 of 47 units tested responded to noxious heat (> 43 degrees C) stimuli. Twenty-five percent of the units that responded to noxious mechanical stimuli also responded to noxious heat stimuli. The only innocuous stimulus that evoked activity in cingulate cortex was a "tap" to the skin and this was effective for 11 of 14 tested units. 3. In 74 units that produced excitatory responses to TCES of the contralateral ear, response latency was 166 +/- 11.3 (SE) ms and response duration was 519 +/- 52.1 ms. 4. Twenty of the 150 units that responded to noxious TCES were initially inhibited. These responses were usually < 1 s in duration (17 of 20 units), whereas responses in the other 3 lasted for over 20 s. 5. Most units had broad receptive fields, because noxious mechanical stimuli anywhere on the dorsal surface of the rabbits, including the face and ears, evoked responses. A small number of units for which the entire body surface was tested (3 of 15 units) had receptive fields limited to the ears, rostral back, and forepaws. 6. Fifteen of 33 units tested had no preferential responses to noxious TCES of the ipsilateral and contralateral ears. Of the remaining units, 10 had a greater response to contralateral and 8 had a greater response to ipsilateral stimuli. 7. The locations of 186 units were histologically verified. Most nociceptive cingulate units were in dorsal area 24b in layers III (n = 35), II (n = 13), or V (n = 9). 8. Cortical knifecut lesions were made in five rabbits to determine if the responses in area 24 were dependent on lateral or posterior cortical inputs. These lesions did not alter the percentage of units driven by noxious stimuli nor response latency. 9. Injections of lidocaine were made into medial parts of the thalamus in six animals and injection and recording sites analyzed histologically.(ABSTRACT TRUNCATED AT 400 WORDS)
Fibers projecting from several levels of the spinal cord to the diencephalon and telencephalon were labeled anterogradely with Phaseolus vulgaris leucoagglutinin injected iontophoretically. Labeled fibers in the thalamus confirmed projections previously observed. In addition, many labeled fibers were seen in the hypothalamus and in telencephalic areas not generally recognized previously as receiving such projections. In the hypothalamus, these areas included the lateral hypothalamus (including the medial forebrain bundle), the posterior hypothalamic area, the dorsal hypothalamic area, the dorsomedial nucleus, the paraventricular nucleus, the periventricular area, the suprachiasmatic nucleus, and the lateral and medial preoptic areas. In the telencephalon, areas with labeled fibers included the ventral pallidum, the globus pallidus, the substantia innominata, the basal nucleus of Meynert, the amygdala (central nucleus), the horizontal and vertical limbs of the diagonal band of Broca, the medial and lateral septal nuclei, the bed nucleus of the stria terminalis, the nucleus accumbens, infralimbic cortex, and medial orbital cortex. These results suggest that somatosensory, possibly including visceral sensory, information is carried directly from the spinal cord to areas in the brain involved in autonomic regulation, motivation, emotion, attention, arousal, learning, memory, and sensory-motor integration. Many of these areas are associated with the limbic system.
The projections from the midline and intralaminar thalamic nuclei to the cerebral cortex were studied in the rat by means of anterograde tracing with Phaseolus vulgaris-leucoagglutinin. The midline and intralaminar nuclear complex taken as a whole projects to widespread, predominantly frontal, cortical areas. Each of the constituent thalamic nuclei has a restricted cortical projection field that overlaps only slightly with the projection fields of adjacent midline and intralaminar nuclei. The projections of the intralaminar nuclei cover a larger cortical area than those of the midline nuclei. The laminar distributions of fibres from individual midline and intralaminar thalamic nuclei are different and include both deep and superficial cortical layers. The parataenial, paraventricular and intermediodorsal midline nuclei each project to circumscribed parts of the prefrontal cortex and the hippocampal and parahippocampal regions. In the prefrontal cortex, the projections are restricted to the medial orbital, infralimbic, ventral prelimbic and agranular insular fields, and the rostral part of the ventral anterior cingular cortex. In contrast to the other midline nuclei, the rhomboid nucleus projects to widespread cortical areas. The rostral intralaminar nuclei innervate dorsal parts of the prefrontal cortex, i.e. the dorsal parts of the prelimbic, anterior cingular and dorsal agranular insular cortical fields, the lateral and ventrolateral orbital areas, and the caudal part of the ventral anterior cingular cortex. Additional projections are aimed at the agranular fields of the motor cortex and the caudal part of the parietal cortex. The lateral part of the parafascicular nucleus sends fibres predominantly to the lateral agranular field of the motor cortex and the rostral part of the parietal cortex. The medial part of the parafascicular nucleus projects rather sparsely to the dorsal part of the prelimbic cortex, the anterior cingular cortex and the medial agranular field of the motor cortex. Individual midline and intralaminar thalamic nuclei are thus in a position to directly influence circumscribed areas of the cerebral cortex. In combination with previously reported data on the organization of the midline and intralaminar thalamostriatal projections and the prefrontal corticostriatal projections the present results suggest a high degree of differentiation in the convergence of thalamic and cortical afferent fibres in the striatum. Each of the recently described parallel basal ganglia-thalamocortical circuits can thus be expanded to include projections at both the cortical and striatal levels from a specific part of the midline and intralaminar nuclear complex. The distinctive laminar distributions of the fibres originating from the different nuclei emphasize the specificity of the midline and intralaminar thalamocortical projections.
