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Antinociceptive effects of fluoxetine in a mouse model of anxiety/depression
Abstract
Pain was reported by 60-90% of patients with depression, and chronic pain states are often linked to depression. Animal models of pain/depression are generally lacking for the identification of centrally active drugs. In the present study, pain sensitivity was assessed in a mouse model of anxiety/depression on the basis of chronic corticosterone (CORT) administration through the drinking water (CORT model). We measured thermal hyperalgesia as shown by a decrease in the latency to hind paw licking in the hot plate test and cold allodynia reflected by a decrease in the time spent on the plate set at 20°C in the thermal preference plate test. Subsequently, we determined the effect of chronic administration of the selective serotonin reuptake inhibitor fluoxetine (an antidepressant known to reverse anxiety/depressive-like state in CORT-treated mice) on pain relief. Fluoxetine administration reduced both heat hyperalgesia and cold allodynia, thus unveiling a putative link between mood and nociception in the CORT model. This hypothesis is consistent with previous clinical studies reporting the analgesic efficacy of fluoxetine in depressed patients suffering from pain disorders. Together, these results suggest that the CORT model, with pain/anxiety/depressive-like state, is a good candidate for translational research.
Supplementary resources (4)
... Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) that is used to treat depressive orders. Pain is reported by 60-90% of patients with depression [6]. Studies in animals and humans have shown that fluoxetine has antinociceptive effects [6]. ...
... Pain is reported by 60-90% of patients with depression [6]. Studies in animals and humans have shown that fluoxetine has antinociceptive effects [6]. However, other studies have failed to show antinociceptive effects of SSRIs [7]. ...
... Previous clinical studies have shown the analgesic efficacy of fluoxetine in patients with depression who were suffering from pain disorders. Hache et al. observed that fluoxetine administration reduced both heat hyperalgesia and cold allodynia [6]. However, in some studies, fluoxetine failed to attenuate mechanical hypersensitivity in rats with chronic constriction injury (CCI) of the sciatic nerve [7]. ...
Exposure to stress could facilitate or inhibit pain responses (stress-induced hyperalgesia or hypoalgesia, respectively). Fluoxetine is a selective serotonin (5-HT) reuptake inhibitor antidepressant. There have been contradictory reports on whether fluoxetine produces antinociceptive effects. The purpose of this study was to elucidate changes in pain sensitivity after chronic stress exposure, and the effects of fluoxetine on these changes. We measured thermal, mechanical, and formalin-induced acute and inflammatory pain by using the tail-flick, von Frey, and formalin tests respectively. The results showed that rats exposed to chronic stress exhibited thermal and formalin-induced acute and inflammatory hypoalgesia and transient mechanical hyperalgesia. Furthermore, fluoxetine promoted hypoalgesia in thermal and inflammatory pain and induced mechanical hyperalgesia. Our results indicate that the 5-HT system could be involved in hypoalgesia of thermal and inflammatory pain and induce transient mechanical hyperalgesia after stress exposure.
... In vitro, escitalopram is described as the most selective SSRI and this property has been repeatedly demonstrated in rodents using intracerebral microdialysis (David et al., 2003, Mork et al., 2003 . Interestingly, we previously reported an analgesic action of the SSRI fluoxetine in an animal model anxiety/depression, specifically on mechanical hypersensitivity (Hache et al., 2012). This finding suggested that SSRIs might exert their analgesic effects under certain pathological conditions, notably when animals or patients display an anxio-/depressive state. ...
... Having demonstrated that OXA induced anxiodepressive-like behavior in mouse, we next asked whether monoaminergic antidepressants reversed this particular phenotype determined in the NSF. However, this paradigm, unlike commonly used tests of antidepressant response, such as the tail suspension test or the forced swim test, is sensitive to chronic but not acute treatment ( Dulawa and Hen, 2005 (Hache et al., 2012). Accordingly, the systemic administration of the SSRI paroxetine showed mild antinociceptive effects in a nerve injured rats associated with a drastic anxiolytic activity . ...
... Rapid retraction, shake and licking hind paw were considered as positive response. Withdrawal responses to the von Frey filaments from both hind paws were counted and then expressed as an overall percentage response.T2PT was performed as described before(Hache et al., 2012). Briefly, mice were allowed to freely explore an enclosure in which the floor is composed by 2 adjoiningthermoelectric computer-managed metal plates (Bioseb Inc., Vitrolles, France). ...
High comorbidity is described between depression and pain disorders. Monoaminergic reuptake inhibitors represent the first choice of treatment for depression and serotonin and norepinephrin reuptake inhibitors are also recommended for the treatment of neuropathic pain disorders. We aims at evaluating analgesic effects of these drugs in animal models sharing anxio-depressive and painful phenotype. We first developed tests to assess pain sensitivity in mice and analgesic properties of pharmacological compounds. Depressive phenotype was assessed using various behavioural paradigms of anxiety/depression.We thus show that fluoxetine, a selective serotonin reuptake inhibitor (SSRI), provide antinociceptive effects in a mice model of anxiety-depression: the CORT model. Fluoxetine may thus exert its analgesic effect by modulating the affective aspect of pain in addition to a putative influence on sensory mechanisms. Moreover we characterized analgesic effects of a new generation of antidepressant, the triple reuptake inhibitors, which simultaneously potentialisate serotoninergic, noradrenergic and dopaminergic neurotransmission, in a mice model of oxaliplatin-induced neuropathy. Our results support that indatraline provide a better analgesic profile than escitalopram and venlafaxine in pain relief in oxaliplatin-treated mice. Although other investigations are required to quantify the putative involvement of DA in the therapeutic action of indatraline, the benefit can be attributed to this additional component. Indeed, reinforcement of descending control pathways though 5-HT and NE systems has been proposed to participate in the analgesic properties of dual reuptake inhibitors. The fact that indatraline was able to enhance dopaminergic transmission in the Anterior Cingulate Cortex argues in favor of a more potent action upon this inhibitory descending control of pain. Results with indatraline in the depression paradigm cannot rule out the possibility that the antidepressant property of the TRI accounts for its analgesic effect.This work provides a support for the need of animal models sharing anxio/depressive and painful phenotype in order to define mechanism responsible for such co-mobidity and optimize the development of newer antidepressants and pain killers.
... The chronic administration of CORT in the drinking water is a well-recognized neuroendocrinebased model of depressive-like behavior (David et al., 2009). As expected and previously reported in mice (David et al., 2009;Hache et al., 2012;Quesseveur et al., 2013b;Le Dantec et al., 2014), we showed that CORT elicited behavioral anomalies typically observed in depressed patients such as carelessness, despair, and anxiety. Because full quantifiable assessment of mood-related behavior is possible when the same animal is exposed to multiple tests covering a wide range of representative symptoms of depression, we established an emotionality z-score integrating all these behavioral parameters into a single value. ...
... En ce sens, différents marqueurs génétiques ont été identifiés comme source de sensibilité accrue à la DM. Différentes revues de la littérature portent sur les variants génétiques susceptibles d'influencer la vulnérabilité à la DM(Mandelli & une étude révèle également qu'une exposition chronique à la CORT induit une augmentation de la sensibilité à la douleur(Hache et al 2012). De manière intéressante, plusieurs classes antidépresseurs ont été décrites comme ayant des effets comportementaux bénéfiques dans ce modèle. ...
Les cellules gliales dont les astrocytes - au moins aussi nombreux que les neurones dans le cerveau - joueraient un rôle important dans l'anxiété, la dépression et probablement dans la réponse aux antidépresseurs. Plusieurs études menées chez l'Homme et l'animal vont dans ce sens puisqu'elles mettent en évidence une association entre des changements d'expression de différents marqueurs astrocytaires et la sévérité de ces troubles psychiatriques. C'est notamment le cas de la connexine 43 (Cx43), une protéine transmembranaire impliquée dans la formation de deux unités fonctionnelles distinctes : les jonctions communicantes (JCs) qui assurent la communication entre deux astrocytes voisins et les hémicanaux (HCs) dont le rôle est de libérer de molécules neuro-actives (gliotransmetteurs i.e. glutamate, ATP, D-sérine) dans la fente synaptique. En effet, une diminution de l'expression des Cx43 a été rapportée dans différentes régions cérébrales de patients dépressifs et dans des modèles murins de dépression. En revanche, d'un point de vue fonctionnel, l'induction d'un phénotype "anxio-dépressif" serait associée à une diminution de l'activité des JCs et à une augmentation de l'activité des HCs. Face à ces effets opposés, l'objectif de cette thèse était de caractériser plus finement le rôle des Cx43 dans les comportements "anxio-dépressifs" et la réponse aux psychotropes en utilisant des approches d'inactivation génétiques et pharmacologiques de ces protéines. Nos résultats montrent que l'inactivation génétique des Cx43 dans l'hippocampe n'entraine aucun effet neuro-comportemental. En revanche, dans un modèle de dépression basé sur l'exposition chronique des souris à la corticostérone (modèle CORT), l'inactivation génétique des Cx43 exerce des effets de type anxiolytiques-antidépresseurs. D'un point de vue mécanistique, ces effets seraient liés à une diminution de la libération hippocampique de glutamate par les HCs et à une atténuation de la réactivité de l'axe hypothalamo-hypophysaire (HPA). Concernant l'inactivation pharmacologique des Cx43, nos travaux apportent des évidences expérimentales sur le fait que l'administration systémique de carbenoxolone, un bloqueur des connexines, potentialise la réponse aiguë d'un inhibiteur de recapture de la sérotonine en conditions basales, mais s'oppose à ses effets bénéfiques chroniques dans un modèle de dépression. Le microenvironnement cellulaire semble donc essentiel dans la manière dont les Cx43 influencent la réponse aux antidépresseurs. L'ensemble de ces résultats de thèse laissent entrevoir un rôle des Cx43 astrocytaires dans la régulation de l'humeur via la modulation de circuits neuronaux convergeant vers l'axe HPA. Ils soulignent également l'intérêt de moduler les Cx43 pour renforcer l'activité thérapeutiques des antidépresseurs actuellement disponibles. Les futures recherches devront préciser les modalités de ces nouvelles stratégies combinant des agents pharmacologiques à tropisme astrocytaire et neuronal.
... the assessment of multiple behavioral tests in the same animals using an etiologically relevant model of depression that is easily replicable between and within laboratories (David et al., 2009;David et al., 2010;Gould, 2011;Mendez-David et al., 2013). Chronic CORT administration induces high emotionality, associated with a decrease in neurogenesis (David et al., 2009) and altered pain sensitivity (Hache et al., 2012). Such behavioral and neurochemical alterations are reversed by classical and innovative antidepressants (Rainer et al., 2011;Hache et al., 2012). ...
... Chronic CORT administration induces high emotionality, associated with a decrease in neurogenesis (David et al., 2009) and altered pain sensitivity (Hache et al., 2012). Such behavioral and neurochemical alterations are reversed by classical and innovative antidepressants (Rainer et al., 2011;Hache et al., 2012). Interestingly, our group recently reported in this model a flattened circadian rhythm and decreased activity in the home-cage, especially during the dark phase (Rainer et al., 2011). ...
Sleep/wake disorders are frequently associated with anxiety and depression and to elevated levels of cortisol. Even though these alterations are increasingly sought in animal models, no study has investigated the specific effects of chronic corticosterone (CORT) administration on sleep. We characterized sleep/wake disorders in a neuroendocrine mouse model of anxiety/depression, based on chronic CORT administration in the drinking water (35 μg/ml for 4 weeks, “CORT model”). The CORT model was markedly affected during the dark phase by non-rapid eye movement sleep (NREM) increase without consistent alteration of rapid eye movement (REM) sleep. Total sleep duration (SD) and sleep efficiency (SE) increased concomitantly during both the 24 h and the dark phase, due to the increase in the number of NREM sleep episodes without a change in their mean duration. Conversely, the total duration of wake decreased due to a decrease in the mean duration of wake episodes despite an increase in their number. These results reflect hypersomnia by intrusion of NREM sleep during the active period as well as a decrease in sleep/wake continuity. In addition, NREM sleep was lighter, with an increased electroencephalogram (EEG) theta activity. With regard to REM sleep, the number and the duration of episodes decreased, specifically during the first part of the light period. REM and NREM sleep changes correlated respectively with the anxiety and the anxiety/depressive-like phenotypes, supporting the notion that studying sleep could be of predictive value for altered emotional behavior. The chronic CORT model in mice that displays hallmark characteristics of anxiety and depression provides an insight into understanding the changes in overall sleep architecture that occur under pathological conditions.
