Painful neuropathy is one of the most common complications of diabetes. First‐line therapeutic agents such as tricyclic antidepressants, dual serotonin/noradrenaline reuptake inhibitors, and alpha2‐delta ligands of calcium channels (i.e., gabapentinoids) are poorly effective. New strategies targeting the serotonin type 6 receptor (5‐HT 6 R) and mechanistic Target Of Rapamycin (mTOR) signaling have recently emerged. Until a few years ago, preclinical studies of pain in rodents were more often carried out in males than in females, despite compelling evidence of sex‐specific mechanisms in pain. Here, we investigated the role of 5−HT 6 R/mTOR signaling in neuropathic pain in streptozocin (STZ)‐induced type 1 diabetes (T1D) in female rats. Mechanical hyperalgesia was attenuated in female diabetic (STZ‐D) rats by systemic injection of 5‐HT 6 ‐R inverse agonists. Further, administration of full (PZ‐1386, SB258585) but not partial (PZ‐1179) 5−HT 6 R inverse agonists alleviated cognitive deficits in female STZ‐D rats. Intrathecal administration of the mTOR inhibitor rapamycin or a cell‐penetrating peptide that disrupts the physical interaction between the 5‐HT 6 R and mTOR also reduced pain and cognitive comorbidity in females. Together with previous data obtained in STZ‐D male rats and in spinal nerve ligation (SNL) and oxaliplatin (OXA) models of neuropathic pain, these results suggest that the analgesic and procognitive effects of 5‐HT 6 R inverse agonists are sex‐specific and dependent on the etiology of neuropathic pain, highlighting the importance of personalizing treatment that considers the patient's sex, etiology of neuropathy, and the presence or absence of comorbid cognitive symptoms. image

Painful neuropathy is one of the most common complications of diabetes. First-line therapeutic agents such as tricyclic antidepressants, dual serotonin/noradrenaline reuptake inhibitors, and alpha2-delta ligands of calcium channels (i.e., gabapentinoids) are poorly effective. New strategies targeting the serotonin type 6 receptor (5-HT6R) and mechanistic Target Of Rapamycin (mTOR) signaling have recently emerged. Until a few years ago, preclinical studies of pain in rodents were more often carried out in males than in females, despite compelling evidence of sex-specific mechanisms in pain. Here, we investigated the role of 5-HT6R/mTOR signaling in neuropathic pain in streptozocin (STZ)-induced type 1 diabetes (T1D) in female rats. Mechanical hyperalgesia was attenuated in female diabetic (STZ-D) rats by systemic injection of 5-HT6-R inverse agonists. Further, administration of full (PZ-1386, SB258585) but not partial (PZ-1179) 5-HT6R inverse agonists alleviated cognitive deficits in female STZ-D rats. Intrathecal administration of the mTOR inhibitor rapamycin or a cell-penetrating peptide that disrupts the physical interaction between the 5-HT6R and mTOR also reduced pain and cognitive comorbidity in females. Together with previous data obtained in STZ-D male rats and in spinal nerve ligation (SNL) and oxaliplatin (OXA) models of neuropathic pain, these results suggest that the analgesic and procognitive effects of 5-HT6R inverse agonists are sex-specific and dependent on the etiology of neuropathic pain, highlighting the importance of personalizing treatment that considers the patient's sex, etiology of neuropathy, and the presence or absence of comorbid cognitive symptoms.

Diabetic neuropathy is often associated with chronic pain. Serotonin type 6 (5-HT6) receptor ligands, particularly inverse agonists, have strong analgesic potential and may be new candidates for treating diabetic neuropathic pain and associated co-morbid cognitive deficits. The current study addressed the involvement of 5-HT6 receptor constitutive activity and mTOR signaling in an experimental model of diabetic neuropathic pain induced by streptozocin (STZ) injection in the rat. Here, we show that mechanical hyperalgesia and associated cognitive deficits are suppressed by the administration of 5-HT6 receptor inverse agonists or rapamycin. The 5-HT6 receptor ligands also reduced tactile allodynia in traumatic and toxic neuropathic pain induced by spinal nerve ligation and oxaliplatin injection. Furthermore, both painful and co-morbid cognitive symptoms in diabetic rats are reduced by intrathecal delivery of a cell-penetrating peptide that disrupts 5-HT6 receptor-mTOR physical interaction. These findings demonstrate the deleterious influence of the constitutive activity of spinal 5-HT6 receptors upon painful and cognitive symptoms in diabetic neuropathic pains of different etiologies. They suggest that targeting the constitutive activity of 5-HT6 receptors with inverse agonists or disrupting the 5-HT6 receptor-mTOR interaction might be valuable strategies for the alleviation of diabetic neuropathic pain and cognitive co-morbidities.