Experiment 1 investigated the effects of catecholaminergic deafferentation or cell body lesions of the amygdala on fear conditioning to explicit and contextual cues. Bilateral infusions of quinolinic acid mainly damaged neurons within the basolateral region of the amygdala. 6-Hydroxydopamine infusions at the same coordinates resulted in an 86% depletion of noradrenaline and a 63% depletion of dopamine from the amygdala, but had no effect on the concentration of 5-hydroxytryptamine. After recovery from surgery, lesioned rats and controls were exposed to pairings of an auditory (clicker) conditioned stimulus and (foot shock) unconditioned stimulus in a distinctive environment. During testing, rats with both 6-hydroxydopamine and cell body lesions showed severely impaired conditioning to explicit cues, compared with controls, indicated by their reduced suppression of drinking when the conditioned stimulus was introduced into a separate, lick-operant chamber. Neither lesion affected fear conditioning to contextual cues, measured as preference for a "safe" environment over the one in which they were shocked. In Experiment 2, rats received bilateral, ibotenic acid-induced lesions of the hippocampal formation. Lesioned rats and controls were again tested for aversive conditioning to explicit and contextual cues. Rats with cell body lesions of the hippocampus showed normal suppression of drinking in the presence of the conditioned stimulus, but were severely impaired in choosing the safe environment based on contextual cues alone. These results suggest a double dissociation of the effects of amygdala and hippocampal damage on fear conditioning to explicit and contextual cues.
Receptors for N-methyl-D-aspartate (NMDA) seem to have a critical role in synaptic plasticity. NMDA antagonists (such as AP5) prevent induction of long-term potentiation, an activity-dependent enhancement of synaptic efficacy mediated by neural mechanisms that might also underlie learning and memory. They also attenuate memory formation in several behavioural tasks; there are few data, however, implicating an NMDA-sensitive measure of conditioning based on local infusion of antagonists into a brain area tightly coupled to the behavioural response used to assess conditioning. We now show that NMDA antagonists infused into the amygdala block the acquisition, but not the expression, of fear conditioning measured with a behavioural assay mediated by a defined neural circuit (fear-potentiation of the acoustic startle reflex). This effect showed anatomical and pharmacological specificity, and was not attributable to reduced salience of the stimuli of light or shock used in training. The data indicate that an NMDA-dependent process in the amygdala subserves associative fear conditioning.
The representation of pain in the cerebral cortex is less well understood than that of any other sensory system. However,
with the use of magnetic resonance imaging and positron emission tomography in humans, it has now been demonstrated that painful
heat causes significant activation of the contralateral anterior cingulate, secondary somatosensory, and primary somatosensory
cortices. This contrasts with the predominant activation of primary somatosensory cortex caused by vibrotactile stimuli in
similar experiments. Furthermore, the unilateral cingulate activation indicates that this forebrain area, thought to regulate
emotions, contains an unexpectedly specific representation of pain.
1. Neurons were recorded in the parabrachial (PB) area, located in the dorsolateral region of the pons (with the use of extracellular micropipette), in the anesthetized rat. Parabrachioamygdaloid (PA) neurons (n = 67) were antidromically identified after stimulation in the centralis nucleus of the amygdala (Ce). The axons of these neurons exhibit a very slow conduction velocity, between 0.26 and 1.1 m/s, i.e., in the unmyelinated range. 2. These PA neurons were located in a restricted region of the PB area: the subnuclei external lateral (PBel) and external medial (PBem). A relative somatotopic organization was found in this region. 3. These units were separated into two groups: 1) a group of nociceptive-specific (NS) neurons (69%), which responded exclusively to noxious stimuli, and 2) a group of nonresponsive (NR) neurons (31%). 4. The NS neurons exhibited low or lacked spontaneous activity. They responded exclusively to mechanical (pinch or squeeze) and/or thermal (waterbath or waterjet greater than 44 degrees C) noxious stimuli with a marked and sustained activation with a rapid onset and generally without afterdischarge. Noxious thermal stimuli generally induced a stronger response than the noxious mechanical stimuli. These neurons exhibited a clear capacity to encode thermal stimuli in the noxious range: 1) the stimulus-response function was always positive and monotonic; 2) the slope of the curve progressively increased up to a maximum where it was very steep, then the steepness of the slope decreased close to the maximum response; and 3) the mean threshold was 44.1 +/- 2 degrees C, and the point of steepest slope of the mean curve was around 47 degrees C. 5. The excitatory receptive fields of the NS neurons were large in the majority (70%) of the cases and included several areas of the body. A more marked activation was often obtained from stimuli applied to one part of the body, denoted as the preferential receptive field (PRF). In the other cases (30%), the excitatory receptive field was relatively small (SRF) and restricted to one part of the body (the tail, a paw, a hemiface, or the tongue). Both the PRF and SRF were more often located on the contralateral side. In addition, noxious stimuli applied outside the excitatory receptive field were found to strongly inhibit the responses of NS neurons. 6. All the NS neurons responded to intense transcutaneous electrical stimulation applied to the PRF or SRF with two peaks of activation.(ABSTRACT TRUNCATED AT 400 WORDS)