... The fluoxetine was also delivered in light-protected opaque bottles but was replaced every 4 days until the end of experiment. The dose and duration were chosen based on the procedures of previous studies [35,39,40]. ...
... Subchronic treatment with fluoxetine for 1 or 2 weeks does not produce a substantial ameliorative effect on depression-like behaviors [35,39,40]. In the present study, the photic stimulation at alpha frequencies that was administered over a short period (8-14 days) produced antidepressant effects. ...
Current therapies for depression consist primarily of pharmacological agents, including antidepressants, and/or psychiatric counseling, such as psychotherapy. However, light therapy has recently begun to be considered as an effective tool for the treatment of the neuropsychiatric behaviors and symptoms of a variety of brain disorders or diseases, including depression. One methodology employed in light therapy involves flickering photic stimulation within a specific frequency range. The present study investigated whether flickering and flashing photic stimulation with light emitting diodes (LEDs) could improve depression-like behaviors in a corticosterone (CORT)-induced mouse model of depression. Additionally, the effects of the flickering and flashing lights on depressive behavior were compared with those of fluoxetine. Rhythmical flickering photic stimulation at alpha frequencies from 9-11 Hz clearly improved performance on behavioral tasks assessing anxiety, locomotor activity, social interaction, and despair. In contrast, fluoxetine treatment did not strongly improve behavioral performance during the same period compared with flickering photic stimulation. The present findings demonstrated that LED-derived flickering photic stimulation more rapidly improved behavioral outcomes in a CORT-induced mouse model of depression compared with fluoxetine. Thus, the present study suggests that rhythmical photic stimulation at alpha frequencies may aid in the improvement of the quality of life of patients with depression.
... Kindly confirm if this is fine. "Binder et al., 2010" as "Binder and Nemeroff, 2010" "Dalvi et al., 1999 as " Dalvi andLucki, 1999" "Giaume et al., 2010" as " Giaume and Theis, 2010" "Hache et al., 2015" as "Hache et al., 2012" "Perea et al., 2009" as "Perea and Araque, 2010" "Rouach et al., 2001" as "Rouach and Giaume, 2001" "Trivedi et al., 2014" as "Trivedi and Greer, 2014" "Wang et al., 1997" as "Wang and Veenstra, 1997" "Võikar et al., 2003" as "Võikar et al., 2004." ...
... The chronic administration of CORT in the drinking water is a well-recognized neuroendocrinebased model of depressive-like behavior (David et al., 2009). As expected and previously reported in mice (David et al., 2009;Hache et al., 2012;Quesseveur et al., 2013b;Le Dantec et al., 2014), we showed that CORT elicited behavioral anomalies typically observed in depressed patients such as carelessness, despair, and anxiety. Because full quantifiable assessment of mood-related behavior is possible when the same animal is exposed to multiple tests covering a wide range of representative symptoms of depression, we established an emotionality z-score integrating all these behavioral parameters into a single value. ...
Clinical and preclinical studies have implicated glial anomalies in major depression. Conversely, evidence suggests that the activity of antidepressant drugs is based, at least in part, on their ability to stimulate density and/or activity of astrocytes, a major glial cell population. Despite this recent evidence, little is known about the mechanism(s) by which astrocytes regulate emotionality. Glial cells communicate with each other through gap junction channels (GJCs), while they can also directly interact with neurons by releasing gliotransmitters in the extracellular compartment via an hemichannels (HCs)-dependent process. Both GJCs and HCs are formed by two main protein subunits: connexins (Cx) 30 and 43 (Cx30 and Cx43). Here we investigate the role of hippocampal Cx43 in the regulation of depression-like symptoms using genetic and pharmacological approaches. The first aim of this study was to evaluate the impact of the constitutive knock-down of Cx43 on a set of behaviors known to be affected in depression. Conversely, the expression of Cx43 was assessed in the hippocampus of mice subjected to prolonged corticosterone (CORT) exposure, given either alone or in combination with an antidepressant drug, the selective serotonin reuptake inhibitor fluoxetine. Our results indicate that the constitutive deficiency of Cx43 resulted in the expression of some characteristic hallmarks of antidepressant-/anxiolytic-like behavioral activities along with an improvement of cognitive performances. Moreover, in a new cohort of wild-type mice, we showed that CORT exposure elicited anxiety and depression-like abnormalities that were reversed by chronic administration of fluoxetine. Remarkably, CORT also increased hippocampal amounts of phosphorylated form of Cx43 whereas fluoxetine treatment normalized this parameter. From these results, we envision that antidepressant drugs may exert their therapeutic activity by decreasing the expression and/or activity of Cx43 resulting from a lower level of phosphorylation in the hippocampus.
... It allows the assessment of multiple behavioral tests in the same animals using an etiologically relevant model of depression that is easily replicable between and within laboratories (David et al., 2009; David et al., 2010; Gould, 2011; Mendez-David et al., 2013). Chronic CORT administration induces high emotionality, associated with a decrease in neurogenesis (David et al., 2009) and altered pain sensitivity (Hache et al., 2012). Such behavioral and neurochemical alterations are reversed by classical and innovative antidepressants (Rainer et al., 2011; Hache et al., 2012). ...
... Chronic CORT administration induces high emotionality, associated with a decrease in neurogenesis (David et al., 2009) and altered pain sensitivity (Hache et al., 2012). Such behavioral and neurochemical alterations are reversed by classical and innovative antidepressants (Rainer et al., 2011; Hache et al., 2012). Interestingly, our group recently reported in this model a flattened circadian rhythm and decreased activity in the home-cage, especially during the dark phase (Rainer et al., 2011). ...
Sleep/wake disorders are frequently associated with anxiety and depression and to elevated levels of cortisol. Even though these alterations are increasingly sought in animal models, no study has investigated the specific effects of chronic corticosterone administration on sleep. We characterized sleep/wake disorders in a neuroendocrine mouse model of anxiety/depression, based on chronic corticosterone administration in the drinking water (35 μg/ml for 4 weeks, "CORT model"). The CORT model was markedly affected during the dark phase by NREM sleep increase without consistent alteration of REM sleep. Total sleep duration and sleep efficiency increased concomitantly during both the 24h and the dark phase, due to the increase in the number of NREM sleep episodes without change in their mean duration. Conversely, the total duration of wake decreased due to a decrease in the mean duration of wake episodes despite an increase in their number. These results reflect hypersomnia by intrusion of NREM sleep during the active period as well as decrease in sleep/wake continuity. In addition, NREM sleep was lighter, with an increased EEG theta activity. With regard to REM sleep, the number and the duration of episodes decreased, specifically during the first part of the light period. REM and NREM sleep changes correlated respectively with the anxiety and the anxiety/depressive-like phenotypes, supporting the notion that studying sleep could be of predictive value for altered emotional behavior. The chronic CORT model in mice that displays hallmark characteristics of anxiety and depression provides an insight into understanding the changes in overall sleep architecture that occur under pathological conditions.
... For example, anxiety and depression are frequently experienced by patients suffering from chronic pain 30,31 , and these conditions are accompanied by impairments in learning and memory 32,33 . The involvement of melanocortins in anhedonia and cognitive deficits might contribute to the multisymptomatic manifestation of depression that follows chronic pain 34,35 (FIG. ...
... Melanocortins seem to be present in symptomatically complex diseases and disorders, in which the appearance of the initial symptom is followed by the development of subsequent undesirable outcomes. For example, heightened nociception in certain pain modalities is typically reported in individuals with depression 30,31 . The involvement of melanocortins in anhedonia and improper cognitive processing (see main text) further contributes to the multisymptomatic manifestation of the disease. ...
The melanocortin system has a well-established role in the regulation of energy homeostasis, but there is growing evidence of its involvement in memory, nociception, mood disorders and addiction. In this Review, we focus on the role of the melanocortin 4 receptor and provide an integrative view of the molecular mechanisms that lead to melanocortin-induced changes in synaptic plasticity within these diverse physiological systems. We also highlight the importance of melanocortin peptides and receptors in chronic pain syndromes, memory impairments, depression and drug abuse, and the possibility of targeting them for therapeutic purposes.
... 75 In fact, Akita and colleagues showed that HPA axis activity is a good marker of disease severity and prognosis in patients with extensive burns. 1 Although little is known about the influence of HPA axis function on burn pain, there is evidence that 8 weeks of cortisol administration by drinking water is coupled with thermal hyperalgesia in rodents. 33 Taken together, these findings suggest that preexisting alterations in HPA axis function resulting from ACE exposure could be mechanistically linked to disadvantageous outcomes after a burn injury in adults with this history. This would be consistent with notions that prolonged activation of stress systems contributes to central sensitization and exacerbated responses to pain and noxae. ...
Adverse childhood experiences (ACEs) affect over half of the adults in the United States and are known to contribute to the development of a wide variety of negative health and behavioral outcomes. The consequences of ACE exposure have been studied in patient populations that include individuals with gynecologic, orthopedic, metabolic, autoimmune, cardiovascular, and gastrointestinal conditions among others. Findings indicate that ACEs not only increase risks for chronic pain but also influence emotional responses to pain in many of these individuals. A growing body of research suggests that these effects may be the result of long-lasting changes induced by ACEs in neurobiological systems during early development. However, one area that is still largely unexplored concerns the effects of ACEs on burn patients, who account for almost 450,000 hospitalizations in the United States annually. Patients with severe burns frequently suffer from persistent pain that affects their well-being long after the acute injury, but considerable variability has been observed in the experience of pain across individuals. A literature search was conducted in CINAHL and PubMed to evaluate the possibility that previously documented ACE-induced changes in biological, psychological, and social processes might contribute to these differences. Findings suggest that better understanding of the role that ACEs play in burn outcomes could lead to improved treatment strategies, but further empirical research is needed to identify the predictors and mechanisms that dictate individual differences in pain outcomes in patients with ACE exposure and to clarify the role that ACE-related alterations play in early healing and recovery from burn injuries.
... Cette association entre anxiété et douleur a déjà été rapporté dans la littérature et on peut émettre l'hypothèse que cette douleur exacerbée soit responsable des troubles émotionnels observés chez les souris STZ. En effet des travaux chez l'humain ou l'animal montrent que l'induction de douleurs neuropathiques (constriction nerf sciatique, injection d'agent intercalent de l'ADN : oxaliplatine) augmente l'état anxieux et provoque des symptômes de type dépressifs chez le rongeur(Hache et al., 2012).ii. Dans un modèle de souris de DT2 combinant des facteurs de risque génétiques (système apelinergique) et environnementaux (alimentation hyper-lipidique) ? ...
Les études épidémiologiques estiment que le risque de dépression majeure (DM) est plus élevé chez les patients diabétiques comparé à la population générale. Des études plus spécifiques mettent en lumière des corrélations entre la dégradation de certains paramètres métaboliques et les symptômes anxio-dépressifs chez l'humain. C'est notamment le cas pour l'insulino-résistance périphérique qui est positivement corrélée à la sévérité de la DM. En revanche, les conséquences de l'insulino-résistance centrale sur les troubles dépressifs n'ont jamais été étudiés de manière approfondie non seulement en clinique mais également chez l'animal de laboratoire. Compte tenu de la présence du récepteur à l'insuline dans le cerveau, une des hypothèses serait que cette hormone module directement (ou indirectement) l'activité des systèmes monoaminergiques et notamment celle des neurones sérotoninergiques (5-HT) majoritairement regroupé dans le noyau dorsal du raphé (NDR). En effet, si l'influence de l'insuline sur le système dopaminergique et le comportement alimentaire a déjà été montré, très peu d'études se sont intéressées à son impact sur le système 5-HT pourtant clé dans la physiopathologie de la DM. Au cours de ce travail de thèse nous avons pu montrer que le récepteur à l'insuline est présent sur les neurones 5-HT du NDR. Grâce à des techniques d'électrophysiologie ex- et in-vivo et de microdialyse intracérébrale réalisées sur modèle murin, nous avons caractérisé l'effet excitateur de l'insuline sur l'activité électrique des neurones 5-HT. Ces résultats nous ont amené à tester les effets comportementaux de l'insuline et à montrer les effets anxiolytiques de son injection intra-raphé et intra-nasale chez la souris saine. Dans un second temps, afin de se placer dans un contexte pathologique et de mieux comprendre l'impact de la perturbation de la signalisation de l'insuline sur l'humeur, nous avons étudié l'activité du système 5-HT et les comportements de type anxio-dépressifs dans des modèles murins de diabète de type 1 et 2 (DT1/DT2). Dans ces deux modèles, que ce soit dans un contexte d'insulinopénie (DT1) ou d'insulino-résistance (DT2), les souris présentent un phénotype anxieux et certains traits de la DM associés à un diminution de l'activité du système sérotoninergique du NDR. Enfin, nous avons tenté d'identifier l'implication de l'apeline, une adipokine connue pour ses propriétés insulino-sensibilisatrice sur les anomalies comportementales induites par un DT2. Nos résultats montrent que les souris présentant une invalidation génétique de l'apeline, sont plus susceptibles à développer une insulino-résistance en réponse à un régime alimentaire diabétogène et des troubles comportementaux. De manière intéressante le traitement par la metformine, un antidiabétique aux propriétés insulino-sensibilisatrice, ne permet pas l'amélioration des paramètres métaboliques de ces souris mutantes mais améliore leur état anxieux. Ainsi ce travail de thèse a permis de souligner l'existence d'interactions anatomiques et fonctionnelles entre le système insulinergique et sérotoninergique central ainsi que leur importance dans l'anxiété, un trouble psychiatrique souvent annonciateur d'un épisode dépressif. [...]