The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) is involved in numerous physiological functions and plays a key role in pain modulation including neuropathic pain. Diabetic neuropathy is a common complication of diabetes mellitus often accompanied by chronic neuropathic pain. Animal models of diabetes offer relevant tools for studying the pathophysiological mechanisms and pharmacological sensitivity of diabetic neuropathic pain and for identifying new therapeutic targets. In this review, we report data from preclinical work published over the last 15 years on the analgesic activity of drugs acting on the serotonergic system, such as serotonin and noradrenaline reuptake inhibitor (SNRI) antidepressants, and on the involvement of certain serotonin receptors-in particular 5-HT1A, 5-HT2A/2c and 5-HT6 receptors-in rodent models of painful diabetic neuropathy.

Douleur & Analgésie, première revue internationale francophone consacrée à la douleur, dont le champ de son expertise s'étend de la recherche fondamentale à la clinique tant sur le plan de l'évaluation de la douleur que de ses traitements.

The diverse signaling pathways engaged by serotonin type 6 receptor (5-HT6R) together with its high constitutive activity suggests different types of pharmacological interventions for the treatment of CNS disorders. Non-physiological activation of mTOR kinase by constitutively active 5-HT6R under neuropathic pain conditions focused our attention on the possible repurposing of 5-HT6R inverse agonists as a strategy to treat painful symptoms associated with neuropathies of different etiologies. Herein, we report the identification of compound 33 derived from the library of 2-aryl-1H-pyrrole-3-carboxamides as a potential analgesic agent. Compound 33 behaves as a potent 5-HT6R inverse agonist at Gs, Cdk5, and mTOR signaling. Preliminary ADME/Tox studies revealed preferential distribution of 33 to the CNS and placed it in the low-risk safety space. Finally, compound 33 dose-dependently reduced tactile allodynia in spinal nerve ligation (SNL)-induced neuropathic rats.

ABSTRACT Introduction Peripheral neuropathic pain is a disabling condition for patients and a challenge for physicians. Although many drugs have been assessed in scientific studies, few have demonstrated clear clinical efficacy against neuropathic pain. Moreover, the paucity of data regarding their safety raises the question of the benefit-risk ratio when used in patients experiencing peripheral neuropathies. Areas covered We conducted a review of double-blind, placebo-controlled, randomized clinical trials to assess the safety of medications used to treat peripheral neuropathic pain. This second review was focused on opioids, cannabinoids, and other medications. The aim was to provide an overview of the treatment-emergent adverse events (TEAEs) (≥10%) and the serious adverse effects described in clinical trials. Expert opinion Opioids and cannabinoids had significantly more TEAEs than placebos. Locally administered analgesics, such as capsaicin, lidocaine, botulinum toxin A seemed to have the most acceptable safety with only local adverse effects. The results for NMDA antagonists were inconclusive since no safety report was available. Less than half of the studies included presented a good description of TEAEs that included a statistical comparison versus a placebo group. Major methodological improvements must be made to ameliorate the assessment of medication safety in future clinical trials.

INTRODUCTION:Peripheral neuropathic pain is a highly disabling condition for patients and a challenge for neurologists and pain physicians. Although many drugs have been assessed in scientific studies, few have demonstrated a clear clinical efficacy against neuropathic pain. Moreover, the paucity of data regarding their safety raised the question on the benefit-risk ratio when used in patients experiencing peripheral neuropathies. AREAS COVERED:The authors conducted a review of double-blind, placebo-controlled, randomized clinical trials to assess the safety of medications used to treat neuropathic pain. This first review was focused on antidepressant and antiepileptic medications. The aim was to provide an overview of the treatment-emergent adverse events (≥10%) and the serious adverse effects described in clinical trials. EXPERT OPINION:Among antiepileptics and antidepressants, duloxetine appeared to have the most detailed safety for the treatment of peripheral neuropathic pain. Over all studies, the most commonly reported adverse effects were dizziness, drowsiness, nausea, and constipation. Only 20.0% of the included studies (N = 90) presented a good description of adverse effects that included a statistical comparison vers usa placebo group. Important methodological improvements must be made to improve the assessment of medication safety in future clinical trials.

