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Serotonin in Pain and Pain Control
Abstract
In pain processing and modulation, serotonin (5-hydroxtryptamine, 5-HT) has excitatory (hyperalgesic) and inhibitory (analgesic) actions, depending on the site of action, the cell type and the type of receptor. In the periphery, 5-HT sensitizes afferent nerve fibers, thus contributing to inflammatory and neuropathic hyperalgesia. In the trigeminal system, agonism at 5-HT1B/D receptors reduces neurotransmitter release, whereas actions through the 5-HT2A receptor may underlie chronic headache. Genetic alterations in the 5-HT system may influence the susceptibility to migraine and to other pain disorders. 5-HT is involved in descending inhibitory pathways in the CNS, and modulation of this system is the most likely mechanism of action of antidepressant drugs in analgesia. Recently, facilitatory serotonergic pathways have been discovered, which may be functionally important.
... As the mechanism of action, sciatic nerve damage [10] and transient receptor potential vanilloid 1 (TRPV1) [11] have been assessed. However, although serotonin is known to be an important neurotransmitter in pain modulation [12] and serotonin-modulatory effect of Z. officinale and its components have been reported [13,14], whether [6]-shogaol can directly influence the serotonin level in the central nervous system (CNS) has never been investigated. ...
... In our previous study, we demonstrated the role of serotonin receptors in GABA activation; however, quantification of the spinal serotonergic system (i.e., serotonin and serotonergic receptors) had not been conducted. In various types of pain, the involvement of the serotonergic system has been reported [12,19,29], and increased activity of spinal cord serotonin neurons was reported to be associated with an analgesic effect [30]. However, the serotonin-modulating effect of [6]-shogaol is not well understood in pain. ...
Oxaliplatin is a chemotherapy drug that can induce severe acute neuropathy in patients within hours of treatment. In our previous study, 10 mg/kg [6]-shogaol (i.p.) significantly alleviated cold and mechanical allodynia induced by a 6 mg/kg oxaliplatin injection (i.p.); however, the precise serotonin-modulatory effect has not been investigated. In this study, we showed that intrathecal injections of NAN-190 (5-HT1A receptor antagonist, 1 µg) and MDL-72222 (5-HT3 receptor antagonist, 15 µg), but not ketanserin (5-HT2A receptor antagonist, 1 µg), significantly blocked the analgesic effect of [6]-shogaol (10 mg/kg, i.p.). Furthermore, the gene expression of the serotonin-synthesizing enzyme tryptophan hydroxylase 2 (TPH2) and serotonin levels in the spinal cord and serum were significantly downregulated (p < 0.0001 and p = 0.0002) and upregulated (p = 0.0298 and p = 0.0099) after oxaliplatin and [6]-shogaol administration, respectively. Moreover, both the gene and protein expression of the spinal serotonin receptors 5-HT1A and 5-HT3 significantly increased after [6]-shogaol injections (p < 0.0001). Finally, intrathecal injections of both receptor agonists (8-OH-DPAT; 5-HT1A receptor agonist, 10 µg and m-CPBG; 5-HT3 receptor agonist, 15 µg) mimicked the effects of [6]-shogaol in oxaliplatin-injected mice. Taken together, these results demonstrate that [6]-shogaol attenuates oxaliplatin-induced neuropathic pain by modulating the spinal serotoninergic system.
... Serotonin (5-hydroxytryptamine; 5-HT) is a monoaminergic neurotransmitter synthesized from tryptophan via the sequential actions of tryptophan hydroxylase. In the CNS, it is produced primarily in the brainstem (rostro ventromedial medulla; RVM) [30], and in the peripheral nervous system (PNS), the main cellular sources of 5-HT are platelets and mast cells [31,32]. ...
... Five studies investigated the role of monoamine neurotransmitters in oxaliplatininduced neuropathic pain (Table 1). Among many neurotransmitters, it is well accepted that 5-HT is involved in the pain modulation, although 5-HT is known to exert both pain faciliatory and inhibitory effect depending on the pain states and the type of receptors [32,35]. However, experimental studies reported that direct application of 5-HT into the spinal cord generally inhibited nociceptive responses [52]. ...
Oxaliplatin is a chemotherapeutic agent widely used against colorectal and breast cancers; however, it can also induce peripheral neuropathy that can rapidly occur even after a single infusion in up to 80–90% of treated patients. Numerous efforts have been made to understand the underlying mechanism and find an effective therapeutic agent that could diminish pain without damaging its anti-tumor effect. However, its mechanism is not yet clearly understood. The serotonergic system, as part of the descending pain inhibitory system, has been reported to be involved in different types of pain. The malfunction of serotonin (5-hydroxytryptamine; 5-HT) or its receptors has been associated with the development and maintenance of pain. However, its role in oxaliplatin-induced neuropathy has not been clearly elucidated. In this review, 16 in vivo studies focused on the role of the serotonergic system in oxaliplatin-induced neuropathic pain were analyzed. Five studies analyzed the involvement of 5-HT, while fourteen studies observed the role of its receptors in oxaliplatin-induced allodynia. The results show that 5-HT is not involved in the development of oxaliplatin-induced allodynia, but increasing the activity of the 5-HT1A, 5-HT2A, and 5-HT3 receptors and decreasing the action of 5-HT2C and 5-HT6 receptors may help inhibit pain.
... The role of serotonin (5-hydroxytryptamine, 5HT) systems in modulating nociception has long been recognized, and increased activity of brain serotonergic neurons is associated with analgesia and enhanced antinociceptive drug potency (Sommer, 2010;Loyd et al., 2013). Recently, it has become clear that 5HT, acting centrally and/or peripherally, exerts both algesic and analgesic effects, depending upon the site of action, nature of nociceptive stimuli and subtypes of activated 5HT receptors (Bardin, 2011;Viguier et al., 2013). ...
... As to peripheral effects, in the model of transient pain used here, it is not very likely that endogenous differences in 5HT level contribute to differences in pain sensitivity between 5HT sublines. It is known that 5HT released from platelets following initial cell injury activates nociceptors and exerts proalgesic effects acting directly or through facilitation of other peripheral pain mediators (Sommer, 2010;Loyd et al., 2013). However, a brief, high intensity thermal stimulus, as applied here, induces little tissue damage (Dray, 1995) and, although some local 5HT release has been shown in both primary and secondary areas after exposure to a radiant heat (Sasaki et al., 2006), increase in tissue 5HT in these conditions is considerably lower than after pain conditions producing peripheral inflammation (Nakajima et al., 2009). ...
BackgroundA role of the serotonin (5HT) transporter, a key regulator of serotonergic transmission, in the physiology, pharmacology and genetics of pain responses has been proposed recently. The present study aimed to explore the impact of constitutive differences in the activity of the serotonin transporter, and 5HT homeostasis in general, on the modulation on pain sensitivity and analgesic responses to drugs that utilize 5HT mechanisms.MethodsA novel genetic animal model, Wistar-Zagreb 5HT rats, obtained by selective breeding of animals for extreme activity of the platelet serotonin transporter was used. As a consequence of breeding, two sublines of this model, termed high-5HT and low-5HT, differ in both central and peripheral serotonin homeostasis. Thermal pain sensitivity of 5HT sublines was assessed at baseline and following administration of analgesic drugs, as determined by paw withdrawal latency to radiant heat stimulation.ResultsAnimals from 5HT sublines show differences in both basal pain sensitivity and analgesic responses. Rats with the low-5HT phenotype displayed decreased baseline paw withdrawal latencies (hyperalgesia) in comparison to their high-5HT counterpart (25%; p < 0.001). They also showed better analgesic response to acute and prolonged treatment with tramadol (p = 0.027) and clomipramine (p = 0.019), respectively, whereas administration of fluvoxamine did not produce an analgesic effect in either 5HT subline.Conclusions
These findings support the idea that functionality of the serotonin transporter is one of the physiological/genetic determinants of individual differences in pain responses and modulation. They also validate Wistar-Zagreb 5HT rats, with constitutionally up-regulated/down-regulated serotonin transporter, as a potential new genetic model for studying serotonergic modulation of pain responses.
... Additionally, serotonin 5-HT 2A/2C receptor antagonist ketanserin was used to examine the contribution of the serotonergic pathway. Serotonin 5-HT 2A/2C receptor subtype is abundant in C fibers which transmit the noxious thermal stimuli to the dorsal horn (Sommer, 2010). According to test results, the contribution of serotonin 5-HT 2A/2C receptors was shown in hot-plate and tail-immersion tests. ...
... Two differences may explain such discrepancy: First, we used a stimulation protocol that mimics the maximum rate of discharge of 5-HT neurons recorded in vivo (5 Hz/5 ms) in place of a high nonphysiological stimulation frequency (20 Hz/15 ms). A frequency-dependent mode of action of 5-HT neurons is in accordance with previous results that show that electric stimulation of the RMg can induce either pronociceptive or analgesic effects (48). Second, in the study from (47), they used a mouse that expressed ChR2 in all the B3 5-HT nuclei including the LPGi that is excluded from our study. ...
Descending control from the brain to the spinal cord shapes our pain experience, ranging from powerful analgesia to extreme sensitivity. Increasing evidence from both preclinical and clinical studies points to an imbalance toward descending facilitation as a substrate of pathological pain, but the underlying mechanisms remain unknown. We used an optogenetic approach to manipulate serotonin (5-HT) neurons of the nucleus raphe magnus that project to the dorsal horn of the spinal cord. We found that 5-HT neurons exert an analgesic action in naïve mice that becomes proalgesic in an experimental model of neuropathic pain. We show that spinal KCC2 hypofunction turns this descending inhibitory control into paradoxical facilitation; KCC2 enhancers restored 5-HT-mediated descending inhibition and analgesia. Last, combining selective serotonin reuptake inhibitors (SSRIs) with a KCC2 enhancer yields effective analgesia against nerve injury-induced pain hypersensitivity. This uncovers a previously unidentified therapeutic path for SSRIs against neuropathic pain.
... According to Gray's concept of BIS, harm avoidance is characterized by excessive anxiety and fear. Serotonin 2C(5-HT 2C ) receptors are linked to some of the adverse motivational effects corresponding to avoidance behaviors (Roberts et al., 2020), but 5-HT 2A receptors have also been reported to be intimately involved in the modulation of negative emotions, such as anxiety, depression, and pain (Baldwin & Rudge, 1995;Sommer, 2009). For instance, higher pessimistic behavior in depressive patients was related to higher frontal 5-HT 2A receptor binding as detected by positron emission tomography (PET) (Meyer et al., 2003). ...
The tendency to avoid punishment, called behavioral inhibition system, is an essential aspect of motivational behavior. Behavioral inhibition system is related to negative affect, such as anxiety, depression and pain, but its neural basis has not yet been clarified. To clarify the association between individual variations in behavioral inhibition system and brain 5-HT 2A receptor availability and specify which brain networks were involved in healthy male subjects, using [ ¹⁸ F]altanserin positron emission tomography and resting-state functional magnetic resonance imaging. Behavioral inhibition system score negatively correlated with 5-HT 2A receptor availability in anterior cingulate cortex. A statistical model indicated that the behavioral inhibition system score was associated with 5-HT 2A receptor availability, which was mediated by the functional connectivity between anterior cingulate cortex and left middle frontal gyrus, both of which involved in the cognitive control of negative information processing. Individuals with high behavioral inhibition system displays low 5-HT 2A receptor availability in anterior cingulate cortex and this cognitive control network links with prefrontal-cingulate integrity. These findings have implications for underlying the serotonergic basis of physiologies in aversion.
... • Liver regeneration 75 • Glucose homeostasis 76 • Pain perception and response [77][78][79] • Lipid metabolism and browning of white adipose tissue 60,76,80,81 The neurotransmitter serotonin ...