... In second place are the anxiety disorders, which often occur concomitantly with depression, affecting twice as many diabetic patients compared to the normoglycemic population (Buchberger et al., 2016;Bystritsky et al., 2014;Jain et al., 2011;Naicker et al., 2017). Based on the relationship between these diabetic complications, several studies suggest that the evaluation of pain, as well as the symptoms of anxiety and depression, should be performed simultaneously in diabetic animal models (Hache et al., 2012). ...
Neuropathic pain, depression, and anxiety are common comorbidities in diabetic patients, whose pathophysiology involves hyperglycemia-induced increased oxidative stress. Bixin (BIX), an apocarotenoid extracted from the seeds of Bixa orellana, has been used in traditional medicine to treat diabetes and has been recognized by its antioxidant profile. We aimed to investigate the effect of the BIX over the mechanical allodynia, depressive, and anxious-like behaviors associated with experimental diabetes, along with its involved mechanisms. Streptozotocin-induced diabetic rats were treated for 17 days (starting 14 days after diabetes induction) with the corresponding vehicle, BIX (10, 30 or 90 mg/kg; p.o), or INS (6 IU; s.c.). Mechanical allodynia, depressive, and anxious-like behavior were assessed by electronic Von Frey, forced swimming, and elevated plus-maze tests, respectively. Locomotor activity was assessed by the open field test. Blood glycated hemoglobin (HbA1) and the levels of lipid peroxidation (LPO) and reduced glutathione (GSH) were evaluated on the hippocampus, pre-frontal cortex, lumbar spinal cord, and sciatic nerve. Diabetic animals developed mechanical allodynia, depressive and anxious-like behavior, increased plasma HbA1, increased LPO, and decreased GSH levels in tissues analyzed. Repeated BIX-treatment (at all tested doses) significantly attenuated mechanical allodynia, the depressive (30 and 90 mg/kg) and, anxious-like behaviors (all doses) in diabetic rats, without changing the locomotor performance. BIX (at all tested doses) restored the oxidative parameters in tissues analyzed and reduced the plasma HbA1. Thereby, bixin may represent an alternative for the treatment of comorbidities associated with diabetes, counteracting oxidative stress and plasma HbA1.
... The latter has been widely used, and several pieces of evidence emphasize its face, construct, and predictive validity. For instance, CORT exposure in mice elicits behavioral response recapitulating the core symptoms of MD such as despair, anhedonia, decreased self-care, and anxiety [5,6], as well as impairment of cognitive performances [7], sleep disruption [8], and somatic pain [9]. Interestingly, the chronic administration of CORT also elicits neurobiological impairments associated with MD, notably the fact that it leads to a significant reduction of adult hippocampal neurogenesis [5,10]. ...
The forced swim stress test (FST) is widely used for screening pharmacological or non-pharmacological strategies with potential antidepressant activities. Recent data have suggested that repeated FST for five consecutive days (i.e., 5d-RFSS) could be used to generate a robust depressive-like phenotype in mice. However, the face, construct, and predictive validities of 5d-RFSS have been recently challenged. This study took advantage of recent findings showing that mice vulnerability to anxiety is enhanced when animals are stressed during the dark phase, to provide new insight into the relevance of this model. Our results showed a progressive increase in time of immobility in 5d-RFSS mice relative to control non-stressed animals (sham). Three weeks later, we noticed that 5d-RFSS mice injected with the vehicle compound (Veh) still exhibited a high level of immobility in the FST whereas this behavior was reversed by the antidepressant drug amitriptyline (AMI). However, 5d-RFSS/Veh and 5d-RFSS mice/AMI mice showed normal performances in the open field, the novelty suppressed feeding and the tail suspension tests. Despite this lack of generalized behavioral deficits, an impairment of different parameters characterizing the hypothalamic-pituitary-adrenal (HPA) axis reactivity was evidenced in 5d-RFSS mice/Veh but not in 5d-RFSS mice/AMI. Despite anomalies in the HPA axis, the activity of the central serotonergic system remained unaffected in 5d-RFSS mice relative to controls. From our results, it is suggested that learned immobility does not replicate the broad spectrum of depressive symptoms observed in other chronic models of depression such as the unpredictable chronic mild stress (UCMS) model, the chronic social defeat stress (CSDS) model or chronic corticosterone (CORT) exposure but its influence on the HPA axis is remarkable. Further experiments are warranted to makes this model suitable for modelling depression and therefore refine its translational applicability.
... Hache G, et al. пришли к выводу, что снижение термической аллодинии в модели хронического стресса у мышей напрямую связано с влиянием препарата на тревожно-депрессивное состояние у животных [44]. ...
The article attempts to generalize the currently known pathogenetic mechanisms of antinociceptive effects of the most widely used antidepressants and to forecast their effectiveness in certain comorbid pathologies
... However, chronic (rather than acute) stress tends to be pronociceptive (Jennings et al., 2014;Olango and Finn, 2014). For example, rodents chronically treated with corticosterone exhibit cold allodynia and heat hyperalgesia (Hache et al., 2012), and prior corticosterone administration enhances mechanical allodynia to a noxious inflammatory stimulus (Loram et al., 2011). Thus, altered programming of the HPA axis by early-life stress may result in chronically elevated CRH/corticosterone and heightened pain responses or compromised stress-induced analgesia under acutely stressful conditions. ...
... Food and water deprivation was not used as stressors due to ethical reasons. The evolution of UCMSinduced depressive-like behaviour was quantified weekly by recording the coat state score, which is a pharmacologically validated index for this purpose (Farooq et al., 2012;Hache et al., 2012;Santarelli et al., 2003). The coat state score consists of evaluating eight different body parts of mice, namely, the head, neck, dorsal coat, ventral coat, tail, forepaws, hind paws and genital region, for signs of degradation. ...
A polymorphism in the P2RX7 gene that encodes for the P2X7 ionotropic ATP-gated receptor (P2X7R) protein has been shown to be associated with an increased risk for developing depressive illnesses. However, the role of P2X7R in depression is still unclear. To better understand the role of P2X7R and its subsequent impact on microglial activation, we compared the effect of the P2X7R antagonist Brilliant Blue G (BBG) with that of fluoxetine in an unpredictable chronic mild stress (UCMS) model of depression in mice. Our results indicate that BBG (50 mg/kg body weight in 0.9% NaCl, 10 ml/kg/day) successfully reversed the degradation of coat states and nest-building scores induced by exposure to UCMS, similar to the conventional antidepressant fluoxetine (15 mg/kg body weight in 0.9% NaCl, 10 ml/kg/day). BBG also reversed the UCMS-induced microglial activation in cortical and hippocampal regions and the basal nuclei of mouse brains and corrected the UCMS-induced hypothalamo-pituitary-adrenal (HPA) axis dysregulation. In contrast to fluoxetine, however, BBG treatment did not increase the density of doublecortin-positive cells in the dentate gyrus, indicating that BBG had no impact on hippocampal neurogenesis. These results suggest that P2X7R is involved in recovery from depressive-like states caused by exposure to UCMS in a mechanism that involves restoration of the HPA axis but not hippocampal neurogenesis. These results add to the evidence that P2X7R antagonist agents may have potential value in the pharmacological management of depression.
... The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. receptors stimulating the release of an array of inhibitory neuropeptides [4][5][6][7]. In fact, monoamines and neuropeptides interact to modulate most, if not all, key behaviors in C. elegans. ...
Monoamines and neuropeptides often modulate the same behavior, but monoaminergic-peptidergic crosstalk remains poorly understood. In Caenorhabditis elegans, the adrenergic-like ligands, tyramine (TA) and octopamine (OA) require distinct subsets of neuropeptides in the two ASI sensory neurons to inhibit nociception. TA selectively increases the release of ASI neuropeptides encoded by nlp-14 or nlp-18 from either synaptic/perisynaptic regions of ASI axons or the ASI soma, respectively, and OA selectively increases the release of ASI neuropeptides encoded by nlp-9 asymmetrically, from only the synaptic/perisynaptic region of the right ASI axon. The predicted amino acid preprosequences of genes encoding either TA- or OA-dependent neuropeptides differed markedly. However, these distinct preprosequences were not sufficient to confer monoamine-specificity and additional N-terminal peptide-encoding sequence was required. Collectively, our results demonstrate that TA and OA specifically and differentially modulate the release of distinct subsets of neuropeptides from different subcellular sites within the ASIs, highlighting the complexity of monoaminergic/peptidergic modulation, even in animals with a relatively simple nervous system.
... However, chronic (rather than acute) stress tends to be pronociceptive (Jennings et al., 2014;Olango and Finn, 2014). For example, rodents chronically treated with corticosterone exhibit cold allodynia and heat hyperalgesia (Hache et al., 2012), and prior corticosterone administration enhances mechanical allodynia to a noxious inflammatory stimulus (Loram et al., 2011). Thus, altered programming of the HPA axis by early-life stress may result in chronically elevated CRH/corticosterone and heightened pain responses or compromised stress-induced analgesia under acutely stressful conditions. ...
A wealth of research over the past 2 decades has expanded our understanding of the impact of early-life adversity on physiological function and, consequently, health and wellbeing in later life. Early-life adversity increases the risk of developing a number of disorders, such as chronic pain, fibromyalgia, and irritable bowel syndrome. Although much of the research has examined the impact of physical maltreatment, an increasing number of studies have been published over the past few years examining the effect of childhood psychological stress and trauma on the development of various types of chronic pain conditions. We review the clinical and preclinical data examining the link among early-life psychological stress, altered nociceptive behavior, and chronic pain in later life. Evidence supporting a role for certain key neurobiological substrates, including the hypothalamic-pituitary-adrenal axis; monoaminergic, opioidergic, endocannabinoid and immune systems; and epigenetic mechanisms in the association between early-life psychological stress and chronic pain, is provided. Greater understanding of the impact of early-life stress may inform the development of personalized treatments for chronic pain in later life and strategies to prevent its onset in susceptible individuals. © 2016 Wiley Periodicals, Inc.
... The dose and duration of corticosterone treatment (CORT model) were selected based on previous studies Hache et al., 2012;Rainer et al., 2012a,b). Exposure to chronic corticosterone results in a phenotype that is similar to a chronic stress phenotype, including a deterioration of the coat state and anxiety/depression-related behaviors. ...
Selective serotonin reuptake inhibitors (SSRIs) display a delayed onset of action of several weeks. Past work demonstrated evidence that the 5-HT4 receptor may be a direct target for treating depression and a new hope for fast acting antidepressant treatment. However, the 5-HT4 hypothesis still needs to be validated in models of anxiety/depression.We decided to investigate whether 5-HT4 receptor stimulation was necessary for the effects of SSRIs in a mouse model of anxiety/depression and whether hippocampal neurogenesis contributed to these effects. Using the mouse corticosterone model of anxiety/depression, we assessed whether chronic treatment with a 5-HT4 receptor agonist (RS67333, 1.5 mg/kg/day) had effects on anxiety and depression-related behaviors as well as on hippocampal neurogenesis in comparison to chronic fluoxetine treatment (18 mg/kg/day). Then, using our model combined with ablation of hippocampal neurogenesis, we investigated whether neurogenesis was necessary for the behavioral effects of subchronic (7-days) or chronic (28-days) RS67333 treatment. We also assessed whether a 5-HT4 receptor antagonist, (GR125487, 1 mg/kg/day) could prevent the behavioral and neurogenic effects of fluoxetine. Chronic treatment with RS67333, similar to fluoxetine, induced anxiolytic/antidepressant-like activity and stimulated adult hippocampal neurogenesis. However, unlike fluoxetine, the anxiolytic effects of RS67333 were already present after 7 days and did not require hippocampal neurogenesis. Chronic treatment with GR125487 prevented both anxiolytic/antidepressant-like and neurogenic effects of fluoxetine, indicating that 5-HT4 receptor activation is necessary for these effects of SSRIs. We then explored whether the fast onset of action of the 5-HT4 receptor agonist RS67333 could be predicted by expression of a peripheral biomarker. The β-arrestin-signaling cascade which is involved in 5-HT4 receptor desensitization and internalization, has recently gained attention as a potential pre-clinical/clinical bridging biomarker for depressive states and treatment effects. To this end, we developed a new method to assess levels of circulating proteins through immunoblot analyses of mouse PBMCs isolated from whole blood of anesthetized animals. While we did not detect any change in β-arrestin 1 in mouse leukocytes after 7 days of fluoxetine in corticosterone-treated animals, a short term treatment with RS67333, restored the level of this protein to control levels. In fluoxetine-treated animals, a restoration was only observed in the corticosterone model after a longer exposure. These results suggest that blood levels of β-arrestin 1 may be a useful biomarker to predict antidepressant/anxiolytic activities. Finally, the activation of 5-HT4 receptors in the brain may represent an innovative and rapid onset therapeutic approach to treat depression with comorbid anxiety.
... The T2PT was performed as described previously ( Hache et al., 2012). Briefly, mice were allowed to freely explore an enclosure in which the floor is composed by two adjoining thermoelectric computer-managed metal plates (Bioseb Inc.). ...
Background: Chronic neuropathic pain can lead to anxiety and depression. Drugs that block reuptake of serotonin, norepinephrine and/or dopamine are widely used to treat depression, and have emerged as useful drugs in the treatment of neuropathic pain. This study compared the acute antinociceptive effects of NS18283, a novel triple monoamine reuptake inhibitor (MRI) with indatraline, venlafaxine and escitalopram in a mouse model of neuropathic pain. Method: Neuropathic pain-like behaviours were induced in mice by repeated injections of oxaliplatin (OXA), and assessed using the von Frey hair test, the cold plate test and the thermal preference plate test. Anxio/depressive phenotype and antidepressant-like properties of compounds were assessed by the novelty suppressed feeding test and the tail suspension test, respectively. Results: In vivo microdialysis experiments showed that each MRI increased extracellular serotonin, norepinephrine and/or dopamine levels in the cingulate cortex, in agreement with their in vitro reuptake inhibitory properties. Indatraline (3 mg/kg) reversed the full repertoire of OXA-induced neuropathic hypersensitivity. NS18283 (10 mg/kg) reversed OXA-induced mechano-hypersensitivity and cold allodynia. Venlafaxine (16 mg/ kg) and escitalopram (4 mg/kg) only reversed cold allodynia and mechano-hypersensitivity, respectively. All MRIs produced antidepressant-like activity in anxio/depressive phenotype of OXA mice. Conclusions: Acute administration of drugs that enhance the activity of serotonin, norepinephrine and dopamine neurotransmission within nociceptive pathways may provide a broader spectrum of antinociception than dual or selective reuptake inhibitors in animal models of neuropathic pain. Whether similar observations would occur after repeated administration of such compounds in an attempt to simulate dosing in humans, or be compromised by dopaminergic-mediated adverse effects warrants further investigation.
... In a very recent and interesting review, Naomi Eisenberger suggests that " the experiences of social pain—the painful feelings associated with social disconnection—rely on some of the same neurobiological substrates that underlie experiences of physical pain " sharing therefore common signaling pathways leading to the modulation of nociceptive threshold throughout life as fine adaptation to emotional life events [70]. Indeed, chronic pain has been also found to be co-morbid with anxiety and depression [71] in a cause– effect vicious circle and recent evidence reports pain relief in a mouse model of stress as a result of chronic treatment with the selective serotonin reuptake inhibitor fluoxetine (an antidepressant able to reverse anxiety/depressive-like state) [72]. Interestingly, Berton and co-workers found that chronic administration of either fluoxetine or imipramine improved social interaction in mice undergoing SD stress, suggesting a link between neuronal pathways involved in the circuitry of reward and sociality [16]; similarly it has been proposed that common pathways involving pain and reward systems might have evolved to support complex social experiences [70,73747576. ...
Animal models with an eco-ethological relevance can help in identifying novel and reliable stress-related markers. To this end, 3-month-old C57BL/6J male mice were exposed to social defeat (SD) stress for 10 days as this stressor shows good face and predictive validity for several models of human affective disorders including depression, social phobia and post-traumatic stress disorder. Social avoidance and pain threshold were assessed 24 h and 4 weeks after the end of SD stress, while corticosterone was assayed at the beginning and at the end of the stressful procedure (days 1 and 10). SD subjects were characterized by increased corticosterone levels (30 min following stress exposure), increased latency to approach the social target in the short-term as well as increased emotionality in the long-term. Moreover, an increase in nociceptive threshold (stress-induced analgesia) was found both in the short-term and 4 weeks after the end of stress. These data indicate that the SD paradigm is able to induce emotional changes associated with a stressful/traumatic event. In addition, they indicate that variations in the nociceptive threshold might represent a physiological marker of both short-and long-term effects of stress.
... The T2PT was performed as described previously (Hache et al., 2012). Briefly, mice were allowed to freely explore an enclosure in which the floor is composed by two adjoining thermoelectric computer-managed metal plates (Bioseb Inc.). ...
Background
Chronic neuropathic pain can lead to anxiety and depression. Drugs that block reuptake of serotonin, norepinephrine and/or dopamine are widely used to treat depression, and have emerged as useful drugs in the treatment of neuropathic pain. This study compared the acute antinociceptive effects of NS18283, a novel triple monoamine reuptake inhibitor (MRI) with indatraline, venlafaxine and escitalopram in a mouse model of neuropathic pain.Method
Neuropathic pain-like behaviours were induced in mice by repeated injections of oxaliplatin (OXA), and assessed using the von Frey hair test, the cold plate test and the thermal preference plate test. Anxio/depressive phenotype and antidepressant-like properties of compounds were assessed by the novelty suppressed feeding test and the tail suspension test, respectively.ResultsIn vivo microdialysis experiments showed that each MRI increased extracellular serotonin, norepinephrine and/or dopamine levels in the cingulate cortex, in agreement with their in vitro reuptake inhibitory properties. Indatraline (3 mg/kg) reversed the full repertoire of OXA-induced neuropathic hypersensitivity. NS18283 (10 mg/kg) reversed OXA-induced mechano-hypersensitivity and cold allodynia. Venlafaxine (16 mg/kg) and escitalopram (4 mg/kg) only reversed cold allodynia and mechano-hypersensitivity, respectively. All MRIs produced antidepressant-like activity in anxio/depressive phenotype of OXA mice.Conclusions
Acute administration of drugs that enhance the activity of serotonin, norepinephrine and dopamine neurotransmission within nociceptive pathways may provide a broader spectrum of antinociception than dual or selective reuptake inhibitors in animal models of neuropathic pain. Whether similar observations would occur after repeated administration of such compounds in an attempt to simulate dosing in humans, or be compromised by dopaminergic-mediated adverse effects warrants further investigation.
... implications and may be relevant to better understanding some mental health disorders (ie, depression, post-traumatic stress disorder), specifically as chronic CORT exposure is commonly used to induce various behavioral aspects of these disorders (Ardayfio and Kim, 2006;Gourley and Taylor, 2009;Hache et al, 2012;Rainer et al, 2011). Further, this is especially relevant given that pharmacological manipulation of mGluR5 and other mGluRs is of interest as potential therapeutics for the treatment of neuropsychiatric disorders (Krystal et al, 2010;Witkin et al, 2007). ...
Escalations in alcohol drinking associated with experiencing stressful life events and chronic life stressors may be related to altered sensitivity to the interoceptive/subjective effects of alcohol. Indeed, through the use of drug discrimination methods, rats show decreased sensitivity to the discriminative stimulus (interoceptive) effects of alcohol following exposure to the stress hormone corticosterone (CORT). This exposure produces heightened elevations in plasma CORT levels (eg, as may be experienced by an individual during stressful episodes). We hypothesized that decreased sensitivity to alcohol may be related, in part, to changes in metabotropic glutamate receptors-subtype 5 (mGluR5) in the nucleus accumbens, as these receptors in this brain region are known to regulate the discriminative stimulus effects of alcohol. In the accumbens, we found reduced mGluR5 expression (immunohistochemistry and Western blot) and decreased neural activation (as measured by c-Fos immunohistochemistry) in response to a moderate alcohol dose (1 g/kg) following CORT exposure (7 days). The functional role of these CORT-induced adaptations in relation to the discriminative stimulus effects of alcohol was confirmed, as both the systemic administration of 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) an mGluR5 positive allosteric modulator and the intra-accumbens administration of (R,S)-2-Amino-2-(2-chloro-5-hydroxyphenyl)acetic acid sodium salt (CHPG) an mGluR5 agonist restored sensitivity to alcohol in discrimination-trained rats. These results suggest that activation of mGluR5 may alleviate the functional impact of the CORT-induced downregulation of mGluR5 in relation to sensitivity to alcohol. Understanding the contribution of such neuroadaptations to the interoceptive effects of alcohol may enrich our understanding of potential changes in subjective sensitivity to alcohol during stressful episodes.
... Recent findings from animal experiments suggest that the 5-HT reuptake inhibition in the brain is related to a reduction of pain (Matsuzawa-Yanagida et al., 2008;Hayashi et al., 2009;Hache et al., 2012). However, there is no report of in vivo human brain 5-HT transporter (5-HTT) occupancy by tramadol. ...
Tramadol is used for the treatment of pain, and it is generally believed to activate the μ-opioid receptor and inhibit serotonin (5-HT) and norepinephrine (NE) transporters. Recent findings from animal experiments suggest that 5-HT reuptake inhibition in brain is related to pain reduction. However, there has been no report of 5-HT transporter (5-HTT) occupancy by tramadol at clinical doses in humans. In the present study, we investigated 5-HTT occupancy by tramadol in five subjects receiving various doses of tramadol by using positron emission tomography (PET) scanning with the radioligand [11C]DASB. Our data showed that mean 5-HTT occupancies in the thalamus by single doses of tramadol were 34.7% at 50 mg and 50.2% at 100 mg. The estimated median effective dose (ED50) of tramadol was 98.1 mg, and the plasma concentration was 0.33 μg/ml 2 h after its administration; 5-HTT occupancy by tramadol was dose-dependent. We estimated 5-HTT occupancy at 78.7% upon taking an upper limit dose (400 mg) of tramadol. The results of the present study support the finding that 5-HTT inhibition is involved in the mechanism underlying the analgesic effect of tramadol in humans, and a clinical dose of tramadol sufficiently inhibits 5-HTT reuptake; this inhibition is similar to that shown by selective serotonin reuptake inhibitors (SSRIs).
... The dose and duration of corticosterone treatment (CORT model) were selected based on previous studies (David et al., 2009; Guilloux et al., 2011; Hache et al., 2012; Rainer et al., 2012a,b ). Exposure to chronic corticosterone results in a phenotype that is similar to a chronic stress phenotype, including a deterioration of the coat state and anxiety/depression-related behaviors. ...