Serotonin gilt als Hauptangriffsstelle gängiger Antidepressiva bei schweren Depressionen, wie bspw. selektive Serotonin-Wiederaufnahmehemmer (SSRI), und -Enhancer (SSRE). Es bleibt offen, ob SSRI / E ausschließlich über die Manipulation des Serotoninspiegels wirken, oder ob alternative Signalwege daran beteiligt sind. Ansatzpunkte hierfür sind beispielsweise die neurotrophen Signalwege (spez. Brain derived neurotophic factor, BDNF) oder die Hypothalamus-Hypophysen-Nebennieren- (HPA) – Signalwege des Stressachsensystems. Ebenfalls wurde in Nagetiermodellen beobachtet, dass mit der Dysregulation des zentralen Serotoninsystems bei schweren Depressionen, ein Rückgang der Neurogenese im Gyrus dentatus des Hippocampus einhergeht. Ziel dieser Arbeit war, das Zusammenspiel von Serotonin, BDNF, adulter Neurogenese und der Stressachse zu untersuchen. Zentrum der Studien ist ein Mausmodell, mit einer genetischen Depletion des zentralen Serotonin-synthetisierenden Enzyms Tryptophanhydroxylase 2 (sog. Tph2-/- Mäuse). Es wurden die physiologische Reaktionen auf die Behandlung mit gängigen Antidepressiva abhängig von der Abwesenheit von Serotonin untersucht, um mögliche alternative Signalwege aufzeigen zu können. Die bekannte Zunahme der Neurogenese nach SSRI/SSRE-Behandlung wurde in Wildtyptieren beobachtet, während die Therapie in Tph2-/- Mäusen keine direkte kausale Wirkung zeigte. Im Gegensatz dazu waren die BDNF-Spiegel in depressionsrelevanten Hirnregionen in Tph2-/- Mäusen nach SSRI, signifikant verringert. Auch zeigen die Studien eine neurobiologische Relevanz von Serotonin im ZNS, bei den antidepressiven Mechanismen einer Elektrokonvulsiven Krampftherapie. Ebenfalls deuten erhöhte Neurogeneseraten bei lebenslanger Abwesenheit von Serotonin im ZNS, Therapiemethoden-unabhängig, möglicherweise auf eine modulierte Stressreaktion hin. Untersuchungen der Parameter des HPA-Stressachsensystems, wiesen auf einen grundlegend veränderten Stresshormonspiegel in Tph2-/- Mäusen hin.
... /2021 The serotonergic system is supposed to be associated with behavioral inhibition in the human brain (Cloninger, 1987). Notably, serotonin 2A (5-HT 2A ) receptor has been reported to be intimately involved in the modulation of negative emotions, such as anxiety, depression, and pain (Baldwin & Rudge, 1995;Sommer, 2009). According to Gray's concept of BIS, harm avoidance is characterized as excessive anxiety and fear, but the evidences for the role of serotonergic system in harm avoidance, so far remains inconclusive. ...
Rationale The tendency to avoid punishment, called behavioral inhibition system (BIS), is an essential aspect of motivational behavior. BIS is related to negative affect, such as anxiety, depression and pain, but its neural basis has not yet been clarified. Objectives To clarify the association between individual variations in BIS and brain 5- HT 2A receptor availability and specify which brain networks were involved in healthy male subjects, using [ 18 F]altanserin positron emission tomography (PET) and resting- state functional magnetic resonance imaging (rs-fMRI). Result s BIS score negatively correlated with 5-HT 2A receptor availability in anterior cingulate cortex (ACC). A statistical model indicated that the BIS score was associated with 5-HT 2A receptor availability, which was mediated by the functional connectivity between ACC and left middle frontal gyrus, both of which involved in the cognitive control of negative information processing. Conclusions Individuals with high BIS displays low 5-HT 2A receptor availability in ACC and this cognitive control network links with prefrontal- cingulate integrity. These findings have implications for underlying the serotonergic basis of physiologies in aversion.
... Serotonin (5-hydroxytryptamine; 5-HT) is a small-molecule neurotransmitter, which is known to be involved in the descending pain inhibitory system [21,22]. It is known to be synthesized in the rostro ventromedial medulla (RVM), and axons of serotonergic neurons are present in the descending pathway to the spinal cord. ...
Oxaliplatin is a platinum derivative chemotherapeutic drug widely used against cancers, but even a single treatment can induce a severe allodynia that requires treatment interruption and dose diminution. The rhizome of Zingiber officinale roscoe (Z. officinale, ginger), has been widely used in traditional medicine to treat various diseases causing pain; however, its effect against oxaliplatin-induced neuropathic pain has never been assessed. In mice, a single oxaliplatin (6 mg/kg, i.p.) treatment induced significant cold and mechanical allodynia. Cold and mechanical allodynia were assessed by acetone drop and von Frey filament tests, respectively. Water extracts of Z. officinale (100, 300, and 500 mg/kg, p.o.) significantly attenuated both cold and mechanical allodynia induced by oxaliplatin. Intrathecal pre-treatment with the antagonist 5-HT1A (NAN-190, i.t., 1 μg), but not with the antagonist 5-HT2A (ketanserin, i.t., 1 μg), significantly blocked the analgesic effect of Z. officinale against both cold and mechanical allodynia. However, 5-HT3 antagonist (MDL-72222, i.t., 15 μg) administration only blocked the anti-allodynic effect of Z. officinale against cold allodynia. Real-time PCR analysis demonstrated that Z. officinale significantly increased the mRNA expression of the spinal 5-HT1A receptor that was downregulated after oxaliplatin injection. These results suggest that Z. officinale may be a viable treatment option for oxaliplatin-induced neuropathic pain.
... Serotonin (5-HT, chemically identified as 5-hydroxytryptamine) is an endogenous monoamine neurotransmitter that is involved in the central nervous system (CNS), regulates lots of brain functions (Sengupta et al. 2017) and it is associated with pain, sleep, and wakefulness; perception; behavior modulation; cognition; mood; aggression; anxiety; and neurological and psychiatric diseases (Forero et al. 2020;Leopoldo et al. 2011;Markov and Goldman 2006;Sommer 2010). It is also the focus of interest for anesthesia studies (Dringenberg 2000;McCardle and Gartside 2012;Zhang et al. 2003). ...
Although several pieces of evidence have indicated the ability of the serotonin-7 receptor (5-HTR7) to modulate N-methyl-D-aspartate receptor (NMDAR) activation, the possible impact on ketamine anesthesia has not been examined directly. The purpose of the present study is thus to investigate the possible role of the 5-HTR7 in ketamine anesthesia using a 5-HTR7 agonist and/or antagonist. The influence of a 5-HTR7 agonist/antagonist on ketamine anesthesia for behavioral impact was assessed by testing potential anesthetic parameters. Its functional impact was assessed by mRNA expression with real-time PCR and immunostaining in the hippocampus and prefrontal cortex of mice. Two different doses of ketamine—high and low—were administered to induce anesthesia. In the high-dose ketamine-applied group in particular, the administration of both the 5-HTR7 agonist and antagonist intensified the anesthetic effect of ketamine. The reflection of the change in anesthesia parameters to 5-HTR7 expression was observed as an increase in the hippocampus and a decrease in the prefrontal cortex in the anesthetized groups by stimulation of 5-HTR7. It is noteworthy that the results of NMDAR expressions are parallel to the results of the 5-HTR7 expressions of both the hippocampus and the prefrontal cortex. The 5-HTR7 may play a role in ketamine anesthesia. It may act through NMDAR in ketamine anesthesia, depending on the parallelism between both receptors.
... We observed that DIO leads to decrease in the levels of tryptophan and serotonin in the brain (Table 1). In obesity, reduced serotonin levels can cause disruption to the effect of satiety and the development of hyperphagia [72][73][74][75][76]. We found that the DDW-normalized serotonin and tryptophan levels in the brain impaired by DIO (Table 1). ...
In this study, we present the potential application of deuterium-depleted water (DDW) for the prevention and adjuvant treatment of obesity in rats. We tested the hypothesis that DDW can alleviate diet-induced obesity (DIO) and its associated metabolic impairments. Rats fed a high-fat diet had an increased body weight index (BWI), glucose concentration, and level of certain proinflammatory cytokines; decreased levels of insulin in the serum; decreased tryptophan and serotonin in the brain, and a decreased concentration of some heavy metals in the liver. Drinking DDW at a concentration of 10 ppm deuterium/protium (D/H) ad libitum for 3 weeks restored the BWI, glucose (serum), tryptophan (brain), and serotonin (brain) levels and concentration of Zn in the liver in the DIO animals to those of the controls. The levels of proinflammatory cytokines (IL-1β, IL-6, IFNγ) and anti-inflammatory TNFα were decreased in DIO rats, while anti-inflammatory cytokine (IL-4, IL-10) levels remained at the control levels, which is indicative of a pathophysiological syndrome. In contrast, in groups of rats treated with DDW, a significant increase in anti-inflammatory (IL-4, IL-10) and proinflammatory cytokines (IFNγ) was observed. This finding indicates a reduction in systemic inflammation in obese animals treated with DDW. Similarly, the high-fat diet caused an increased level of oxidative stress products, which was accompanied by decreased activity of both superoxide dismutase and catalase, whereas the administration of DDW decreased the level of oxidative stress and enhanced antioxidant enzyme activities.
... In particular, serotonin (5-HT) disturbances have been frequently implicated in both migraine and eating disorders (Brewerton, 1995;D'Andrea et al., 2009D'Andrea et al., , 2012. This is not surprising as disturbances in 5-HT are hypothesized to play a role in appetite dysregulation (Blundell, 1984;Blundell, Lawton, & Halford, 1995;Voigt & Fink, 2015), anxiety (Schinka, Busch, & Robichaux-Keene, 2004), as well as pain perception and regulation (Lindstedt et al., 2011;Sommer, 2010). Considerable evidence suggests that such disturbances in 5-HT are present in patients with eating disorders and persist after recovery (Steiger, 2004). ...
Although less recognized than other disruptions in functioning, individuals with chronic pain frequently display disturbances in eating associated with pain, changes in appetite, medication side effects, and prescribed elimination diets. Not only may changes in nutritional status and weight increase the risk for the development of an eating disorder, there is evidence that individuals with chronic pain and those with eating disorders share similar vulnerabilities that place them at risk for both conditions, as well as their comorbidity. This review will describe the temperamental, behavioral, and neurobiological risk factors linking chronic pain and eating disorders. We propose that these risk factors may reflect central sensitization, a condition of over-activation of the central nervous system that increases sensitivity to internal and external conditions. To manage high levels of sensitivity, individuals may develop unique patterns of behavioral avoidance, pain behaviors and/or restrictive eating. Using the framework of central sensitization, this review will discuss relevant assessment and intervention strategies to address sensitivity in eating disorders and chronic pain.
... Analgesia is a complex process involving many neurochemicals at central and peripheral pathways. 17,18 Efficacy and safety problems with current analgesics lead researchers to develop drugs targeting other systems that play a role in the pain control process. In this context, one of the salient pathways is the Larginine/NO (nitric oxide)-cGMP (cyclic guanosine monophosphate)/ATP sensitive K + (KATP) channel pathway. ...
Ferulic acid is a bioactive phenolic compound that is found intensely in plants used in traditional medicine such as Ferula assa-foetida L.. The analgesic effect of various medicinal plants has been associated with its constituent, ferulic acid. However, there are limited number of studies about mechanism of its analgesic action. The aim of this study was to evaluate the contribution of NO/cGMP/PKG/KATP pathway in peripheral analgesic effect of ferulic acid by acetic acid-induced (0.6 % acetic acid, i.p.) writhing test in mice. For this purpose, following the determination of the analgesic effect of ferulic acid at the doses of 20, 40, 80 and 160 mg/kg (p.o.), NO precursor 100 mg/kg L-arginine (i.p.), nitric oxide synthase inhibitor 30 mg/kg L-NAME (i.p.), guanylate cyclase inhibitor 20 mg/kg methylene blue (i.p.) and KATP channel blocker 10 mg/kg glibenclamide (i.p.) were administered separately prior to ferulic acid treatment at the dose effective for clarifying the mechanism of action. Reduction in the number of writhes was evaluated as peripheral analgesic activity. Ferulic acid significantly decreased the number of writhes at the doses of 40, 80 and 160 mg/kg. 80 mg/kg ferulic acid and 100 mg/kg acetyl salicylic acid demonstrated similar efficacy. L-arginine and methylene blue relatively reversed the reduction in the number of writhes caused by ferulic acid at 80 mg/kg, whereas L-NAME did not. Glibenclamide pre-treatment significantly inhibited analgesic effect induced by ferulic acid. The results of the study indicate that ferulic acid has peripheral analgesic activity and it is mediated predominantly by activation of KATP channels and partially by cGMP. In conclusion, findings of this study demonstrate that ferulic acid may provide an advantage in KATP channel-targeted management of pain.