A limited number of biomarkers in the central and peripheral systems which are known may be useful for diagnosing major depressive disorders and predicting the effectiveness of antidepressant (AD) treatments. Since 60% of depressed patients do not respond adequately to medication or are resistant to ADs, it is imperative to delineate more accurate biomarkers. Recent clinical studies suggest that β-arrestin 1 levels in human mononuclear leukocytes may be an efficient biomarker. If potential biomarkers such as β-arrestin 1 could be assessed from a source such as peripheral blood cells, then they could be easily monitored and used to predict therapeutic responses. However, no previous studies have measured β-arrestin 1 levels in peripheral blood mononuclear cells (PBMCs) in anxious/depressive rodents. This study aimed to develop a method to detect β-arrestin protein levels through immunoblot analyses of mouse PBMCs isolated from whole blood. In order to validate the approach, β-arrestin levels were then compared in na\"{\i}ve, anxious/depressed mice, and anxious/depressed mice treated with a selective serotonin reuptake inhibitor (fluoxetine, 18~mg/kg/day in the drinking water). The results demonstrated that mouse whole blood collected by submandibular bleeding permitted isolation of enough PBMCs to assess circulating proteins such as β-arrestin 1. β-Arrestin 1 levels were successfully measured in healthy human subject and na\"{\i}ve mouse PBMCs. Interestingly, PBMCs from anxious/depressed mice showed significantly reduced β-arrestin 1 levels. These decreased β-arrestin 1 expression levels were restored to normal levels with chronic fluoxetine treatment. The results suggest that isolation of PBMCs from mice by submandibular bleeding is a useful technique to screen putative biomarkers of the pathophysiology of mood disorders and the response to ADs. In addition, these results confirm that β-arrestin 1 is a potential biomarker for depression.
... The cold plate test was performed to assess nociception to a cold painful stimulus [66]. Mice were placed individually on a cold plate at 2.060.3uC, with four 30.5-cm ...
Limited information is available regarding the cellular mechanisms of oxaliplatin-induced painful neuropathy during exposure of patients to this drug. We therefore determined oxidative stress in cultured cells and evaluated its occurrence in C57BL/6 mice. Using both cultured neuroblastoma (SH-SY5Y) and macrophage (RAW 264.7) cell lines and also brain tissues of oxaliplatin-treated mice, we investigated whether oxaliplatin (OXA) induces oxidative stress and apoptosis. Cultured cells were treated with 2-200 µM OXA for 24 h. The effects of pharmacological inhibitors of oxidative stress or inflammation (N-acetyl cysteine, ibuprofen, acetaminophen) were also tested. Inhibitors were added 30 min before OXA treatment and then in combination with OXA for 24 h. In SH-SY5Y cells, OXA caused a significant dose-dependent decrease in viability, a large increase in ROS and NO production, lipid peroxidation and mitochondrial impairment as assessed by a drop in mitochondrial membrane potential, which are deleterious for the cell. An increase in levels of negatively charged phospholipids such as cardiolipin but also phosphatidylserine and phosphatidylinositol, was also observed. Additionally, OXA caused concentration-dependent P2X7 receptor activation, increased chromatin condensation and caspase-3 activation associated with TNF-α and IL-6 release. The majority of these toxic effects were equally observed in Raw 264.7 which also presented high levels of PGE2. Pretreatment of SH-SY5Y cells with pharmacological inhibitors significantly reduced or blocked all the neurotoxic OXA effects. In OXA-treated mice (28 mg/kg cumulated dose) significant cold hyperalgesia and oxidative stress in the tested brain areas were shown. Our study suggests that targeting P2X7 receptor activation and mitochondrial impairment might be a potential therapeutic strategy against OXA-induced neuropathic pain.
... Hence, regarding SNRIs, it clearly appears that their « acceptability » is lower than that of SSRIs [203] thereby challenging their superiority. In addition, the current evaluations of antidepressants are mainly focusing on mood, whereas other types of symptoms regulated by 5-HT and NE such as pain [207] or cognition [208] should be considered as well. For example, growing evidence suggests that changes in emotional memory are particularly relevant to antidepressant response [209]. ...
Introduction:
One third of depressed patients do not respond adequately to conventional antidepressants including the selective serotonin reuptake inhibitors (SSRIs). Therefore, multi-target drugs or augmentation strategies have been developed for the management of SSRIs-resistant patients. In this context, the 5-HT(2) receptor subtypes represent promising targets but their precise roles have yet to be determined.
Areas covered:
The aim of this review is to shed some light on the preclinical evidence supporting the use of 5-HT(2A) and/or 5-HT(2C) receptor antagonists such as antipsychotics, as potential effective adjuncts in SSRIs-resistant depression. This review synthesizes the current literature about the behavioral, electrophysiological and neurochemical effects of 5-HT(2) receptors ligands on the monoaminergic systems but also on adult hippocampal neurogenesis.
Expert opinion:
Although studies support the hypothesis that the inactivation of 5-HT(2A) and/or 5-HT(2C) receptors might be of interest to reinforce different facets of the therapeutic activity of SSRIs, this pharmacological strategy remains debatable notably because of the lack of chronic data in relevant animal models. Conversely, emerging evidence suggests that the activation of 5-HT(2B) receptor is required for antidepressant-like activity, opening the way to new therapeutic approaches. However, the potential risks related to the enhancement of monoaminergic neurotransmissions could represent a major concern.
In the present study, we examined the neurobehavioral effects of a sensory functional food ingredient mainly based on Citrus sinensis extracts (D11399) using a battery of tests recapitulating various endophenotypes of depression such as anxiety in the open field (OF), the elevated plus-maze (EPM), and the novelty suppressed feeding (NSF), self-care in the splash test (ST), despair in the forced swimming task (FST) but also anhedonia in the sucrose preference test (SPT) in mice. A one-week oral administration of D11399 promoted anxiolytic- and antidepressant-like responses in naïve mice subjected to the NSF and FST. In a marked contrast, the administration of D11399 by oral gavage or the inhibition of olfaction by methimazole prevented such beneficial effects. We further investigated the neurobehavioral properties of a ten-week oral administration of D11399 in the corticosterone (CORT) mouse model of depression. Interestingly, D11399 also elicited anxiolytic- and antidepressant-like effects in various paradigms. To characterize the putative underpinning neurobiological mechanisms in CORT mice, we investigated whether cellular and molecular processes commonly associated with antidepressant responses such as monoaminergic neurotransmission and neuronal maturation in the hippocampus were impacted. Although D11399 did not modify the hippocampal extracellular levels of monoamines (i.e. serotonin and norepinephrine), it reversed the ability of CORT to decrease serotonin neurons firing rate in the dorsal raphe and neuronal maturation in the hippocampus. These findings suggest that the anxiolytic- and antidepressant-like effects of this sensory functional food ingredient are closely related with olfaction and likely a concomitant change in the activity of the central serotonergic system. Further experiments are warranted to precise the neuronal circuits linking sensorial and emotional modalities and identify innovative therapeutic strategies aimed to relieve depressive endophenotypes.
Pain is the most common sensation installed in us naturally which plays a vital role in defending us against severe harm. This neurological mechanism pathway has been one of the most complex and comprehensive topics but there has never been an elaborate justification of the types of analgesics that used to reduce the pain sensation through which specific pathways. Of course, there have been some answers to curbing of pain which is a lifesaver in numerous situations—chronic and acute pain conditions alike. This has been explored by scientists using pain-like behavioral study methodologies in non-anesthetized animals since decades ago to characterize the analgesic profile such as centrally or peripherally acting drugs and allowing for the development of analgesics. However, widely the methodology is being practiced such as the tail flick/Hargreaves test and Von Frey/Randall–Selitto tests which are stimulus-evoked nociception studies, and there has rarely been a complete review of all these methodologies, their benefits and its downside coupled with the mechanism of the action that is involved. Thus, this review solely focused on the complete protocol that is being adapted in each behavioral study methods induced by different phlogogenic agents, the different assessment methods used for phasic, tonic and inflammatory pain studies and the proposed mechanism of action underlying each behavioral study methodology for analgesic drug profiling. It is our belief that this review could significantly provide a concise idea and improve our scientists’ understanding towards pain management in future research.
Background:
A sex-difference in susceptibility to chronic pain is well-known. Although recent studies have begun to reveal the sex-dependent mechanisms of nerve injury-induced pain sensitization, sex differences in the affective and cognitive brain dysfunctions associated with chronic pain have not been investigated. Therefore, we tested whether chronic pain leads to affective and cognitive disorders in a mouse neuropathic pain model and whether those disorders are sexually dimorphic.
Methods:
Chronic neuropathic pain was induced in male and female mice by L5 spinal nerve transection (SNT) injury. Pain sensitivity was measured with the von Frey test. Affective behaviors such as depression and anxiety were assessed by the forced swim, tail suspension, and open field tests. Cognitive brain function was assessed with the Morris water maze and the novel object location and novel object recognition tests.
Results:
Mechanical allodynia was induced and maintained for up to 8 weeks after SNT in both male and female mice. Depressive- and anxiety-like behaviors were observed 8 weeks post-SNT injury regardless of sex. Chronic pain-induced cognitive deficits measured with the Morris water maze and novel object location test were seen only in male mice, not in female mice.
Conclusions:
Chronic neuropathic pain is accompanied by anxiety- and depressive-like behaviors in a mouse model regardless of sex, and male mice are more vulnerable than female mice to chronic pain-associated cognitive deficits.
Painful diabetic neuropathy (PDN) is known to adversely affect psychosocial functioning by enhancing levels of anxiety and depression. This study was designed to verify the antihypernociceptive, anxiolytic, and antidepressant-like effects of Combretin A and Combretin B (two triterpenes cycloartane-type isolated from the leaves of Combretum fragrans) in streptozotocin-induced diabetic neuropathy in mice. PDN was induced in mice by the administration of streptozotocin (STZ, 200 mg/kg, i.p.). The effect of oral administration of Combretin A (25 and 50 mg/kg) and Combretin B (25 and 50 mg/kg) on nociception (mechanical allodynia, thermal hyperalgesia, cold allodynia, and chemical hyperalgesia), anxiety (elevated plus maze, light-dark box test, social interaction), and depressant (open field test, forced swimming test, tail suspension test) was evaluated. Combretin A (25 and 50 mg/kg) and Combretin B (25 and 50 mg/kg) caused antihypernociceptive, anxiolytic, and antidepressant-like effects in in STZ-induced diabetic neuropathy in mice. Both compounds also caused a decrease in blood glucose and improved body weight in treated animals. They also significantly (p < 0.001) reduced tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), malondialdehyde (MDA), and nitric oxide (NO) production in serum and sciatic nerves, and, significantly (p < 0.001) increased superoxide dismutase (SOD) and catalase (CAT) activity in serum, sciatic nerves, and brain. Combretin A and Combretin B also showed a great systemic effect, conserving values of evaluated parameters close to normal in treated mice. The results of this study confirm the antihypernociceptive, antianxiety, and antidepressant activities of Combretin A and Combretin B.
Agomelatine, a novel antidepressant exerting its effects through melatonergic and serotonergic systems, implicated to be effective against pain including neuropathic pain but without any knowledge of mechanism of action. To explore the possible role of agomelatine on nociceptive transmission at the peripheral level, the effects of agomelatine on intracellular calcium ([Ca²⁺]i) signaling in peripheral neurons were investigated in cultured rat dorsal root ganglion (DRG) neurons. Using the fura‐2‐based calcium imaging technique, the effects of agomelatine on [Ca²⁺]i and roles of the second messenger‐mediated pathways were assessed. Agomelatine caused [Ca²⁺]i signaling in a dose‐dependent manner when tested at 10 and 100 μM concentration. Luzindole, a selective melatonin receptor antagonist, almost completely blocked the agomelatine‐induced calcium signals. The agomelatine‐induced calcium transients were also nearly abolished following pretreatment with the 100 ng/ml pertussis toxin, a Gi/o protein inhibitor. The stimulatory effects of agomelatine on [Ca²⁺]i transients were significantly reduced by applications of phospholipase C (PLC) and protein kinase C (PKC) blockers, 10 μM U73122, and 10 μM chelerythrine chloride, respectively. The obtained results of agomelatine‐induced [Ca²⁺]i signals indicates that peripheral mechanisms are involved in analgesic effects of agomelatine. These mechanisms seems to involve G‐protein‐coupled receptor activation and PLC and PKC mediated mechanisms.
Fluoxetine is one of the top ten prescribed antidepressants. Other therapeutic applications were approved for fluoxetine including, anxiety disorders, bulimia nervosa, and premature ejaculation. However, the role of fluoxetine in nociceptive pain management is still unclear. In this review, we discuss an overview of five possible roles of fluoxetine in pain management: intrinsic antinociceptive effect, enhancement of acute opioid analgesia, attenuation of tolerance development to opioid analgesia, attenuation of dependence development and abstinence syndrome, and attenuation of opioid induced hyperalgesia.
Conflicting data were reported about fluoxetine intrinsic anti-nociceptive effect in preclinical and clinical studies except for inflammatory pain. Similar controversy was described in preclinical and clinical studies which explored the possible enhancement of opioid analgesia by fluoxetine co-administration. However, fluoxetine was found to have a promising effect on opioid tolerance and dependence in animal and human studies. Regarding opioid induced hyperalgesia, no studies examined fluoxetine effects in this regard.
Our literature review revealed that, the most likely beneficial use of fluoxetine in nociceptive pain management is for alleviation of inflammatory pain and attenuation of opioid tolerance and dependence. Non-steroidal anti-inflammatory and corticosteroids carry many adverse effects and toxicities. Effective alleviation of opioid tolerance and dependence represents a huge health burden and growing unmet medical need. Moreover, most agents used to attenuate these phenomena are either experimental or poorly tolerable drugs which limit their transitional value. Fluoxetine offers an effective, safe, and tolerable alternative for management of both inflammatory pain and opioid tolerance and dependence presently available to clinicians.
Objective
To investigate the potential alleviating effects of acupuncture on maternal separation (MS)-induced changes in plasma pro-inflammatory cytokine levels of rat pups. Methods
On postnatal day 15, rat pups were randomly assigned to 4 groups (n=6 per group) using a random number table: normal, MS, MS with acupuncture stimulation at Shenmen (HT 7) acupoint (MS+HT 7), and MS with acupuncture stimulation at Chengshan (BL 57) acupoint (MS+BL 57) groups. Rat pups in the normal group were housed with their mothers under standard conditions; those in the MS, MS+HT 7 and MS+BL 57 groups were maternally separated and individually maintained. Acupuncture stimulation was performed at HT 7 or BL 57 acupoints once a day for 7 consecutive days. A tail suspension test was performed to measure immobility time of rats and the plasma was collected on postnatal day 21, then levels of corticosterone (CORT), interleukin (IL)-1β, IL-6 and glial cell-derived neurotrophic factor (GDNF) in plasma were measured. ResultsCompared with the normal group, the immobility time and the plasma levels of CORT, IL-1β, IL-6 and GDNF in the MS group were significantly increased (P<0.05 or P<0.01). Compared with the MS group, the immobility time and the plasma levels of CORT, IL-1β, IL-6 and GDNF were significantly reduced in the MS+HT 7 group (P<0.05 or P<0.01). Moreover, the immobility time and plasma levels of IL-1β and IL-6 in the MS+HT 7 group were significantly lower than those in the MS+BL 57 group (P<0.05). Conclusion
Acupuncture stimulation at HT 7 can alleviate the behavioral impairment and changes of the cytokines by MS, indicating that acupuncture can help to relieve MS-induced depression.
Mood disorders and chronic pain are closely linked, but limited progress has been made in understanding the role of chronic and neuropathic pain in the aetiopathogenesis of depression. To explore the pathological mechanisms that mediate the association between pain and depressive-like behaviours, we studied the time-dependent effect of neuropathic pain on the development of anxiety-like and despair behaviours in CD1 mice. We analysed behavioural data, neuroinflammation reactions and changes in neurotransmitter (glutamate and serotonin) levels in the mouse prefrontal cortex. Sciatic-operated mice displayed long-lasting anxiety-like and despair behaviours, starting 5 and 20 days after partial sciatic nerve ligation, respectively. Glutamatergic neurotransmission and IL-1β cytokine expression were enhanced in the prefrontal cortex of mice with neuropathic pain. We found no change in serotonin metabolism, cytokine IL-6 or brain-derived neurotrophic factor levels. While sciatic-operated mice exposed to intermittent ethanol intake (20% v/v) using the drinking in the dark procedure consumed higher amounts of ethanol than sham-operated mice, thermal allodynia and despair behaviour were not attenuated by ethanol consumption. Our findings reveal an association between glutamatergic neurotransmission and pain-induced mood disorders, and indicate that moderate ethanol consumption does not relieve nociceptive and depressive behaviours associated with chronic pain in mice.
The olfactory bulbectomized (OB) rat, an animal model of chronic depression with comorbid anxiety, exhibits a profound dysregulation of the brain serotonergic signalling, a neurotransmission system involved in pain transmission and modulation. We here report an increased nociceptive response of OB rats in the tail flick test which is reverted after chronic, but not acute, administration of fluoxetine. Autoradiographic studies demonstrated down-regulation of 5-HT transporters ([(3)H]citalopram binding) and decreased functionality of 5-HT1A receptors (8-OH-DPAT-stimulated [(35)S]GTPγS binding) in the dorsal horn of the lumbar spinal cord in OB rats. Acute administration of fluoxetine (5-40 mg/kg i.p.) did not modify tail flick latencies in OB rats. However, chronic fluoxetine (10 mg/kg/day s.c., 14 days; osmotic minipumps) progressively attenuated OB-associated thermal hyperalgesia, and a total normalization of the nociceptive response was achieved at the end of the treatment with the antidepressant. In these animals, autoradiographic studies revealed further down-regulation of 5-HT transporters and normalization in the functionality of 5-HT1A receptors on the spinal cord. On the other hand, acute morphine (0.5-10 mg/kg s.c.) produced a similar analgesic effect in OB and sham and OB rats, and no changes were detected in the density ([(3)H]DAMGO binding) and functionality (DAMGO-stimulated [(35)S]GTPγS binding) of spinal μ-opioid receptors in OB rats before and after chronic fluoxetine. Our findings demonstrate the participation of the spinal serotonergic system in the increased thermal nociception exhibited by the OB rat and the antinociceptive effect of chronic fluoxetine in this animal model of depression.
The present study investigated the possible role of acupuncture in alleviating depression-like behavioral changes and examined changes in the levels of serotonin (5-HT), dopamine (DA), and their metabolites in the hippocampus (HP) and prefrontal cortex (PFC) of maternally separated rat pups. On postnatal day 15, rat pups were maternally separated and received acupuncture stimulation at acupoint HT7 or ST36 once a day for 7 days. Then, on postnatal day 21, a tail suspension test was performed, and the HP and PFC were harvested. Levels of 5-HT, 5-hydroxyindole-3-acetic acid (5-HIAA), DA, and 3,4-dihydroxyphenylacetic acid (DOPAC) in the tissue and corticosterone (CORT) in plasma were then measured. The total duration of immobility in maternally separated rat pups increased after maternal separation, and this increase was alleviated by acupuncture stimulation at HT7. The 5-HIAA/5-HT ratio and the levels of 5-HT and 5-HIAA were not significantly changed, but those of the DA and the DOPAC/DA ratio were significantly lower and that of CORT was significantly higher after maternal separation. The maternal separation-induced changes of the DOPAC/DA ratio and the CORT level significantly alleviated after acupuncture stimulation at HT7. These results suppose that the functional recovery of prefrontal-limbic system by acupuncture stimulation plays an important role in acupuncture-induced benefits in this animal model of depression.
Most preclinical studies investigating the effects and the mechanism of action of antidepressants have been performed in naive rodents. This is inappropriate because antidepressants act on specific symptoms of the pathological condition, such as distress and anxiety. We have developed a mouse model of anxiety/depression based on addition of corticosterone to drinking water. This model is highly reproducible and easy to set up compared with unpredictable chronic mild stress. The serotonin 1A (5-HT(1A)) autoreceptor is known to play a role in mood disorders and their treatments. An increase in somatodendritic 5-HT(1A) autoreceptor density in the dorsal raphe (DR) attenuates the therapeutic activity of selective serotonin-reuptake inhibitors (SSRIs), whereas their functional desensitization promotes activation of brain serotonergic transmission, thereby representing an adaptive change relevant to their therapeutic effect. Here we assessed the effects of sustained administration of the SSRI fluoxetine on 5-HT(1A) autoreceptor sensitivity in mice administered with corticosterone. Fluoxetine attenuated hypothermia induced by the 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin, decreased DR 5-HT neuronal activity, and decreased 5-HT release in both vehicle- and corticosterone-pretreated mice. However, such desensitization was more pronounced in corticosterone-pretreated mice. This change had an overall effect on serotonergic tone because we found a greater firing rate of 5-HT neurons associated with an enhancement of 5-HT outflow in the DR of corticosterone-pretreated mice in response to fluoxetine compared with the corresponding group of vehicle-pretreated mice. These results provide cellular explanations for the antidepressant effects produced by SSRIs in subjects with pathological conditions but not in naive animals or healthy volunteers.
Fibromyalgia (FM) is characterized by chronic widespread pain, which is often refractory to conventional painkillers. Numerous clinical studies have demonstrated that antidepressants are effective in treating FM pain. We previously established a mouse model of FM-like pain, induced by intermittent cold stress (ICS).
In this study, we find that ICS exposure causes a transient increase in plasma corticosterone concentration, but not in anxiety or depression-like behaviors. A single intrathecal injection of an antidepressant, such as milnacipran, amitriptyline, mianserin or paroxetine, had an acute analgesic effect on ICS-induced thermal hyperalgesia at post-stress day 1 in a dose-dependent manner. In addition, repeated daily antidepressant treatments during post-stress days 1-5 gradually reversed the reduction in thermal pain threshold, and this recovery was maintained for at least 7 days after the final treatment. In addition, relief from mechanical allodynia, induced by ICS exposure, was also observed at day 9 after the cessation of antidepressant treatment. In contrast, the intravenous administration of these antidepressants at conventional doses failed to provide relief.
These results suggest that the repetitive intrathecal administration of antidepressants permanently cures ICS-induced FM pain in mice.
Mice experiencing repeated aggression develop a long-lasting aversion to social contact, which can be normalized by chronic,
but not acute, administration of antidepressant. Using viral-mediated, mesolimbic dopamine pathway–specific knockdown of brain-derived
neurotrophic factor (BDNF), we showed that BDNF is required for the development of this experience-dependent social aversion.
Gene profiling in the nucleus accumbens indicates that local knockdown of BDNF obliterates most of the effects of repeated
aggression on gene expression within this circuit, with similar effects being produced by chronic treatment with antidepressant.
These results establish an essential role for BDNF in mediating long-term neural and behavioral plasticity in response to
aversive social experiences.
Agomelatine (S20098) is a novel antidepressant drug with melatonergic agonist and 5-HT2C receptor antagonist properties, displaying antidepressant/anxiolytic-like properties in animal models and in humans. In a depression/anxiety-like mouse model in which the response of the HPA axis is blunted, we investigated whether agomelatine could reverse behavioural deficits related to depression/anxiety compared to the classical selective serotonin reuptake inhibitor, fluoxetine. Adult mice were treated for 8 wk with either vehicle or corticosterone (35 μg/ml.d) via drinking water. During the final 4 wk, animals were treated with vehicle, agomelatine (10 or 40 mg/kg i.p.) or fluoxetine (18 mg/kg i.p.) and tested in several behavioural paradigms and also evaluated for home-cage activity. Our results showed that the depressive/anxiety-like phenotype induced by corticosterone treatment is reversed by either chronic agomelatine or fluoxetine treatment. Moreover, agomelatine increased the dark/light ratio of home-cage activity in vehicle-treated mice and reversed the alterations in this ratio induced by chronic corticosterone, suggesting a normalization of disturbed circadian rhythms. Finally, we investigated the effects of this new antidepressant on neurogenesis. Agomelatine reversed the decreased cell proliferation in the whole hippocampus in corticosterone-treated mice and increased maturation of newborn neurons in both vehicle- and corticosterone-treated mice. Overall, the present study suggests that agomelatine, with its distinct mechanism of action based on the synergy between the melatonergic agonist and 5-HT2C antagonist properties, provides a distinct antidepressant/anxiolytic spectrum including circadian rhythm normalization.
Duloxetine is a serotonin-norepinephrine reuptake inhibitor approved by the US Food and Drug Administration for the treatment of fibromyalgia and painful diabetic neuropathy at doses of 60 mg daily. Duloxetine has been shown to significantly improve the symptoms of chronic pain associated with these disorders, as measured by the Fibromyalgia Impact Questionnaire, Brief Pain Inventory scores, the Clinical Global Impressions Scale, and other various outcome measures in several placebo-controlled, randomized, double-blind, multicenter studies. Symptom improvement generally began within the first few weeks, and continued for the duration of the study. In addition, the efficacy of duloxetine was found to be due to direct effects on pain symptoms rather than secondary to improvements in depression or anxiety. Adverse events including nausea, constipation, dry mouth, and insomnia, were mild and transient and occurred at relatively low rates. In conclusion, duloxetine, a selective inhibitor for the serotonin and norepinephrine transporters, is efficacious in the treatment of chronic pain associated with fibromyalgia or diabetic neuropathy, and has a predictable tolerability profile, with adverse events generally being mild to moderate.