... Rodent models of nociception demonstrate altered 5-HT and NE system function, and certain antidepressants enhance 5-HT and NE transmission. Both 5-HT and NE play a role in the descending inhibitory pathway, formed by projections descending from the brainstem or the midbrain to the spinal cord, which normally suppress painful inputs; thus, malfunction of these neurotransmitters may play a role in somatic syndromes, such as fibromyalgia and chronic headache (21). ...
Somatic symptoms include a range of physical experiences, such as pain, muscle tension, body shaking, difficulty in breathing, heart palpitation, blushing, fatigue, and sweating. Somatic symptoms are common in major depressive disorder (MDD), anxiety disorders, and some other psychiatric disorders. However, the etiology of somatic symptoms remains unclear. Somatic symptoms could be a response to emotional distress in patients with those psychiatric conditions. Increasing evidence supports the role of aberrant serotoninergic and noradrenergic neurotransmission in somatic symptoms. The physiological alterations underlying diminished serotonin (5-HT) and norepinephrine (NE) signaling may contribute to impaired signal transduction, reduced 5-HT, or NE release from terminals of presynaptic neurons, and result in alternations in function and/or number of receptors and changes in intracellular signal processing. Multiple resources of data support each of these mechanisms. Animal models have shown physiological responses, similar to somatic symptoms seen in psychiatric patients, after manipulations of 5-HT and NE neurotransmission. Human genetic studies have identified many single-nucleotide polymorphisms risk loci associated with somatic symptoms. Several neuroimaging findings support that somatic symptoms are possibly associated with a state of reduced receptor binding. This narrative literature review aimed to discuss the involvement of serotonergic and noradrenergic systems in the pathophysiology of somatic symptoms. Future research combining neuroimaging techniques and genetic analysis to further elucidate the biological mechanisms of somatic symptoms and to develop novel treatment strategies is needed.
... However, an intermittent release of serotonin at higher concentration may induce headache attack by binding to 5-HT2A receptors. [19] Generalized body pain was the chief complaint in 7% of patients. Generalized body pain was one of the accompanying features in some case reports in the literature. ...
Introduction
Serotonin syndrome (SS) is a drug-induced clinical syndrome that results from the excess intrasynaptic concentration of serotonin. Prospective observations are limited for SS.
Methods
We prospectively recruited 45 consecutive adult patients (>18 years) fulfilling the Hunter's criteria for SS. All patients were subjected to a detailed clinical history and examinations. Patients were subjected to appropriate investigations to find out the other causes. The causation of SS to serotonergic drugs was assessed according to Naranjo adverse drug reaction probability scale.
Results
The mean age was 37.3 years (range: 18–59 years). Sixty-two percent of patients were male. There were 15 different underlying clinical syndromes for which serotonergic drugs were started. Psychiatry conditions (36%) and cough/respiratory tract infection (16%) were the two most common clinical conditions for starting serotonergic drugs. We noted 49 different symptoms and physical signs. Overall, tremor (78%) and dizziness (47%) were the two most common symptoms. Headache (16%) and dizziness (16%) were the two most common initial (or first) symptoms. However, gait difficulty and febrile encephalopathy were the two most common reasons to visit the hospital. We noted 18 different drugs causing SS. Thirty-eight percent of patients received single serotonergic agent antidepressants, pain medicines and cough syrups were other important drugs causing SS.
Conclusions
This study represents the largest clinic-based study on SS. SS is not rare in clinical practice. However, various aspects of this syndrome are still to be determined. All patients on serotonergic drugs should be physically examined for the presence of SS on the development of any new symptom.
... Other mediators (e.g. 5-HT, NGF) can sensitize the peripheral nociceptors inducing neuropathic pain (Sommer 2010), or can modify the innervation pattern of salivary glands resulting their atrophy (Kerr et al. 1996) and dry mouth symptoms (xerostomia) as a consequence of reduced saliva flow after 7 days of PEF treatment (Kelentey et al. 1996, Kerr et al. 1996. ...
Pefloxacin is a second-generation fluoroquinolone antibiotic. Besides its advantageous characteristics, side effects including the hypofunction of salivary glands, decreased saliva production, and peripheral neuropathy were observed during the administration of pefloxacin. The aim of this study was to investigate the changes in the number of serotonergic immunoreactive fibers and mast cells after pefloxacin treatment in the parotid and sublingual glands of rats to detect the possible neurotoxic effect of pefloxacin. The adult female rats were treated with intraperitoneal (i.p.) injection of pefloxacin for three or seven days (at a concentration of 20 mg/100g body weight) and the serotonergic innervation pattern along with the change in mast cell number were evaluated by using histochemistry and immunohistochemistry in the parotid and sublingual glands. We found that a three-day treatment significantly increased the number of immunoreactive serotonergic nerve fibers, but after a seven-day treatment the number of serotonin positive nerve fibers decreased almost to values of the control group. The alteration of mast cell number was parallel with the changes of the serotonin positive fibers during the treatment. These results suggest that pefloxacin treatment can modify the finely controlled communication between the immune- and the peripheral nervous systems, resulting neurogenic inflammatory process. The background of this process is the altered serotonergic innervation and the increased number of activated mast cells releasing different mediators for example histamine, which can finally lead to reduced number of serotonin positive nerve fibers after a seven-day treatment of pefloxacin leading to atrophy and hypofunction of the salivary glands.
... The serotonergic pathway, one of the main inhibitory mechanisms in the CNS, may also be functionally important in facilitating peripherally mediated visceral pain [4]. Most antidepressants gradually increase serotonin level in the brain. ...
... However, further studies targeting the other serotonin 5-HT receptors and noradrenergic receptor subtypes such as β 2 and α 1 adrenoceptors (Barrot et al., 2009;Wei et al., 2016) which are involved in allodynia process should be perform to make clear this speculative claim. Moreover, descending fibers are known to inhibit pain transmission through hyperpolarizing afferent sensory neurons by using serotonin and noradrenaline along with endogen opioids, the main inhibitory mediators (Marks et al., 2009;Sommer, 2010). Based on this clue, it was investigated whether opioid system mediates the effect of valnoctamide, by using a non-selective opioid receptor antagonist naloxone. ...
... [13] Many studies demonstrated that serotonin (5-hydroxytryptamine ) and a number of serotonergic receptor agonists have antinociception effect, these results suggest that serotonergic antinociceptive mechanisms are similar to the opioid system. [14,15] Furthermore, it was demonstrated that adrenergic system has a major role in pain perception in multiple parts of the brain. [16] Previous study showed that venlafaxine interaction with opioidergic system and mimics opioids like peptides effects. ...
Chronic abuse of opiates induces dependency, but the neurobiological mechanisms of this event remain unclear. The aim of this study was to evaluate the effects of intracerebroventricular of venlafaxine on the morphine dependence and pain perception.
A total of 80 adult male rats were divided into two major groups: (1) 40 of them was divided into groups of positive control (morphine dependent) negative control (received saline) and morphine dependent groups under treatment by central administration of venlafaxine at various dosages (25, 50, or 100 μg), after drug treatment total withdrawal index (TWI), latency time of withdrawal syndrome expression and blood cortisol as marker of anxiety were measured and compared with positive control and negative control. (2) Forty rats were grouped in control; indometacin treated (5 mg/kg) and grouped which received central administration of venlafaxine at three doses (25, 50, or 100 μg) and then pain perception and expression was assessed in the writhing test (acetic acid induced abdominal constriction), tail flick, and hot plate test.
Central administration of three doses (25, 50, or 100 μg,) of venlafaxine attenuates TWI to 47 ± 1.2, 38 ± 1.5, and 23 ± 1.1 and decrease blood cortisol level to 14 ± 1, 13.75 ± 0.5, and 12.5 ± 0.8, this decreases was significant in comparison with the positive control group (P < 0.05). Central administration of venlafaxine at mentioned doses significantly attenuates pain response with 37%, 24%, and 20% inhibition in writhing test, 69%, 34%, and 23% inhibition in hot plate test, and 29%, 23%, and 15% inhibition in tail flick test in comparison with control group (P < 0.05).
This study suggested that central administration of venlafaxine attenuated morphine withdrawal index and can be effective in modulation of pain that was induced by morphine dependency.
... A reduction in 5-HT neuronal activity or 5-HT release may not only result in an elimination of locomotor activity ), but may also contribute to anesthesia (Roizen et al. 1978;Zhang et al. 2003a). 5-HT controls pain pathways at brainstem level (Sommer 2010). Furthermore, it is essential for synaptic plasticity required for memory formation (Cassel 2010). ...
J. Neurochem. (2011) 119 , 419–446.
Abstract
Anesthesia describes a complex state composed of immobility, amnesia, hypnosis (sleep or loss of consciousness), analgesia, and muscle relaxation. Bottom‐up approaches explain anesthesia by an interaction of the anesthetic with receptor proteins in the brain, whereas top‐down approaches consider predominantly cortical and thalamic network activity and connectivity. Both approaches have a number of explanatory gaps and as yet no unifying view has emerged. In addition to a direct interaction with primary target receptor proteins, general anesthetics have massive effects on neurotransmitter activity in the brain. They can change basal transmitter levels by interacting with neuronal activity, transmitter synthesis, release, reuptake and metabolism. By that way, they can affect a great number of neurotransmitter systems and receptors. Here, we review how different general anesthetics affect extracellular activity of neurotransmitters in the brain during induction, maintenance, and emergence from anesthesia and which functional consequences this may have. Commonalities and differences between different groups of anesthetics in their action on neurotransmitter activity are discussed. We also review how general anesthetics affect the response dynamics of the neurotransmitter systems after sensory stimulation. More than 30 years of research have now yielded a complex picture of the effects of general anesthetics on brain neurotransmitter basal activity and response dynamics. It is suggested that analyzing the effects on neurotransmitter activity is the logical next step after protein interactions in a bottom‐up analysis of anesthetic action in the brain on the way to a unifying view of anesthesia.
Adolescent alcohol use can permanently alter brain function and lead to poor health outcomes in adulthood. Emerging evidence suggests that alcohol use can predispose individuals to pain disorders or exacerbate existing pain conditions, but the underlying neural mechanisms are currently unknown. Here we report that mice exposed to adolescent intermittent access to ethanol (AIE) exhibit increased pain sensitivity and depressive-like behaviors that persist for several weeks after alcohol cessation and are accompanied by elevated CD68 expression in microglia and reduced numbers of serotonin (5-HT)-expressing neurons in the dorsal raphe nucleus (DRN). 5-HT expression was also reduced in the thalamus, anterior cingulate cortex (ACC) and amygdala as well as the lumbar dorsal horn of the spinal cord. We then found that chronic minocycline administration after AIE alleviated hyperalgesia and social deficits, while chemogenetic activation of microglia in the DRN of ethanol-naïve mice reproduced the effects of AIE on pain and social behavior. Chemogenetic activation of microglia also reduced tryptophan hydroxylase 2 (Tph2) expression and was negatively correlated with the number of 5-HT-immunoreactive cells in the DRN. Taken together, these results indicate that microglial activation in the DRN may be a primary driver of pain, negative affect, and 5-HT depletion after AIE.
Vortioxetine is a multimodal antidepressant drug that affects several brain neurochemicals and has the potential to induce various pharmacological effects on the central nervous system. Therefore, we investigated the centrally mediated analgesic efficacy of this drug and the mechanisms underlying this effect. Analgesic activity of vortioxetine (5, 10 and 20 mg/kg, p.o.) was examined by tail-clip, tail-immersion and hot-plate tests. Motor performance of animals was evaluated using Rota-rod device. Time course measurements (30–180 min) showed that vortioxetine (10 and 20 mg/kg) administrations significantly increased the response latency, percent maximum possible effect and area under the curve values in all of the nociceptive tests. These data pointed out the analgesic effect of vortioxetine on central pathways carrying acute thermal and mechanical nociceptive stimuli. Vortioxetine did not alter the motor coordination of mice indicating that the analgesic activity of this drug was specific. In mechanistic studies, pre-treatments with p-chlorophenylalanine (serotonin-synthesis inhibitor), NAN-190 (serotonin 5-HT1A receptor antagonist), α-methyl-para-tyrosine (catecholamine-synthesis inhibitor), phentolamine (non-selective α-adrenoceptor blocker), and naloxone (non-selective opioid receptor blocker) antagonised the vortioxetine-induced analgesia. Obtained findings indicated that vortioxetine-induced analgesia is mediated by 5-HT1A serotonergic, α-adrenergic and opioidergic receptors, and contributions of central serotonergic and catecholaminergic neurotransmissions are critical for this effect.
The neurotransmitter serotonin, involved in the regulation of pain and emotion, is critically regulated by the 5‐HT 1A autoreceptor and the serotonin transporter (5-HTT). Polymorphisms of these genes affect mood and endogenous pain modulation, both demonstrated to be altered in fibromyalgia subjects (FMS). Here, we tested the effects of genetic variants of the 5‐HT 1A receptor (CC/G-carriers) and 5-HTT (high/intermediate/low expression) on mood, pain sensitivity, cerebral processing of evoked pain (functional MRI) and concentrations of GABA and glutamate (MR spectroscopy) in rostral anterior cingulate cortex (rACC) and thalamus in FMS and healthy controls (HC). Interactions between serotonin-relevant genes were found in affective characteristics, with genetically inferred high serotonergic signalling (5-HT 1A CC/5-HTT high genotypes) being more favourable across groups. Additionally, 5‐HT 1A CC homozygotes displayed higher pain thresholds than G-carriers in HC but not in FMS. Cerebral processing of evoked pressure pain differed between groups in thalamus with HC showing more deactivation than FMS, but was not influenced by serotonin-relevant genotypes. In thalamus, we observed a 5‐HT 1A -by-5-HTT and group-by-5-HTT interaction in GABA concentrations, with the 5-HTT high expressing genotype differing between groups and 5‐HT 1A genotypes. No significant effects were seen for glutamate or in rACC. To our knowledge, this is the first report of this serotonergic gene-to-gene interaction associated with mood, both among FMS (depression) and across groups (anxiety). Additionally, our findings provide evidence of an association between the serotonergic system and thalamic GABA concentrations, with individuals possessing genetically inferred high serotonergic signalling exhibiting the highest GABA concentrations, possibly enhancing GABAergic inhibitory effects via 5-HT.
Effective treatment for many pain disorders is still lacking, which is due to the complexity of pain in general and of the underlying pathology of many pain syndromes in particular. This results in the majority of investigational analgesic drugs failing to reach registration; either due to lack of efficacy, or due to the drug's adverse effect profile. To increase the number of analgesics that reach the patient, it is essential to carefully and rationally plan the clinical development program. By including proof-of-mechanism (PoM) and/or proof-of-concept (PoC) methods in early-phase clinical drug studies, the analgesic drug developer will be better informed regarding the key characteristics of the studied drug, which will aid in making crucial decisions during the development process. Here, we describe the top 10 currently most developed analgesic drug classes, link them mechanistically to appropriate methods to demonstrate PoM and PoC in early-phase clinical trials, and include pros and cons of each of the methods described. Lastly, we discuss how each analgesic drug class requires a tailored experimental approach for proper evaluation of PoM and PoC, and how this can contribute to an efficient and question-based approach in early-phase analgesic drug research.
Introduction:
Serotonin (5-HT) plays a role in migraine pathophysiology, but whether brain 5-HT is involved in the conversion from episodic to chronic migraine is unknown. Here, we investigated brain 5-HT levels, as indexed by 5-HT4 receptor binding, in chronic migraine patients and evaluated whether these were associated with migraine frequency.
Methods:
Sixteen chronic migraine patients underwent a dynamic PET scan after injection of [11C]SB207145, a specific 5-HT4 receptor radioligand. Data from 15 episodic migraine patients and 16 controls were included for comparison. Quantification of 5-HT4 receptor binding was used as a proxy for brain 5-HT levels, since 5-HT4 receptor binding is inversely related to brain 5-HT levels.
Results:
Chronic migraine patients had 9.1% (95% CI: [-17%; -1.0%]) lower 5-HT4 receptor binding compared to controls ( p = 0.039). There was no difference in 5-HT4 receptor binding between chronic and episodic migraine patients ( p = 0.48) and no association between number of monthly migraine days and 5-HT4 receptor binding (slope estimate 0.003, 95% CI: [-0.004; 0.715], p = 0.39).
Conclusion:
The finding of low 5-HT4 receptor binding suggests that cerebral levels of 5-HT are elevated in chronic migraine patients. This is in line with observations made in patients with episodic migraine. Elevated brain 5-HT levels may thus be an inherent trait of the migraine brain rather than a risk factor for conversion from episodic to chronic migraine.
Plant cannabinoids have been used historically as a therapeutic agent in some folk medicine for the treatment of headache, fibromyalgia, and irritable bowel and related conditions in which serotonergic pathways are considered to play a crucial role in pathogenesis and treatment modalities. Serotonergic system has important modulatory role in acute and chronic pain conditions. The analgesic efficacy of cannabinoids in acute and chronic pain appear to be mediated, at least in part, through the regulation of the serotonergic system. In this chapter, we review the interaction between cannabinoids and serotonergic system in the peripheral, spinal and supraspinal sites with special emphasis on serotonin in central sites by which cannabinoid CB1 receptor activation reinforce descending serotonergic pathways to produce antinociceptive effects.
The serotonin transporter (5-HTT) plays a key-role in the control of serotoninergic neurotransmission and is the target of some antidepressants. Possible adaptive changes in brain 5-HT2A receptors were investigated in knock-out mice that do not express the 5-HTT. Autoradiographic labeling of these receptors by the selective antagonist [3H]MDL 100,907 and saturation experiments with cortical membranes revealed: (1) a new localization of these receptors in the external field of striatum (possibly in striosomes); (2) regional variations in adaptive changes in the density of 5-HT2A receptors in 5-HTT−/− mutants (−30–40% in the claustrum, cerebral cortex and lateral striatum; no significant change in the striatum core) as compared to wild-type mice.
Serotonin (5-HT) is a key neurotransmitter in the central nervous system. It is suggested that serotonergic dysfunction may be involved in the pathophysiology of fibromyalgia syndrome (FS). In this study, we aimed to investigate T102C polymorphism of the 5-HT2A receptor gene in FS. Fifty-eight patients with FS and 58 unrelated healthy volunteer controls were included in the study. In both groups, the C/C, C/T, and T/T genotypes of the 5-HT gene were represented in 31% (22.4% in controls), 50% (53.4%), and 19% (24.1%), respectively. The 5-HT2A receptor gene polymorphism results were not significantly different between patients and controls (chi squared test, P>0.05). There was a significant correlation between patients with the T/T genotype and the subgroup according to the SCL-90-R test, (analysis of variance, PConclusion. T102C polymorphism of the 5-HT2A receptor gene is not associated with the etiology of FS. Our results also indicate that the T/T genotype may be responsible for psychiatric symptoms of FS.
Objective
To systematically review the efficacy of treatment of fibromyalgia syndrome (FMS) with antidepressants.Methods
We screened Medline, PsychINFO, SCOPUS, and the Cochrane Library databases (through October 2007) and the reference sections of original studies, meta-analyses, and evidence-based guidelines and recommendations on antidepressants in FMS. Randomized controlled trials (RCTs) on the treatment of FMS with antidepressants were analyzed. Inclusion criteria, study characteristics, quality, and all outcome measures were investigated.ResultsTwenty-six of 167 studies were included. The main outcome variables reviewed were pain, fatigue, sleep, depressiveness, and quality of life. Amitriptyline, studied in 13 RCTs, was efficient in reducing pain with a moderate magnitude of benefit (pain reduction by a mean of 26%, improvement in quality of life by 30%). Selective serotonin reuptake inhibitors (SSRIs) were studied in 12 RCTs, which also showed positive results, except for 2 studies on citalopram and 1 on paroxetine. Three RCTs on the dual serotonin and noradrenaline reuptake inhibitors (SNRIs) duloxetine and milnacipran and 1 of the 2 RCTs using the monoamine oxidase inhibitor moclobemide reported a positive result. The longest study duration was 12 weeks.Conclusion
Amitriptyline 25–50 mg/day reduces pain, fatigue, and depressiveness in patients with FMS and improves sleep and quality of life. Most SSRIs and the SNRIs duloxetine and milnacipran are probably also effective. Short-term treatment of patients with FMS using amitriptyline or another of the antidepressants that were effective in RCTs can be recommended. Data on long-term efficacy are lacking.
Fibromyalgia syndrome (FMS) is a chronic condition characterized by widespread pain, tender points, fatigue, and sleep disturbance. FMS leads to high disability levels, poor quality of life, and extensive use of medical care. Effective pharmacological treatment options are rare, and treatment effects are often of limited duration. Duloxetine is a new selective serotonin and norepinephrine reuptake inhibitor that is licensed for the treatment of pain in diabetic neuropathy. So far two randomized, placebo-controlled trials have investigated the short-term safety and efficacy of duloxetine 60 mg/day and 120 mg/day in patients suffering from FMS over a period of 12 weeks. Both dosages were superior to placebo in pain relief, and improvement in quality of life and depressive symptoms. The analgesic effect was largely independent of the antidepressant action of duloxetine. The higher dose of 120 mg/day further reduced the tender point count and elevated the tender point pain thresholds. Only mild to moderate adverse effects were reported. Duloxetine 60 mg/day and 120 mg/day has proven to be beneficial in the treatment of FMS symptoms. As true for other antidepressants further studies are needed to assess the long-term efficacy and safety of duloxetine as an additional pharmacological treatment option in FMS.
The 5-hydroxytryptamine (5-HT) has been implicated in migraine pathophysiology for the past 50 years. A low central 5-HT disposition associated with an increase in 5-HT release during attack is the most convincing change of 5-HT metabolism implicated in migraine. Peripheral studies on plasma/platelet have not generally shown low 5-HT levels. Studies on 5-HT reactivity showed hypersensitivity, also expressed as reduced tachyphylaxis (habituation), which successively was evidenced as the most characteristic marker of an altered sensory neurotransmission. Even the gender and seasonal variations of 5-HT parameters seem to agree with a low 5-HT turnover with receptoral hypersensitivity. The interpretation of the effects of some serotonergic drugs and recent neuroimaging studies give major evidence for this cascade of events. Although the exact mechanism that links abnormal 5-HT neurotransmission to the manifestation of head pain has yet to be fully understood, a deficit on 5-HT descending pain inhibitory system is still probably today the most implicated in migraine pathophysiology. This short review focuses and discusses the alteration of peripheral and central 5-HT parameters in migraine patients.
Although 5-HT is clearly involved in spinal analgesia, its mode of action remains obscure, perhaps because it has multiple and often opposing effects mediated by its multiple receptor subtypes. This investigation uses selective agonists and antagonists directed at the most recently defined class of 5-HT receptors (5-HT3 receptors) in behavioral and electrophysiological studies of nociception in the spinal cord of rodents. The results demonstrate uniformly inhibitory effects of a selective 5-HT3 agonist on responses to noxious stimuli. Intrathecally administered 2-methyl 5-HT produced dose-dependent antinociception in the tail-flick test and inhibited behaviors elicited by intrathecally administered agonists for excitatory amino acid and neurokinin receptors, namely NMDA and substance P (SP). All 20 dorsal horn neurons we examined, which projected to the brain and responded to both noxious stimuli and NMDA, were inhibited in a current-related manner by this 5-HT3 agonist applied iontophoretically. Both the behavioral and electrophysiological effects were blocked not only by the 5-HT3 antagonists zacopride and ICS 205-930, but also by antagonists to the inhibitory amino acid GABA. Therefore, 5-HT via an action at 5-HT3 receptors may evoked release of GABA, which may in turn inhibit nociceptive transmission at a site postsynaptic to terminals of primary afferent fibers. If the descending serotonergic analgesic system in humans operates similarly, understanding it may enable the development of new nonopioid, nonaddictive analgesics.