Over 75% of depressed patients suffer from painful symptoms predicting a greater severity and a less favorable outcome of depression. Imaging, anatomical and functional studies have demonstrated the existence of common brain structures, neuronal pathways and neurotransmitters in depression and pain. In particular, the ascending serotonergic and noradrenergic pathways originating from the raphe nuclei and the locus coeruleus; respectively, send projections to the limbic system. Such pathways control many of the psychological functions that are disturbed in depression and in the perception of pain. On the other hand, the descending pathways, from monoaminergic nuclei to the spinal cord, are specifically implicated in the inhibition of nociception providing rationale for the use of serotonin (5-HT) and/or norepinephrine (NE) reuptake inhibitors (SSRIs, NRIs, SNRIs), in the relief of pain. Compelling evidence suggests that dopamine (DA) is also involved in the pathophysiology and treatment of depression. Indeed, recent insights have demonstrated a central role for DA in analgesia through an action at both the spinal and suprasinal levels including brain regions such as the periaqueductal grey (PAG), the thalamus, the basal ganglia and the limbic system. In this context, dopaminergic antidepressants (i.e., containing dopaminergic activity), such as bupropion, nomifensine and more recently triple reuptake inhibitors (TRIs), might represent new promising therapeutic tools in the treatment of painful symptoms with depression. Nevertheless, whether the addition of the dopaminergic component produces more robust effects than single- or dual-acting agents, has yet to be demonstrated. This article reviews the main pathways regulating pain transmission in relation with the monoaminergic systems. It then focuses on the current knowledge regarding the in vivo pharmacological properties and mechanism of action of monoaminergic antidepressants including SSRIs, NRIs, SNRIs and TRIs. Finally, a synthesis of the preclinical studies supporting the efficacy of these antidepressants in analgesia is also addressed in order to highlight the relative contribution of 5-HT, NE and DA to nociception.
The role of the opioid system in mediating effects of alcoholism and stress in depression is far from clear. We studied, therefore, the effects of chronic mild stress (CMS) and alcohol drinking on depression-like behavior and nociception in lines of mice selected for high (HA) or low (LA) swim stress-induced analgesia. Compared to the LA mice, the HA animals display up-regulation of opioid receptor system function and depression-like behavior in tail suspension test (TST). We report now that alcohol reverses depressive and pronociceptive effect of CMS in HA mice. In contrast, in LA mice CMS does not affect nociception or behavior in TST and the animals are not susceptible to alcohol under CMS. The results suggest that opioid system activity may determine the effects of alcohol on behavior under stress and, therefore, link predispositions to depression and to alcoholism.
Various chronic antidepressant treatments increase adult hippocampal neurogenesis, but the functional importance of this phenomenon
remains unclear. Here, using genetic and radiological methods, we show that disrupting antidepressant-induced neurogenesis
blocks behavioral responses to antidepressants. Serotonin 1A receptor null mice were insensitive to the neurogenic and behavioral
effects of fluoxetine, a serotonin selective reuptake inhibitor. X-irradiation of a restricted region of mouse brain containing
the hippocampus prevented the neurogenic and behavioral effects of two classes of antidepressants. These findings suggest
that the behavioral effects of chronic antidepressants may be mediated by the stimulation of neurogenesis in the hippocampus.
Repeated forced-swim stress (FSS) produced analgesia, immobility and potentiation of cocaine-conditioned place preference (CPP) in wild-type C57Bl/6 mice, but not in littermates lacking the kappa opioid receptor (KOR) gene. These results were surprising because kappa agonists are known to produce conditioned place aversion and to suppress cocaine-CPP when coadministered with cocaine. The possibility that disruption of the kappa system blocked the stress response by adversely affecting the hypothalamic-pituitary axis was examined by measuring plasma corticosterone levels. However, disruption of the dynorphin/kappa system by gene deletion or receptor antagonism did not reduce the FSS-induced elevation of plasma corticosterone levels. A second explanation for the difference is that kappa receptor activation caused by FSS occurred prior to cocaine conditioning rather than contemporaneously. To test this hypothesis, we measured the effects of the kappa agonist (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide (U50,488) administered to mice at various intervals preceding cocaine conditioning. The results showed that the interaction between the kappa system and cocaine reinforcement depended on the timing of the drug pairing. Mice given U50,488 60 min prior to cocaine showed a robust, nor-BNI-sensitive potentiation of cocaine-CPP, whereas administration 15 min before cocaine significantly suppressed cocaine-CPP. In the absence of cocaine, U50,488 given 60 min prior to saline conditioning produced no place preference, whereas administration 15 min before saline conditioning produced significant place aversion. The results of this study suggest that kappa receptor activation induced by FSS prior to the cocaine-conditioning session may be both necessary and sufficient for potentiation of the reinforcing actions of cocaine.
Previous studies have demonstrated that repeated forced-swim stress-induced behaviors (including analgesia, immobility, and increased drug reward) were mediated by the release of endogenous prodynorphin-derived opioid peptides and subsequent activation of the kappa opioid receptor (KOR). We tested the generality of these effects using a different type of stressful situation: repeated social defeat. C57Bl/6 mice subjected to social defeat stress (SDS) over 3 days showed a characteristic stress-induced immobility and defeated-postural response, as well as stress-induced analgesia (SIA). Daily pretreatment with the KOR antagonist nor-binaltorphimine (nor-BNI, 10 mg/kg, i.p.) blocked the SIA and significantly reduced the stress-induced immobility on the second and third days of SDS exposure. In contrast, prodynorphin gene-disrupted mice showed no significant increase in immobility, socially defeated postures, or SIA following repeated exposure to SDS. Since both stress and the kappa opioid system can modulate the response to drugs of abuse, we tested the effects of SDS on cocaine-conditioned place preference (CPP). SDS-exposed mice conditioned with cocaine (15 mg/kg, s.c.) showed significant potentiation of place-preference for the drug-paired chamber over the responses of unstressed mice. Nor-BNI pretreatment blocked stress-induced potentiation of cocaine-CPP. Consistent with this result, mice lacking the prodynorphin gene did not show stress-induced potentiation of cocaine-CPP, whereas wild-type littermates did. The findings suggest that chronic SDS may activate the kappa opioid system to produce analgesia, immobility, social defeat postures, and resulting in a potentiation of the acute rewarding properties of cocaine.
Tricyclic antidepressants (TCA) have potent local anesthetic properties and may produce a long-lasting pain blockade that could be of interest in relieving chronic pain states such as neuropathic pain, but there are only few data comparing their dose-response curves of analgesic activity under the same experimental conditions. This study examines the time course of pain-relieving properties of 7 TCA in heat-induced paw withdrawal after subcutaneous administration. Mixed inhibitors of norepinephrine and serotonin uptake (amitriptyline, nortriptyline, imipramine, desipramine, doxepin) and selective inhibitors of serotonin uptake (fluoxetine and fluvoxamine) were assayed. The TCA with the longest analgesic activity were selected to test its antiallodynic effect in the neuropathic pain model of chronic sciatic nerve constriction injury. Bupivacaine was used as a reference drug in both experiments. A dose versus time of maximal analgesic effect curve was constructed for each drug. The longest analgesic effect was obtained for doxepin and imipramine. Although low doses of amitriptyline showed the same activity than doxepin, higher doses failed to reach the same effect. Selective inhibitors of serotonin showed no action at all doses tested. In the chronic sciatic nerve constriction injury model, doxepin and, to a smaller degree, amitriptyline and imipramine protected from allodynia; bupivacaine was ineffective. The antiallodynic effect always lasted less long than the analgesic effect. These observations provide support for the potential use of TCA as durable analgesics. Doxepin overall showed the most outstanding results in pain relief.
Corticosterone (CORT) localized to the amygdala induces anxiety-like behavior coupled with increased behavioral responses to visceral and somatic stimuli. In the current study, we investigated the long-term consequences of briefly exposing the amygdala to elevated levels of CORT with the hypothesis that modulation of the amygdala with CORT results in persistent increases in anxiety-like behavior and viscerosomatic sensitivity.
This second European Federation of Neurological Societies Task Force aimed at updating the existing evidence about the pharmacological treatment of neuropathic pain since 2005.
Studies were identified using the Cochrane Database and Medline. Trials were classified according to the aetiological condition. All class I and II randomized controlled trials (RCTs) were assessed; lower class studies were considered only in conditions that had no top-level studies. Treatments administered using repeated or single administrations were considered, provided they are feasible in an outpatient setting.
Most large RCTs included patients with diabetic polyneuropathies and post-herpetic neuralgia, while an increasing number of smaller studies explored other conditions. Drugs generally have similar efficacy in various conditions, except in trigeminal neuralgia, chronic radiculopathy and HIV neuropathy, with level A evidence in support of tricyclic antidepressants (TCA), pregabalin, gabapentin, tramadol and opioids (in various conditions), duloxetine, venlafaxine, topical lidocaine and capsaicin patches (in restricted conditions). Combination therapy appears useful for TCA-gabapentin and gabapentin-opioids (level A).
There are still too few large-scale comparative studies. For future trials, we recommend to assess comorbidities, quality of life, symptoms and signs with standardized tools and attempt to better define responder profiles to specific drug treatments.
To verify the efficacy and safety of fluoxetine in treating patients with persistent somatoform pain disorder (PSPD).
In this 8-week, randomized double-blind placebo-controlled study, 80 patients with an ICD-10 diagnosis of PSPD were randomly assigned to receive 20mg fluoxetine or a placebo. Several psychological scales including Medical Outcomes Study Pain Measures (MOSPM), Hamilton Depression Scale-17 items (HAMD(17)) and Treatment Emergent Symptom Scale (TESS) were used to assess analgesic efficacy and safety of fluoxetine, and the possible analgesic mechanism of fluoxetine was preliminarily analyzed. All data were analyzed by SPSS11.5 with t-test, one-way ANOVA and a mixed-effects model repeated measures analysis. Intent-to-treat (ITT) analysis was performed and the last observation carry forward (LOCF) was used for missing values.
There was a significant difference of MOSPM total score between the fluoxetine and placebo group after 2 weeks of treatment. The analgesic effect of fluoxetine was related with treatment time, and depressive patients showed a better analgesic effect than non-depressive patients. An adverse effect of fluoxetine was scarcely found.
Fluoxetine has a better analgesic effect than a placebo in treating persistent somatoform pain disorder, and is considered a safe treatment; its analgesic effect may be related to an antidepressant effect.
Understanding the physiopathology of affective disorders and their treatment relies on the availability of experimental models that accurately mimic aspects of the disease. Here we describe a mouse model of an anxiety/depressive-like state induced by chronic corticosterone treatment. Furthermore, chronic antidepressant treatment reversed the behavioral dysfunctions and the inhibition of hippocampal neurogenesis induced by corticosterone treatment. In corticosterone-treated mice where hippocampal neurogenesis is abolished by X-irradiation, the efficacy of fluoxetine is blocked in some, but not all, behavioral paradigms, suggesting both neurogenesis-dependent and -independent mechanisms of antidepressant action. Finally, we identified a number of candidate genes, the expression of which is decreased by chronic corticosterone and normalized by chronic fluoxetine treatment selectively in the hypothalamus. Importantly, mice deficient in one of these genes, beta-arrestin 2, displayed a reduced response to fluoxetine in multiple tasks, suggesting that beta-arrestin signaling is necessary for the antidepressant effects of fluoxetine.
Unrelieved pain has major negative effects on the lives of millions of people worldwide, and is associated with huge societal costs. Breakthroughs in pain therapy have been rare in the past 50 years, but there is increasing hope that advances in multiple areas of pain research could lead to the introduction of much-needed novel and more effective analgesics.
The objectives of the study were: (i) to elaborate an ethogram of the rat's behaviour during the hot plate test, (ii) to analyse the rat's responses to the nociceptive heat stimulus by using ethological techniques, and (iii) to discern the suitable pattern or patterns to evaluate the rat's reaction to the noxious stimulus. Male Wistar rats (n = 30) were employed, and one hot plate test was carried out for each rat. The platform (Socrel DS37) was maintained at 55.0 +/- 0.5 degrees C, and the exposure time was 45 s. Behaviour was videotaped and analysed by an ethogram and a software package. Every pattern parameter (frequency, duration and latency for the first occurrence) was quantified. Cluster and Markovian analyses were also employed, whereby a dendrogram and a Markov chain were obtained, respectively. The ethogram was composed of twelve patterns: immobile-sniff, walk-sniff, rearing, forepaw-licking, hindpaw-licking, face-washing, body-cleaning, stamping, hindleg-withdrawal, leaning posture, jumping off, and freezing. Cluster analysis indicated that the most frequent patterns could be classified into three categories: sniffing responses (immobile-sniff, walk-sniff), primary noxious-evoked patterns (forepaw-licking, hindpaw-licking, stamping), and escape noxious-evoked responses (leaning posture, jumping off). Hindleg-withdrawal would be an independent noxious-evoked pattern, and freezing an alerting behaviour. The ethological information could be useful to better elucidate effects on rats' behaviour of drug treatment or other phenomena during the hot plate test.