To develop criteria for the classification of fibromyalgia, we studied 558 consecutive patients: 293 patients with fibromyalgia and 265 control patients. Interviews and examinations were performed by trained, blinded assessors. Control patients for the group with primary fibromyalgia were matched for age and sex, and limited to patients with disorders that could be confused with primary fibromyalgia. Control patients for the group with secondary-concomitant fibromyalgia were matched for age, sex, and concomitant rheumatic disorders. Widespread pain (axial plus upper and lower segment plus left- and right-sided pain) was found in 97.6% of all patients with fibromyalgia and in 69.1% of all control patients. The combination of widespread pain and mild or greater tenderness in greater than or equal to 11 of 18 tender point sites yielded a sensitivity of 88.4% and a specificity of 81.1%. Primary fibromyalgia patients and secondary-concomitant fibromyalgia patients did not differ statistically in any major study variable, and the criteria performed equally well in patients with and those without concomitant rheumatic conditions. The newly proposed criteria for the classification of fibromyalgia are 1) widespread pain in combination with 2) tenderness at 11 or more of the 18 specific tender point sites. No exclusions are made for the presence of concomitant radiographic or laboratory abnormalities. At the diagnostic or classification level, the distinction between primary fibromyalgia and secondary-concomitant fibromyalgia (as defined in the text) is abandoned.
The effect of the selective serotonin reuptake inhibitor paroxetine on diabetic neuropathy symptoms was examined in comparison to imipramine and placebo in a randomised, double-blind, cross-over study. Paroxetine was given as a fixed dose of 40 mg/day, while the dose of imipramine was adjusted to yield optimal plasma levels of imipramine plus desipramine of 400–600 nM.Paroxetine significantly reduced the symptoms of neuropathy as measured by both observer- and self-rating, but was somewhat less effective than imipramine. However, patients showing a weaker response to paroxetine than to imipramine had lower plasma concentrations of paroxetine than patients with similar response to the 2 drugs.On imipramine 5 patients dropped out because of intolerable side effects and 4 of 19 patients completing the study reported withdrawal symptoms after discontinuing imipramine. On paroxetine no patients dropped out due to side effects and no withdrawal symptoms were reported.Self-rating showed no depressive symptoms at baseline, and no changes during the study. Neither paroxetine nor imipramine caused changes in objective measures of peripheral nerve function.In conclusion, 40 mg paroxetine/day significantly reduced the symptoms in peripheral diabetic neuropathy and it was suggested that by dose adjustment on the basis of drug level monitoring, paroxetine may become as effective as imipramine. Paroxetine was devoid of the often disturbing autonomic side effects limiting the use of imipramine in several patients.
Some characters of thick-wall pipeline with high dynamic pressure were analyzed and the ways to detect its pressure was discussed. It has been proven by certain experiments that the parameters of dynamic pressure in the pipeline can be gained by utilizing its strain signals at pipeline. The result can be used to monitor the condition of fuel system in engine or the condition of hydraulic system in construction machinery, mine machine and vehicle.
In 15 patients suffering from typical migraine, there was an increase in the urinary 5-hydroxyndoleacctic acid excretion during the attacks. This suggests that a change in the serotonin metabolism occurs during migraine attacks.
The possible presynaptic action of the anti-migraine drug sumatriptan on primary afferent fibres containing substance P and/or calcitonin gene-related peptide was investigated on superfused rat horizontal spinal cord slices with attached dorsal roots. Electrical stimulation of dorsal roots triggered a significant overflow of both peptides; this could be reduced by sumatriptan in a concentration-dependent manner. As expected from the involvement of 5-HT1B/1D[beta] receptors, methiothepin, (-)tertatolol and GR 127,935, but not WAY 100,635, prevented the inhibitory effect of sumatriptan. These data support the idea that the anti-migraine action of sumatriptan may involve, at least in part, a presynaptic inhibitory control of nociceptive (trigeminovascular) substance P-and/or calcitonin gene-related peptide-containing sensory fibres.
(C) Lippincott-Raven Publishers.
• The effect of serotonin (5-HT) on the hyperpolarization-activated cation current (IH) was studied in small-, medium- and large-diameter acutely isolated rat dorsal root ganglion (DRG) cells, including cells categorized as type 1, 2, 3 and 4 based on membrane properties. 5-HT increased IH in 91 % of medium-diameter DRG cells (including type 4) and in 67 % of large-diameter DRG cells, but not other DRG cell types. • The increase of IH by 5-HT was antagonized by spiperone but not cyanopindolol, and was mimicked by 5-carboxyamidotryptamine, but not (+)-8-hydroxydipropylaminotetralin (8-OH-DPAT) or cyanopindolol. These data suggested the involvement of 5-HT7 receptors, which were shown to be expressed by medium-diameter DRG cells using RT-PCR analysis. • 5-HT shifted the conductance-voltage relationship of IH by +6 mV without changing peak conductance. The effects of 5-HT on IH were mimicked and occluded by forskolin, but not by inactive 1,9-dideoxy forskolin. • At holding potentials negative to -50 mV, 5-HT increased steady-state inward current and instantaneous membrane conductance (fast current). The 5-HT-induced inward current and fast current were blocked by Cs+ but not Ba2+ and reversed at -23 mV, consistent with the properties of tonically activated IH. • In medium-diameter neurons recorded from in the current clamp mode, 5-HT depolarized the resting membrane potential, decreased input resistance and facilitated action potential generation by anode-break excitation. • The above data suggest that in distinct subpopulations of DRG neurons, 5-HT increases cAMP levels via activation of 5-HT7 receptors, which shifts the voltage dependence of IH to more depolarized potentials and increases neuronal excitability.
Objective.—To determine the effect of the 5-HT2A receptor in control of spinal nociception, cerebral circulation, and nitric oxide synthase (nNOS) expression in trigeminovascular neurons.
Background.—The plasticity of the 5-HT2A receptor is a possible factor determining the course of migraine. Up-regulation of this receptor has been demonstrated to correlate with the increasing frequency of migraine attacks and may underlie the development of chronic daily headache.
Methods.—Adult male Wistar rats were divided into groups receiving the 5-HT2A agonist, 1,2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI), nitroglycerin, or normal saline. The tail flick test and chemical nociception-evoked Fos-expression in dorsal horn neurons were used as indicators of nociception. Regional cerebral blood flow was monitored using laser Doppler flowmetry. Expression of Fos and nNOS was studied using immunohistochemical method.
Results.—Administration of DOI led to the shortening of tail flick latency (1.3 ± 0.2 and 7.2 ± 0.6 seconds for DOI-treated and control groups, respectively). The number of Fos-immunoreactive neurons was also greater in the DOI-treated group compared with the control group. DOI also produced long-lasting cerebral hyperemia (123% of baseline value) associated with the enlargement of perivascular nNOS-immunoreactive nerve fibers and increased nNOS-immunoreactive neurons in trigeminal ganglia and trigeminal nucleus caudalis. These findings resembled those observed in the rats exposed to nitroglycerin.
Conclusion.—Our results suggest that activation of the 5-HT2A receptor leads to an enhancement of NO production in trigeminovascular pathway. NO may trigger migraine attacks by inducing cerebral vasodilation and sensitizing the perivascular nociceptors and central nociceptive neurons in trigeminovascular system. Up-regulation of this pronociceptive receptor can increase headache attacks and contributes to the development of chronic daily headache.
To develop criteria for the classification of fibromyalgia, we studied 558 consecutive patients: 293 patients with fibromyalgia and 265 control patients. Interviews and examinations were performed by trained, blinded assessors. Control patients for the group with primary fibromyalgia were matched for age and sex, and limited to patients with disorders that could be confused with primary fibromyalgia. Control patients for the group with secondary-concomitant fibromyalgia were matched for age, sex, and concomitant rheumatic disorders. Widespread pain (axial plus upper and lower segment plus left- and right-sided pain) was found in 97.6% of all patients with fibromyalgia and in 69.1% of all control patients. The combination of widespread pain and mild or greater tenderness in ⩾ 11 of 18 tender point sites yielded a sensitivity of 88.4% and a specificity of 81.1%. Primary fibromyalgia patients and secondary-concomitant fibromyalgia patients did not differ statistically in any major study variable, and the criteria performed equally well in patients with and those without concomitant rheumatic conditions. The newly proposed criteria for the classification of fibromyalgia are 1) widespread pain in combination with 2) tenderness at 11 or more of the 18 specific tender point sites. No exclusions are made for the presence of concomitant radiographic or laboratory abnormalities. At the diagnostic or classification level, the distinction between primary fibromyalgia and secondary-concomitant fibromyalgia (as defined in the text) is abandoned.
Die lokale Injektion des 5-HT3-Rezeptor- Antagonisten Tropisetron zeigt bei den verschiedenen lokalen Erkrankungen im Bereich
des Bewegungsapparats wie Tendinopathien, Periarthropathien,myofaszialen Schmerzzuständen, bei Trigger points und entzündlichen
Gelenkprozessen einen deutlichen analgetischen Effekt.Dieser entspricht demjenigen der gebräuchlichen Lokalanästhetika wie
Lidocain,Prilocain u. a., hält jedoch erheblich länger an. Als Ursache für diesen Befund kommt eine gleichzeitige antiphlogistische
Wirkung der 5-HT3-Rezeptor-Antagonisten in Frage, die aufgrund tierexperimenteller und klinischer Befunde nahe liegend ist.
Local injection of the 5-HT3 receptor antagonist tropisetron manifests a distinct analgesic effect in various local diseases
of the locomotor system such as tendinopathies, peri-arthropathies,myofascial pain syndrome, in trigger points, and in inflammatory
joint processes.This effect corresponds to that exerted by local anesthetics in general use such as lidocaine and prilocaine
among others, but the effect lasts considerably longer. The reason for this finding is found in a simultaneous antiphlogistic
effect of the 5-HT3 receptor antagonist as evidenced by animal experiments and clinical data.
Migraine is effectively treated by drugs acting via 5-HT1B/1D receptors; however, the antinociceptive effects of such agents have not been fully investigated, particularly in models in which sensitization may be present. The aim of these studies was to evaluate the effects of the 5-HT1B/1D receptor agonist sumatriptan in specific models of pain states: a mouse model of inflammation-induced thermal hyperalgesia and a rat model of nerve injury-induced thermal hyperalgesia. In female mice, following intraplantar injection of carrageenan 225 min earlier, sumatriptan (300 μg/kg intraperitoneally; ip) increased paw withdrawal latency (PWL) from 3.1 ± 0.4 s in the saline group to 5.6 ± 0.9 s, measured 240 min postcarrageenan (P < 0.05 ANOVA followed by post hoc Dunnett's test). A similar effect was seen in male mice. Sumatriptan was also effective in male mice when given ip and subcutaneously 15 min precarrageenan, with a maximum effect at 30 μg/kg (ip latency 7.4 ± 1.3 s compared to saline group, 2.6 ± 0.7 s; iv latency 5.9 ± 0.8 s compared to saline group, 2.9 ± 0.3 s; P < 0.05 ANOVA followed by post hoc Dunnett's test). The number of mice required to give a response that could be reliably attributed to sumatriptan (number needed to treat) was calculated using discriminant analysis and found to be 2.6. The ability of sumatriptan to attenuate the carrageenan-induced reduction in PWL was blocked by the mixed 5-HT1B/1D receptor antagonist GR-127935 (3 mg/kg ip) but not by the 5-HT1B receptor antagonist SB-224289 (10 mg/kg ip). Sumatriptan had no effect on thermal hyperalgesia induced by sciatic nerve ligation in the rat at any time point. These data demonstrate that sumatriptan attenuates the hypersensitivity to noxious thermal stimuli induced by intraplantar carrageenan.
The present study was designed to investigate which subtype of spinal 5-HT receptors were involved in acetaminophen-induced antinociception using the paw-pressure test. Propacetamol (prodrug of acetaminophen, 400 mg/kg, injected intravenously, corresponding to 200 mg/kg of acetaminophen) produced a significant antinociceptive effect in this test. This effect was at least partially inhibited by intrathecal (i.t.) pretreatment with the 5-HT1B (penbutolol), 5-HT2A (ketanserin), 5-HT2C (mesulergine) receptor antagonists, but not by the 5-HT1A (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride, WAY 100635) and 5-HT3 (granisetron) receptor antagonists. This profile was very close to that obtained recently with 5-HT, which suggests an implication of 5-HT in the spinal antinociceptive effect of acetaminophen. These results, the lack of binding of acetaminophen to 5-HT receptors and the increase of central 5-HT levels induced by this drug suggest that acetaminophen-induced antinociception could be indirectly mediated by 5-HT.
In light of evidence suggesting the proinflammatory and nociceptive action of peripheral serotonin (5-HT), the present study examined dose-dependent parameters of edema and algesia produced by intraplantar injections of 5-HT and the role of heterogeneous 5-HT receptors in these 5-HT-induced responses. Intraplantar 5-HT (0.05, 0.25, 0.5, or 1.0 μmol) produced paw edema at each 5-HT concentration and produced concentration-dependent increases in the nociceptive response as indexed by lifts of, and licks to the affected paw. Intraplantar pretreatment with the 5-HT1 receptor antagonist methysergide at concentrations ≥3 nmol attenuated the 5-HT-induced (25 μmol) inflammatory and nociceptive responses. At concentr ations ≥300 nmol, both 5-HT2 receptor antagonists ketanserin and 5-HT3 receptor antagonist odansetron pretreatment blocked 5-HT-induced inflammatory and nociceptive responses. These result more completely define peripheral 5-HT-receptor-dependent systems of 5-HT-induced inflammation and nociception in rats.
Supraspinal opioid analgesia is mediated in part by connections between the midbrain periaqueductal gray (PAG) and the ventral-medial medulla, including the nucleus raphe magnus (NRM) and nucleus reticularis gigantocellularis (NRGC). A serotonergic synapse appears to participate in this pathway since methysergide microinjected into the NRM-NRGC significantly reduced morphine analgesia elicited from the PAG. The present study evaluated the role of specific serotonin receptor subtypes by pretreating rats with microinjections of either the 5HT2 antagonist, ritanserin or the 5HT3 antagonist, ICS205930, into the NRM-NRGC and examining their effects upon morphine (2.5 μg) analgesia elicited from the PAG. Mesencephalic morphine analgesia was significantly reduced following pretreatment with both ritanserin (0.25–2.5 μg) on the tail-flick (81%) and jump (65%) tests and ICS205930 (0.25–5 μg) on the tail-flick (91%) and jump (63%) tests. Neither ritanserin nor ICS205930 altered basal nociceptive thresholds. Medullary placements ventral or lateral to the NRM/NRGC failed to support these antagonistic effects. These data indicate that ventro-medial medullary 5HT2 and 5HT3 serotonergic receptors modulate the transmission of opioid pain-inhibitory signals from the PAG.
The present study examined distribution and duration of muscle hyperalgesia to pressure stimuli after intramuscular bolus-infusions of serotonin (5-HT, 20 nmol) and bradykinin (BKN, 10 nmol) in 10 volunteers. Infusions were given into the tibialis anterior (TA) muscle over 20 s with an inter-infusions interval of 3 min. Infusions of isotonic saline (NaCl, 0.9%) were given as control. Pain intensity was continuously scored on a visual analogue scale (VAS), and subjects drew the distribution of the pain areas on an anatomical map. Pressure pain thresholds (PPTs) were assessed with an electronic algometer at the injection site (10 cm below the patella), 2, 5, and 10 cm distal from the injection site, and at the ankle. Control assessments of PPTs were done at the contralateral TA and ankle. Skin sensibility was assessed with a Von Frey hair at the same sites. All measurements were done before and 5, 20, 40, and 60 min after infusions. The VAS-peak after BKN was significantly higher (P<0.05) compared with 5-HT and the second infusion of NaCl. The duration of the increase in VAS after 5-HT+BKN was significantly longer (P<0.05) compared with the infusions of NaCl. The local pain area after infusion of BKN was significantly larger (P<0.05) compared with 5-HT and control infusions. Cutaneous sensibility to tactile stimuli was not affected by any of the combinations. PPTs at the injection site and 2 cm (5, 20, and 40 min) were significantly decreased (P<0.05) after 5-HT+BKN compared with baseline and isotonic saline. In addition, PPTs were significantly decreased (P<0.05) after 5-HT+BKN at 5 cm (5 and 20 min) and 10 cm (5 min). Serotonin may enhance the effect of bradykinin in producing experimental muscle pain and muscle hyperalgesia to mechanical stimuli. The combination of serotonin and bradykinin can produce muscle hyperalgesia, lasted for up to 40 min and located within the muscle. No widespread hyperalgesia to the ankle and other leg (tested at 10 cm below the patella and ankle) was observed suggesting a predominant peripheral origin of the experimentally induced hyperalgesic stage.
The antinociceptive effect of sarpogrelate, a new selective 5-hydroxytriptamine (5-HT)2A receptor antagonist, in the formalin test was examined in rats. Sarpogrelate was administered intraperitoneally, locally (subcutaneously at the formalin test site) or intrathecally 10 min before formalin injection. Intraperitoneal (1–100 mg/kg) and local (0.01–1 mg) administration of sarpogrelate suppressed flinching behavior in both phases 1 (0–9 min) and 2 (10–60 min) in a dose-dependent manner. Intraperitoneal (100 mg/kg) and local (1 mg) injection 7 min after formalin injection reduced phase 2 flinches to the same degree as with the pre-treatment. Intrathecal administration (1–100 μg) showed no antinociceptive action, and facilitated phase 2 flinches at 10 μg. The plasma concentration of sarpogrelate after local administration of 1 mg was lower than after intraperitoneal administration of 10 mg/kg, although local administration produced more potent antinociception. The data imply that the antinociceptive effect of sarpogrelate results mainly from an action at peripheral sites.
We have previously reported that Schwann cells cultured from rat sciatic nerves express 5-HT2A receptors. In this study we extend these in vitro observations to Schwann cells in situ. Since the serotonin (5-HT) levels in rat sciatic nerve are elevated following nerve injury, we examined Schwann cells in healthy and injured adult rat sciatic nerves. These nerves were double-labeled immunohistochemically with an anti-idiotypic antibody that recognizes 5-HT1B, 5-HT2A, and 5-HT2C receptors and an antibody against S100β, a Schwann cell marker. 5-HT receptor labeling was observed in Schwann cells of healthy and regenerating nerves, but not of degenerating nerves, while S100β labeling was observed in the Schwann cells of all nerves examined. The 5-HT receptor immunolabeling was cytoplasmic, as with the cultured Schwann cells. While staining was observed at the nodes of Ranvier, it was not restricted to these locations. These results suggest that myelinating rat Schwann cells normally express 5-HT receptors in vivo, and that receptor expression is reduced during times when 5-HT levels are elevated in the sciatic endoneurium. © 1997 Elsevier Science B.V. All rights reserved.
Harold Wolff's theory of vasodilation in migraine is well-known. Less known is his search for a perivascular factor that would damage local tissues and increase pain sensitivity during migraine attacks. Serotonin was found to be among the candidate agents to be included. In the same period, serotonin was isolated (1948) and, because of its actions, an anti-serotonin drug was needed. Methysergide was synthesized from lysergic acid (LSD) by adding a methyl group and a butanolamid group. This resulted in a compound with selectivity and high potency as a serotonin (5-HT) inhibitor. Based on the possible involvement of serotonin in migraine attacks, it was introduced in 1959 by Sicuteri as a preventive drug for migraine. The clinical effect was often excellent, but 5 years later it was found to cause retroperitoneal fibrosis after chronic intake. Consequently, the use of the drug in migraine declined considerably, but it was still used as a 5-HT antagonist in experimental studies. In 1974 Saxena showed that methysergide had a selective vasoconstrictor effect in the carotid bed and in 1984 he found an atypical receptor. This finding provided an incentive for the development of sumatriptan. Bredberg et al. showed that methysergide is probably a prodrug for its active metabolite methylergometrine. Whereas methysergide is 'a clean drug', methylergometrine is 'a relatively dirty drug' with additional dopaminergic activity. The mechanism for the preventive effect of methysergide (methylergometrine) in migraine remains elusive. We describe the rise, fall and subsequent use as a third-choice drug of the first effective migraine prophylactic, methysergide.
Preclinical and clinical studies have suggested that milnacipran, a dual norepinephrine-serotonin reuptake inhibitor, may be efficacious in the treatment of fibromyalgia (FM).
This study was conducted to evaluate the efficacy and tolerability of milnacipran in treating the multiple domains of FM.
This was a multicenter, double-blind, placebo-controlled trial. Adult patients (age 18-70 years) who met 1990 American College of Rheumatology criteria for FM were randomized to receive milnacipran 100 mg/d, milnacipran 200 mg/d, or placebo for 15 weeks. Because this was a pivotal registration trial, the primary end points were chosen to investigate efficacy for 2 potential indications: the treatment of FM and the treatment of FM pain. Thus, the 2 primary efficacy end points were rates of FM composite responders and FM pain composite responders. FM composite responders were defined as patients concurrently experiencing clinically meaningful improvements in the following 3 domain criteria: pain (> or = 30% improvement, as recorded in an electronic diary); patients' global status (a rating of very much improved or much improved on the Patient Global Impression of Change [PGIC] scale); and physical function (a > or = 6-point improvement on the 36-item Short-Form Health Survey [SF-36] Physical Component Summary score). FM pain composite responders were defined as those who met the pain and PGIC criteria. Adverse events reported by patients or observed by investigators were recorded throughout the trial.
Of 2270 patients screened, 1196 were randomized to receive milnacipran 100 mg/d (n = 399), milnacipran 200 mg/d (n = 396), or placebo (n = 401). The majority of patients were female (96.2%) and white (93.5%). The population had a mean age of 50.2 years, a mean baseline weight of 180.8 pounds, and a mean baseline body mass index of 30.6 kg/m(2). Compared with placebo, significantly greater proportions of milnacipran-treated patients were FM composite responders (100 mg/d: P = 0.01; 200 mg/d: P = 0.02) and FM pain composite responders (100 mg/d: P = 0.03; 200 mg/d: P = 0.004). Milnacipran was associated with significant improvements in pain after 1 week of treatment (100 mg/d: P = 0.004; 200 mg/d: P = 0.04), as well as significant improvements in multiple secondary efficacy end points, including global status (PGIC: P<0.001 for both doses), physical function (SF-36 physical functioning domain-100 mg/d: P < 0.001; 200 mg/d: P = 0.02), and fatigue (Multidimensional Fatigue Inventory- 100 mg/d: P = 0.04). The most commonly reported adverse events with milnacipran were nausea (100 mg/d, 34.3%; 200 mg/d, 37.6%), headache (18.0% and 17.7%, respectively), and constipation (14.3% and 17.9%). Adverse events resulted in premature study discontinuation in 19.5% and 23.7% of those who received milnacipran 100 and 200 mg/d, respectively, compared with 9.5% of placebo recipients.
In these adult patients with FM, both doses of milnacipran (100 and 200 mg/d) were associated with significant improvements in pain and other symptoms. Clinical Trials Identification Number: NCT00098124.
There is a large body of evidence that serotonin [5-hydroxytryptamine (5-HT)] plays an important role in the transmission and regulation of pain. Here we used positron emission tomography (PET) to study the relationship between baseline 5-HT(2A) binding in the brain and responses to noxious heat stimulation in a group of young healthy volunteers. Twenty-one healthy subjects underwent PET scanning with the 5-HT(2A) antagonist, [(18)F]altanserin. In addition, participants underwent a battery of pain tests using noxious heat stimulation to assess pain threshold, pain tolerance and response to short-lasting phasic and long-lasting (7-minute) tonic painful stimulation. Significant positive correlations were found between tonic pain ratings and [(18)F]altanserin binding in orbitofrontal (r=0.66; p=0.005), medial inferior frontal (r=0.60; p=0.014), primary sensory-motor (r=0.61; p=0.012) and posterior cingulate (r=0.63; p=0.009) cortices. In contrast, measures of regional [(18)F]altanserin binding did not correlate with pain threshold, pain tolerance, or suprathreshold phasic pain responses. These data suggest that cortical 5-HT(2A) receptor availability co-varies with responses to tonic pain. The correlation between [(18)F]altanserin binding in prefrontal cortex and tonic pain suggests a possible role of this brain region in the modulation and/or cognitive-evaluative appreciation of pain.