Amitriptyline, a non-selective noradrenaline (NA) and 5-hydroxytryptamine (5-HT) reuptake inhibitor, has recently been demonstrated to produce a peripheral antinociceptive action in an inflammatory (formalin test) and a neuropathic pain model (spinal nerve ligation). In the present study, we determined whether desipramine, a selective NA reuptake inhibitor, and fluoxetine, a selective 5-HT reuptake inhibitor, could produce peripheral antinociceptive actions in these same tests. Effects on paw volume also were determined. In the 2.5% formalin test, desipramine and fluoxetine 10-300 nmol produced a dose-related reduction in phase 2 (16-60 min) flinching and biting/licking behaviours when coadministered with the formalin. Phase 1 flinch behaviours (0-12 min) were significantly reduced at the highest dose. These actions are peripherally mediated, as they were not seen when desipramine or fluoxetine (100, 300 nmol) were injected into the contralateral hindpaw. The peripheral action of desipramine and fluoxetine was not altered by coadministration of caffeine 1500 nmol. In the spinal nerve ligation model, desipramine 100 nmol, but not fluoxetine 100 nmol, produced a peripheral anti-hyperalgesic action in the hindpaw corresponding to the ligated side when thresholds were determined using a thermal paw stimulator. In paw volume experiments, desipramine, at doses which are maximally effective in behavioural tests, produced only a slight increase in paw volume, but fluoxetine (10-300 nmol) produced a robust and sustained dose-related increase in paw volume. Amitriptyline also produced minimal effects on paw volume. When coinjected with formalin, no agent significantly altered the degree of paw swelling produced by formalin. The increase in paw volume produced by fluoxetine was inhibited by ketanserin (5-HT2 receptor antagonist), mepyramine (histamine H1 receptor antagonist) and phentolamine (alpha-adrenergic receptor antagonist), but not by the other selective 5-HT receptor antagonists tested or caffeine. The pronounced peripheral pain alleviating actions in the absence of marked changes in paw volume produced by desipramine and amitriptyline, but not fluoxetine, in the formalin test and the spinal nerve ligation model suggest that these agents could be developed as cream or gel formulations to recruit a peripheral antinociceptive action in inflammatory and neuropathic pain states. Such a formulation might permit the attainment of higher and more efficacious concentrations in the region of the sensory nerve terminal, with limited systemic side effects.
Tricyclic antidepressants have been extensively studied and frequently used in the treatment of various chronic pain syndromes. Newer antidepressants, namely fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, trazodone, nefazodone, bupropion, mirtazapine, and venlafaxine, have also been considered for this indication, although they have been less extensively studied. This article reviews the available publications, including placebo-controlled trials, other outcome studies, and case reports, pertaining to the use of these medications for chronic pain. Although some of these newer compounds may be effective for specific types of pain, making generalizations regarding their use as analgesics is difficult, given the limitations of existing data. Additional observations based on the data are presented in the hope that they may help to guide further research and clinical use.
Antidepressant drugs are reported to be used as co-analgesics in clinical management of migraine and neuropathic pain. The mechanism through which they alleviate pain remains unknown. The present study explores the possible mechanism of a selective serotonin reuptake inhibitor (SSRI) fluoxetine-induced antinociception in animals. Acetic acid-induced writhing, hot plate and tail-flick test were used to assess fluoxetine-induced antinociception. Fluoxetine (5-20 mg kg(-1), i.p.) produced a significant and dose-dependent antinociceptive effect against acetic acid-induced writhing in mice. Fluoxetine (20 mg kg(-1)) also exhibited antinociceptive effect in tail flick as well as hot plate assays. Further, i.c.v. administration of fluoxetine showed significant antinociception against writhing test in rats. However, fluoxetine (1 microg/10 microl/rat, i.c.v.) did not exhibit any antinociceptive effect in serotonin-depleted animals. Further, pindolol (10 mg kg(-1), i.p.) enhanced fluoxetine-induced antinociceptive effect. The antinociceptive effect of fluoxetine was sensitive to blockade by naloxone (5 mg kg(-1), i.p.) and naltrexone (5 mg kg(-1), i.p.). These data suggest that fluoxetine-induced antinociception involves both central opioid and the serotoninergic pathways.
Upon receipt in the dorsal horn (DH) of the spinal cord, nociceptive (pain-signalling) information from the viscera, skin and other organs is subject to extensive processing by a diversity of mechanisms, certain of which enhance, and certain of which inhibit, its transfer to higher centres. In this regard, a network of descending pathways projecting from cerebral structures to the DH plays a complex and crucial role. Specific centrifugal pathways either suppress (descending inhibition) or potentiate (descending facilitation) passage of nociceptive messages to the brain. Engagement of descending inhibition by the opioid analgesic, morphine, fulfils an important role in its pain-relieving properties, while induction of analgesia by the adrenergic agonist, clonidine, reflects actions at alpha(2)-adrenoceptors (alpha(2)-ARs) in the DH normally recruited by descending pathways. However, opioids and adrenergic agents exploit but a tiny fraction of the vast panoply of mechanisms now known to be involved in the induction and/or expression of descending controls. For example, no drug interfering with descending facilitation is currently available for clinical use. The present review focuses on: (1) the organisation of descending pathways and their pathophysiological significance; (2) the role of individual transmitters and specific receptor types in the modulation and expression of mechanisms of descending inhibition and facilitation and (3) the advantages and limitations of established and innovative analgesic strategies which act by manipulation of descending controls. Knowledge of descending pathways has increased exponentially in recent years, so this is an opportune moment to survey their operation and therapeutic relevance to the improved management of pain.
Three previous reviews have reached conflicting conclusions regarding the efficacy of antidepressants for patients with back pain.
To systematically review the efficacy of antidepressants for the treatment of patients with back pain and to determine whether there is evidence that outcomes vary between classes of antidepressants.
Best evidence synthesis of randomized, placebo-controlled trials of oral antidepressive agents in patients with back pain. Studies were identified by searching MEDLINE, PsycINFO, and the Cochrane Controlled Trials Registry. Two independent reviewers performed data extraction and assessed included studies with a 22-point methodologic quality assessment scale. Effect sizes were calculated if sufficient data were available.
Twenty-two trials of antidepressants for the treatment of back pain were identified, of which seven studies of chronic low back pain met inclusion criteria. Among studies using antidepressants that inhibit norepinephrine reuptake (tricyclic or tetracyclic antidepressants), four of five found significant improvement in at least one relevant outcome measure. Assessment of these agents' impact on functional measures produced mixed results. No benefit in pain relief or functional status was found in three studies of antidepressants that do not inhibit norepinephrine reuptake.
Based on a small number of studies, tricyclic and tetracyclic antidepressants appear to produce moderate symptom reductions for patients with chronic low back pain. This benefit appears to be independent of depression status. SSRIs do not appear to be beneficial for patients with chronic low back pain. There is conflicting evidence whether antidepressants improve functional status of patients with chronic low back pain.
A dysfunction of the serotonergic and noradrenergic pathways is commonly accepted as playing a major role in the aetiology of depression. Serotonergic cell bodies, located in the raphe nucleus, send projections to various parts of the brain where they are involved in the control of mood, movement, emotions such as anxiety and regulate behaviours such as eating, sexual activity and the feeling of pleasure. Similarly, the noradrenergic neurons, located in the locus coeruleus, project to the same regions where they regulate, in addition, attention and cognition. A further projection to the cerebellum regulates motor control. A dysfunction at the level of the monoamine neurons thus results in the classical symptoms of depression. In addition to these ascending pathways, however, the neurons in the raphe nucleus and the locus ceruleus also project to the spinal cord. These descending pathways serve to inhibit input from the intestines, the skeletal muscles and other sensory inputs. Under normal conditions, these inhibitory effects are modest, but in times of stress, in the interests of the survival of the individual, they can completely inhibit the input from painful stimuli. A dysfunction at the level of the serotonergic and noradrenergic neurons can thus affect both the ascending and descending pathways resulting in the psychological and somatic symptoms of depression but also in physical painful symptoms.
Fluoxetine is used in treatment of depression caused by a variety of different factors and from year to year new indications are being added, especially in conditions followed with strong bouts of pain. Additional fluoxetine based therapy that is known to help in improvement of mental state and mood stabilization can significantly increase analgesic effects. Analgesic effects of fluoxetine as well as of fluoxetine in combination with morphine were analyzed on albino mice of both genders. The sense of pain was induced by thermal stimulus by the method of hot plate. Analgesic effect was measured 30, 60, 90 and 120 minutes after a single i.p. administration of fluoxetine in following dosages: 5, 10 and 20 mg/kg. The control group was treated with 0.1 ml/10 g physiological solution. Test group injected with morphine s.c. (7 mg/kg) was used to observe the effect of fluoxetine in combination with morphine. Fluoxetine applied in 5 mg/kg dosage causes increased pain reaction 60 and 90 minutes (p=0.049 and p=0.002) (t-test) following application when compared with corresponding values of control group. When fluoxetine is applied in 10 mg/kg dosage duration of pain reaction is significantly increased after 30 (p=0.01), 60 (p=0.001) and 90 minutes (p=0.026), when compared to the control group. When fluoxetine is applied in 20 mg/kg dosage duration of pain reaction is increased 60 and 120 minutes (p<0.001) after application when compared to the control group. After application of fluoxetine (5 mg/kg) in combination with morphine, reaction time to pain is significantly extended (p<0.001) 60, 90 and 120 minutes after application when compared to the control group injected exclusively with morphine. Fluoxetine causes analgesic effect in all three applied dosages as well as it significantly increases analgesic effect when applied in 5 mg/kg dosage in combination with morphine.
For patients with chronic pain, the experience of pain is intimately linked with psychologic distress. Epidemiologic studies indicate that depression is a common comorbidity accompanying chronic pain states. Longitudinal studies also suggest that depression can predict the emergence of chronic pain in selected populations. Emerging evidence suggests numerous pathophysiologic mechanisms that underlie the coexistence of depression and chronic pain states. Comorbid depression can complicate the presentation, clinical course, and response to treatment of patients with chronic pain. The literature reviewed herein focuses on treatment approaches applicable to chronic, nonmalignant pain states predominantly. Although antidepressants offer advantages in simultaneously producing pain relief and mitigating depression, not all antidepressants share equal efficacy; those with noradrenergic and serotonergic influences seem to fare better than agents with single neurotransmitter influences. Treatment of depression may be essential to fully enlist the patient with chronic pain in comprehensive pain management and rehabilitative approaches. Management plans of patients with chronic pain can be designed with specific individual patient needs in mind, and may involve concurrent use of antidepressants, analgesics, and psychotherapeutic approaches.
The four-plates test (FPT) is an animal model of anxiety in which the exploration of the novel surroundings is suppressed by the delivery of a mild electric foot shock. The anti-nociceptive system has been reported to be activated by a variety of stressful stimuli such as footshock. The present study was thus designed to compare effects of drugs in the FPT and in the hot-plate test (an animal model of pain), in order to disambiguate the drug-induced anti-punishment effects obtained in the FPT from alterations in pain sensitivity. Various compounds, known to be implicated in anxiety states as well as nociception, have been studied. Although morphine induced a strong anti-nociceptive effect, it did not modify the number of shocks received in the FPT. Alprazolam and diazepam induced an anxiolytic-like effect in the FPT, at doses that did not induce any effect in the hot-plate test. The antidepressants previously reported anxiogenic (desipramine, maprotiline) in the FPT were found to be analgesic at the same doses. Milnacipran, venlafaxine and paroxetine did not modify the pain threshold, whereas they have previously been shown to induce anxiolytic-like effects in the FPT. The dopaminergic antidepressant agent nomifensine was without effect on both tests. Our results suggest that the reported drug-induced anti-punishment effects in the FPT are not related to modifications of pain threshold but to a pure anxiolytic-like effect.