The trapezius muscle often develops pain as the result of repetitive and stressful work tasks although it is unclear to what extent this pain is due to alterations in muscle concentrations of algesic/nociceptive substances. Twenty women with chronic neck- and shoulder pain (TM) whose work required highly repetitive work tasks and 20 pain-free female colleagues (CON) were studied during and after a full 8-hour workday. We collected microdialysates from their dominant/most painful trapezius muscle; concentrations of serotonin, glutamate, lactate, pyruvate, potassium, bradykinin, and cytokines and blood flow were determined. In addition, we measured surface electromyogram, task exposure level, pain intensity, perceived mental stress, and urine-cortisol. In connection to the clinical neck and shoulder examination, we determined pressure pain thresholds (PPTs) over the trapezius and tibialis muscles. TM had higher concentrations of glutamate (71+/-42 vs. 36+/-15 micromol l(-1)) and pyruvate (187+/-89 vs. 125+/-63 micromol l(-1)) than CON. Interstitial serotonin was higher in TM (before work: 10.6+/-10.8 vs. 2.2+/-1.2 nM; after work: 9.2+/-8.3 vs. 1.5+/-2.9 nM). The trapezius blood flow during the working day was higher in TM than in CON. TM had lower PPT and higher pain intensity throughout the working day. No differences in EMG, task exposure level, mental stress, or urine-cortisol in the groups were found. These findings support the idea that peripheral nociceptive processes are activated in occupationally active subjects, who are diagnosed with trapezius myalgia. In contrast, no sign of low blood flow or increased stress or muscle activity markers were found in TM.
We recently showed that peripheral and spinal 5-HT2A receptors (5-HT2AR) are involved in a rodent model of neuropathy induced by a nucleoside analogue reverse transcriptase inhibitor. In this paper, we show that 5-HT2AR are also involved in neuropathy induced by an anti-neoplasic drug, vincristine. Vincristine-treated rats (0.1mg/kg, daily i.p. administration for two 5-day cycles) developed thermal allodynia and mechanical hypersensitivity, which decreased in a dose-related manner after epidural injection a 5-HT2A receptor antagonist. Moreover, 5-HT2A-/- mice did not develop vincristine-induced neuropathy contrarily to their 5-HT2A+/+ littermates. In vincristine-treated rats, the number of nociceptive dorsal root ganglion cells expressing the 5-HT2AR was increased by 38%, and 5-HT2AR immunolabelling was enhanced in layers I-IV of the dorsal horn. At the EM level, a 76.3% increase in the density of 5-HT2AR immunopositive axon terminals within superficial layers of the dorsal horn was noted after vincristine treatment. Immunocytochemical study of Fos expression in vincristine-treated rats revealed a significant increase in the number of Fos-positive neurons not only in regions where nociceptive fibres terminate superficial (I-II) and deep layers (V-VI) of the spinal cord, but also in intermediate layers, suggesting that Abeta fibres could be involved in the spinal sensitization observed in this model. Double labelling experiments showed that Fos-positive neurons were endowed with 5-HT2AR immunolabelling in the dorsal horn of vincristine-treated rats. These data provide support to the idea that, in vincristine-induced neuropathy, 5-HT2AR are involved in the sensitization of peripheral nociceptors and spinal nociceptive processing.
The effects of iontophoretic applications of 5-hydroxytryptamine (5-HT) were tested upon primate spinothalamic tract neurons recorded extracellularly in the spinal cord of anesthetized monkeys. The activity of most high threshold and wide dynamic range spinothalamic tract cells was depressed. 5-HT also reduced the responses of the cells to glutamate pulses which by themselves had a powerful excitatory action. It is concluded that 5-HT has a depressant action upon the postsynaptic membranes of spinothalamic tract cells, although the action has a slow time course. The observations are consistent with, but by no means prove, the hypothesis that serotonergic pathways descending from the brain stem produce a postsynaptic inhibiton of spinothalamic tract neurons.
The anatomy, physiology, and pharmacology of an intrinsic neural network that monitors and modulates the activity of pain-transmitting neurons is reviewed. This system can be activated by opiate administration or by electrical stimulation of discrete brainstem sites. Evidence is presented that its pain-suppressing action is mediated in part by endogenous opiatelike compounds (endorphins).
This pain suppression system is organized at three levels of the neuraxis: midbrain, medulla, and spinal cord. Activation of neurons in the midbrain periaqueductal gray matter (by electrical stimulation, opiates, and possibly psychological factors) excites neurons of the rostral medulla, some of which contain serotonin. The medullary neurons, in turn, project to and specifically inhibit the firing of trigeminal and spinal pain-transmission neurons. As part of a negative feedback loop, the output of the pain transmission neurons, i.e., pain itself, is an important factor in activating the pain-suppression system. A neural model which incorporates the experimental findings is proposed, and the clinical implications of the model are discussed.
Rats, rabbits and cats were chronically implanted with catheters in the lumbar spinal subarachnoid space. Serotonin administered through these catheters produced a significant, dose-dependent elevation in the response of all three species to otherwise aversive thermal stimuli. These effects were unaccompanied by any detectable changes in voluntary motor function, although higher doses produced some signs of tremor and a mild myoclonus. The effects of intrathecal serotonin were potentiated by blockade of monoamine oxidase (Lilly 51641) or reuptake (fluoxetine, imiprimine) while the effects were antagonized in a surmountable fashion with methysergide and cyproheptadine. This potentiation and inhibiton was observed when the several drugs were administered intrathecally suggesting that the observed effects were direct at the spinal level and not indirect via an action on brainstem cell bodies. MK 212 and quipazine produced similar effects but other indoles had little (5-methoxytryptamine) or no (tryptamine, 5-hydroxyindoleacetic acid, 5-hydroxytryptophan) effect. Intrathecal administration of 5-hydroxytryptophan produced a delayed antinociceptive effect which was antagonized by methysergide and potentiated by inhibition of monoamine oxidase and reuptake. Inhibition of decarboxylation (Ro-44601) completely abolished this effect. Intrathecal 5-hydroxytryptophan also produced frequent wet shakes and strong tremor. The effects of intrathecal serotonin were not antagonized by papaverine (a vasodilator), phenoxybenzamine, phentolamine or naloxone. Collectively, these data suggest that intrathecally administered serotonin mimics the effects produced when descending serotonergic pathways are activated. These data support the proposition that spinal serotonin terminals can modulate spinal function so as to alter the cephalad transmission of nociceptive information. In sum they demonstrate the behavioral relevance of the spinal serotonin system to changes in the nociceptive threshold.
In spinal cats anaesthetized with α‐chloralose, a study was made of the effects of methionine enkephalin and methionine enkephalin amide on the responses of neurones of spinal laminae IV and V to noxious and innocuous skin stimuli. The enkephalins were ejected from micropipettes either in the region of cell bodies or in the substantia gelatinosa.
Administered near cell bodies the enkephalins reduced spontaneous firing and cell responses to both types of skin stimuli. These effects were antagonized by naloxone when administered near cell bodies but not when given intravenously in doses (0.3‐0.6 mg/kg) more than adequate to antagonize analgesic doses of morphine.
Administered in the substantia gelatinosa the enkephalins were more selective in their action. The predominant effect was a reduction in nociceptive responses with little effect on non‐nociceptive responses although spontaneous firing was commonly reduced. Naloxone administered either in the substantia gelatinosa or intravenously (0.1‐0.3 mg/kg) reversed these effects of the enkephalins.
The excitation of muscular group IV afferent units by the pain-producing substances 5-hydroxytryptamine (5-HT), histamine, and potassium ions was studied in cats and compared with the bradykinin effects of an earlier investigation. The substances were injected into the sural artery and the action potentials of single group IV afferent fibres from the gastrocnemius-soleus muscle were recorded extracellularly. About half of the 180 units tested with chemical stimulation could be excited by amounts of the above agents which are likely to be present in pathologically altered tissues. Of the tested substances, 5-HT was the most and potassium the least effective stimulant; in comparison with bradykinin, 5-HT was by far less potent, though. The molar ratios of approximately equivalent doses of bradykinin, 5-HT, histamine, and potassium were found to be about 1:30:66:4000. The threshold injection doses of KC1 for activation of muscular group IV units were such that an unspecific depolarizaing mode of action seems probable. Differences in the chemosensitivity of individual group IV units might be indicative of the existence of different receptor sites at the nerve endings. The sensitivity of muscle receptors with group IV afferent fibres to pain-producing substances--especially to bradykinin and 5-HT--supports the view that these units might participate in the mediation of muscle pain.
A broad mixture of inflammatory mediators ("inflammatory soup") was used to investigate the responsiveness of primary afferents from rat hairy skin in an in vitro skin-saphenous nerve preparation. In addition, a conditioning effect of the tachykinin substance P on chemosensitivity of nociceptors was examined. Inflammatory soup (IS) was made up in synthetic interstitial fluid from bradykinin, serotonin, histamin and prostaglandin E2 (all 10(-5) M). In addition, the potassium and the hydrogen ion concentration (7 mM, pH 7.0) and the temperature (39.5 degrees C) were elevated. The latter agents, in a control solution, did not excite nociceptors (n = 5). IS was repeatedly superfused over the receptive fields for 5 min at 10 min intervals; substance P (SP 10(-6) and 10(-5) M) was applied during the last 5 min of the interval and during the subsequent IS stimulation. IS excited more than 80% of the mechano-heat sensitive ("polymodal") afferents with slowly conducting nerve fibres (n = 72), but none of the low-threshold mechanoreceptive slow and fast conducting units (n = 17). Slow conducting afferents with high mechanical threshold (n = 35) were weakly, and less frequently (< 20%), driven by IS. A majority, but not all, of the responsive units showed tachyphylaxis upon repeated IS application. None, however, lost its responsiveness completely. Conditioning heat stimulation (32-46.5 degrees C in 20 s) did not enhance the subsequent IS response, which may indicate that sensitizing substances normally released by a noxious heat stimulus were already contained in IS. No sensitization to mechanical (von Frey) or heat stimulation could be established in the period after the IS response had subsided and after the washout was completed, respectively. A short-lived sensitization may have been overlooked under these temporal restrictions. Conditioning SP in 10(-5) M but not in 10(-6) M concentration significantly increased the IS response of polymodal C fibres, by 58% on average (n = 14). SP did not excite the units. Comparing with previous data, we conclude that there is a significant synergism between inflammatory mediators, acting to induce more intense and more sustained discharge via many nociceptors than single mediators alone could achieve. Conditioning substance P can further enhance this algogenic action. Mechanisms of interaction and relative contributions of single substances remain to be elucidated.
The fibromyalgia syndrome (FMS) is a non-articular rheumatic disorder associated with disturbances in serotonin metabolism. In order to evaluate whether patients with FMS suffer from an autoimmune disorder, we tested sera from 50 clinically well-defined FMS patients for non-organ-specific and organ-specific antibodies by enzyme-linked immunosorbent assay and immunofluorescence test. Common antibodies against nuclei, mitochondria, and microsomes were not increased in these patients compared to healthy controls. However, 74% had antibodies against serotonin and gangliosides. The clinical and diagnostic relevance of these antibodies is supported by the absence of anti-serotonin antibodies in other rheumatic disorders such as rheumatoid arthritis, polymyalgia rheumatica, and collagen diseases. These antibodies may belong to the group of antireceptor antibodies, considering the fact that gangliosides are an important component of the serotonin receptor. It remains to be determined whether these antibodies are of pathogenetic relevance, interfering with serotonin binding and thereby inducing symptoms associated with FMS.
The density of serotonin reuptake receptors on peripheral platelets from 22 patients with primary fibromyalgia syndrome (FS) and the serum serotonin concentrations in 9 patients with FS were compared with those of matched healthy controls. The mean serum serotonin concentration was lower (p = 0.01) in FS than in controls, while the binding of 3H-imipramine was higher (p = 0.035) and normalized with treatment using a combination of ibuprofen and alprazolam. Improvement in selected clinical measures of FS disease activity during treatment correlated with the change in platelet 3H-imipramine binding. These findings support the proposed hypothesis of aberrant pain perception in FS resulting from a deficiency of serotonin.
To compare the levels of biogenic amines in the cerebrospinal fluid (CSF) of primary fibromyalgia syndrome (PFS) patients with those in the CSF of controls.
Metabolites of serotonin, norepinephrine, and dopamine were identified in CSF, using high performance liquid chromatography with coulometric detection.
CSF levels of metabolites from all 3 neurotransmitters were lower in PFS patients than in controls.
A low rate of turnover of several neurotransmitters supports the proposed hypothesis of a metabolic defect in PFS and suggests that the defect occurs at a neuroregulatory level.
The effect of the selective serotonin reuptake inhibitor citalopram on diabetic neuropathy symptoms was examined in a double-blind, placebo-controlled, crossover study for two 3-week periods. Citalopram was given as a fixed dose of 40 mg/day. Data from 15 patients could be included in the statistical analysis. Citalopram significantly relieved the symptoms of neuropathy as measured by both observer- and self-rating in comparison with placebo. The steady-state plasma concentration of citalopram was 10 to 890 nmol/L. There was no significant relationship between the plasma concentration of citalopram and the effect of treatment as measured by observer- or self-rating. Two of 17 patients, both receiving citalopram, left the study because of side effects (nausea and vomiting or gastric upset and diarrhea). Side-effect ratings were significantly higher during administration of citalopram than during administration of placebo, but citalopram was generally well tolerated. Compared with earlier results obtained with imipramine administered on the basis of plasma level monitoring, citalopram appeared to be less effective, but seemed to be better tolerated.
The effects of serotonin (5-HT) were investigated by intracellular recording from 179 dorsal root ganglion (DRG) cells classified by conduction velocity. Bath applied 5-HT depolarized 82% and hyperpolarized 4% of the A-type cells. In C-type cells, 5-HT depolarized only 41%, but hyperpolarized 39% of the cells. The depolarizing responses were of two types; an increase or decrease in R(in), mediated by 5-HT2or3 receptors, respectively. These receptors were observed in both A- and C-type cells. Hyperpolarizing responses were largely confined to A(delta)- and C-type cells. Carboxamidotryptamine and 8-OH-dipropylamino-tetralin were full agonists in eliciting hyperpolarization, and metitepin, spiperone and spiroxitrine behaved as competitive antagonists. This indicated that hyperpolarization was mediated by a 5-HT1A receptor. A 5-HT1A&3 receptor were found co-localized on some C-type cells. A strong depolarizing response to capsaicin was observed in the subgroup of C-type neurons that were also hyperpolarized by 5-HT. Thus a co-localization of capsaicin and 5-HT1A receptors was also observed.
In cats anesthetized with alpha-chloralose, extracellular recordings were made from fine afferent units belonging to the medial articular nerve (MAN) of the knee joint. The excitatory and sensitizing effects on articular afferents of serotonin (5-HT) applied intra-arterially close to the joint were examined. The joints were either normal or an experimental arthritis had been induced some hours before the recording session. Bolus injections of 1.35-135 micrograms 5-HT excited about 43% of group III (CV: 2.5-20 m/sec) and 73% of group IV units (CV: less than 2.5 m/sec) from normal joints. The latency was usually between 10 and 30 sec, and the duration and size of the responses were dose-dependent. Fast group III units (CV: greater than 16 m/sec) and group II units (CV: greater than 20 m/sec) were never excited by 5-HT. Repetitive administration led to pronounced tachyphylaxis of the 5-HT response. Inflammation induced an enhanced sensitivity of group III articular afferent units to close intra-arterial application of 5-HT. In particular the total duration of each response was considerably prolonged (4-10 min against 1-2 min under normal conditions). At the same time the tachyphylaxis seen under normal conditions was greatly reduced. In contrast, group IV articular afferent units did not become sensitized to 5-HT in the course of inflammation. In normal joints 5-HT did not sensitize fine afferent units for movement-induced responses. However, after inflammation, a distinct sensitization to such movements by 5-HT application could be observed both in group III and group IV fiber ranges. The sensitization had a short time course not exceeding 7 min. The tonic component of the movement-induced response was more enhanced than the phasic one. The bolus application of 5-HT led to temporary vasoconstriction of the knee joint vessels. This vasoconstriction was especially pronounced in inflamed joints and impeded the access of subsequently applied substances to the terminal regions of the afferent units under observation. It is concluded that the present results support the notion that 5-HT may participate in the mediation of pain from inflamed tissue such as an arthritic joint by exciting and sensitizing fine afferent units. During inflammation group III units are particularly sensitive to 5-HT and, thus, may carry the bulk of the 5-HT-induced nociceptive messages.
In this study, we have investigated serotonin hyperalgesia employing the mechanical paw withdrawal nociceptive threshold test in the rat. Intradermally injected serotonin was found to produce a dose-dependent hyperalgesia that was not attenuated by procedures which eliminate the known indirect mechanisms of hyperalgesia such as sympathectomy, polymorphonuclear leukocyte depletion or cyclooxygenase inhibition. In addition, the latency to onset of serotonin hyperalgesia is extremely short, with maximal hyperalgesia observed in less than 1 min, a similar temporal onset to direct-acting hyperalgesic agents such as prostaglandin E2. The results suggest, therefore, that the hyperalgesic effects of serotonin in our animal model are exerted by direct action on primary afferent neurons. Only the intradermal injection of selective serotonin (5-hydroxytryptamine; 5-HT) agonists for the 1A receptor subset (5-HT1A), (+/-)-2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydronaphthaline hydrobromide and N,N-dipropyl-5-carboxamido-tryptamine maleate, produced dose-dependent hyperalgesia. No hyperalgesia was seen after 5-HT1B, CGS-12066B maleate and m-trifluoromethylphenyl-piperazine hydrochloride; 5-HT2+IC, alpha methyl 5HT and (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl; or 5-HT3, 2-methyl-5-hydroxytryptamine maleate and phenylbiguanide, agonists. Similarly, only the 5-HT1A antagonists, spiroxatrine and spiperone, attenuated the hyperalgesia induced by intradermally injected serotonin. 5-HT2+IC antagonists, mesulergine and ketanserin, and 5-HT3 antagonists, quipazine and 3-tropanyl-indole-3-carboxylate, did not significantly attenuate 5-HT hyperalgesia. We conclude that serotonin produces hyperalgesia by a direct action on the primary afferent neuron via the 5-HT1A subset of serotonin receptors.
Microdialysis sampling was used to characterize the release of norepinephrine and serotonin upon impact injury to the rat spinal cord. Increases in extracellular norepinephrine concentrations in response to injury were small and of short duration. In contrast, serotonin concentrations quickly rose 35-90 times following injury and took 30-45 min to return to control levels. Bleeding caused by injury was probably the major source of the increased serotonin levels. Our results allow a role for serotonin in secondary damage upon injury to the spinal cord but suggest that norepinephrine is not a very significant contributor to such damage.
In order to examine the vital reaction in wounds, catecholamines, serotonin (5-HT) and their metabolites in the incised skin wounds of guinea pigs were analyzed simultaneously by high-performance liquid chromatography (HPLC) using electrochemical detection (ECD). The principal changes in the levels of these compounds in vital wounds were as follows: a considerable decrease in norepinephrine (NE) content was observed 12-24 h after injury which persisted to at least 7 days. 3,4-Dihydroxyphenylacetic acid (DOPAC) decreased slightly for up to 30 min and then showed no significant difference compared with postmortem levels. Epinephrine and dopamine were barely detected by the HPLC-ECD method employed. 5-HT concentrations which showed an increase up to 24 h showed maximum levels 800 microns from the wound edge at 10 and 30 min after injury. 5-Hydroxyindoleacetic acid (5-HIAA) was significantly higher than the postmortem level over almost the entire period of these experiments. A 5-HIAA content of at least twice the postmortem level was observed 800 microns from the wound edge of a 10-min-old vital wound. Therefore, 5-HIAA is a likely candidate as a new marker for evaluating the vital reaction in wounds. The vital characteristics of NE, DOPAC, 5-HIAA and 5-HT in 10-min-old wounds persisted for up to 12 h at room temperature after death. These results suggest that the HPLC-ECD method used here is very useful for simultaneous examination of the vital reaction in wounds from the earliest to the later stages of the wound-healing period.
Electrical stimulation in the nucleus reticularis gigantocellularis (NGC) and gigantocellularis pars alpha (NGC alpha) produces facilitation and/or inhibition of spinal nociceptive transmission in behavioral and electrophysiological studies. The present study examined spinal neurotransmitter receptors mediating descending facilitation from the NGC/NGC alpha. As previously demonstrated, electrical stimulation in the NGC/NGC alpha at low intensities (approximately equal to 10 microA) produced facilitation and at greater intensities (approximately equal to 38 microA) inhibition of the tail-flick (TF) reflex. Intrathecal pretreatment with the non-selective serotonin (5-HT) receptor antagonist methysergide attenuated or completely abolished facilitation of the TF reflex produced by electrical stimulation in the NGC/NGC alpha; intrathecal pretreatment with atropine, phentolamine, naloxone or mecamylamine was without effect on stimulation-produced facilitation. Descending inhibition from the NGC/NGC alpha produced by electrical stimulation was attenuated or completely abolished by bilateral transection of the dorsolateral funiculi (DLF) of the cervical spinal cord. Descending facilitation produced by electrical stimulation, however, was unaffected or enhanced following DLF transections. Glutamate microinjections (1.7 nmol/0.17 microliters) into the NGC/NGC alpha produced a rapid, repeatable and short-duration facilitation of the TF reflex in rats with bilateral DLF transections and such facilitation was attenuated by intrathecal pretreatment with methysergide, but not atropine, xylamidine (5-HT2 selective receptor antagonist) or MDL-72222 (5-HT3 selective receptor antagonist). These findings suggest that facilitation of the TF reflex from the activation of the cell bodies in the NGC/NGC alpha is mediated by a descending serotonergic pathway traveling in the ventrolateral funiculi and by spinal 5-HT1 receptors.
1. Properties of sensory receptors with slowly conducting nerve fibers (less than 10 m/s) were studied using a rat skin-saphenous nerve in vitro preparation where receptive fields of identified single units can be isolated and superfused at the corium side with defined chemical solutions. 2. With mechanical search stimuli, 150 slowly adapting units were identified, 88% C-fibers, and the remainder, A delta-fibers. The majority of these units (65%) were categorized as mechano-heat sensitive ("polymodal") with controlled radiant heat stimulation. The remaining units were classified as low- or high-threshold mechanoreceptors according to their von Frey thresholds. 3. Bradykinin (BK), in concentrations of 10(-8) to 10(-4) M, was repeatedly applied for 1 min at 10-min intervals. Fifty-six percent of the polymodal C-fibers responded to BK (up to 10(-5) M), in contrast to 17% of the heat-insensitive units (P less than 0.01). No correlation between BK sensitivity and conduction velocity or von Frey threshold was found. 4. The BK "threshold concentrations" to excite C- and A delta-fibers were about equally distributed over a range from 10(-8) to 10(-5) M. 5. There was a large interindividual variability in pattern and magnitude of the response to BK. Intraindividually, a marked tachyphylaxis upon repeated BK stimulation was observed. 6. In fibers with a slow development of tachyphylaxis, the effects of conditioning application of different chemicals on BK responsiveness were studied. Norepinephrine in 10(-7) M concentration did not produce a significant effect, whereas 10(-5) M and 10(-4) M seemed to increase the BK responses. 7. Prostaglandin E2 (10(-6) M) caused a weak sensitization to BK on average (n.s.), but serotonin (10(-6) M) was clearly effective (P less than 0.05). 8. The strongest sensitization to BK (P = 0.01) resulted from conditioning heat stimulation, which also uncovered a responsiveness in some units initially insensitive to BK. 9. In some experiments the calcium concentration in the superfusate of receptive fields was lowered to 0.3 mM, which induced ongoing activity in C-fibers and markedly increased the BK responses in two polymodal units tested. Increasing the calcium concentration to 3.0 mM reversed these effects. 10. After completing the BK test protocol, polymodal C-fibers were exposed to other chemicals.(ABSTRACT TRUNCATED AT 400 WORDS)