Chronic neuropathic pain is a highly disabling syndrome that is poorly controlled by currently available analgesics. Here, we show that painful symptoms and associated cognitive deficits induced by spinal nerve ligation in the rat are prevented by the administration of serotonin 5-HT6 receptor inverse agonists or by the mTOR inhibitor rapamycin. In contrast, they are not alleviated by the administration of 5-HT6 receptor neutral antagonists. Likewise, activation of mTOR by constitutively active 5-HT6 receptors mediates allodynia in oxaliplatin-induced peripheral neuropathy in rats but not mechanical nociception in healthy rats. Furthermore, both painful and co-morbid cognitive symptoms in neuropathic rats are strongly reduced by intrathecal delivery of a cell-penetrating peptide that disrupts 5-HT6 receptor/mTOR physical interaction. Collectively, these findings demonstrate a deleterious influence of non-physiological mTOR activation by constitutively active spinal 5-HT6 receptors upon painful and cognitive symptoms in neuropathic pains of different etiologies. They suggest that targeting the constitutive activity of 5-HT6 receptors with inverse agonists or disrupting the 5-HT6 receptor/mTOR interaction might be valuable strategies for the alleviation of neuropathic pain and cognitive co-morbidities.

Les ruminants sont des animaux sensibles, doués de capacités émotionnelles et cognitives, pouvant être soumis à différents types de douleur (excès de nociception ou neuropathique) et ceci dans différents contextes (élevage ou expérimentation). L’évaluation de ces douleurs est souvent délicate car, dans la plupart des cas, il n’existe pas d'outil unique et spécifique mais plutôt un ensemble d'indicateurs dont les valeurs informatives sont complémentaires. Une évaluation adéquate de la douleur est essentielle afin d'optimiser sa prise en charge en utilisant au mieux l'arsenal thérapeutique actuellement à la disposition des prescripteurs. A travers cette synthèse, nous montrerons en quoi i) l’évaluation du type et du niveau de douleur est indispensable à une prise en charge optimale de la douleur, ii) une évaluation reposant sur une approche multiparamétrique est l'approche la plus adaptée à cet objectif.

Vision is the sensory sensitivity devoted to the perception and integration of visual information. The stages of this mechanism include the refraction of light, which depends on the eye's biophysical properties, phototransduction assured by photoreceptors, the detection of differences in brightness by the retina and the conscious perception of the scene by the central visual areas. (C) 2018 Elsevier Masson SAS. All rights reserved

Serotonin (5-hydroxytryptamine, 5-HT) is a key modulator of spinal nociceptive transmission. Among 5-HT receptors, the 5-HT2A subtype plays a critical role in the modulation of nociceptive information. Both pro-and antinociceptive effects of 5-HT2A receptor activation have been reported but converging evidence indicates an excitatory role for peripheral 5-HT2A receptors on pain transmission in acute, sub-chronic and chronic pain conditions. The central effects of 5-HT2A agonists which produce either anti-hyperalgesic or anti-allodynic effect seem to depend on the pathophysiology of pain. Neverthless, some data indicate that 5-HT acting drugs such as selective serotonin reuptake inhibitor (SSRI) antidepressants involve the 5-HT2A receptor to produce analgesia and that restoring 5-HT2A receptor functionality may contribute to enhance the analgesic efficacy of SSRI in metabolic and traumatic neuropathic pain.

Neuropathic pain is a common diabetic complication. It is characterized by symptoms of spontaneous and stimulus-evoked pain including hyperalgesia and allodynia. l-Arginine is a common precursor of many metabolites of biological interest, in particular, nitric oxide (NO), ornithine, and hence polyamines. In central nervous system, NO, glutamate, and polyamines share an N-methyl-d-aspartate (NMDA) receptor-mediated effect. We hypothesized that a variation in arginine metabolism caused by diabetes may contribute to development and maintenance of neuropathic pain and to the worsening of clinical and biological signs of diabetes.

Antidepressants are first-line treatments of neuropathic pain but not all these drugs are really effective. Agomelatine is an antidepressant with a novel mode of action, acting as an MT1/MT2 melatonergic receptor agonist and a 5-HT2C receptor antagonist that involves indirect norepinephrine release. Melatonin, serotonin, and norepinephrine have been involved in the pathophysiology of neuropathic pain. Yet, no study has been conducted to determine agomelatine effects on neuropathic pain in animal models. Using 3 rat models of neuropathic pain of toxic (oxaliplatin/OXA), metabolic (streptozocin/STZ), and traumatic (sciatic nerve ligation/CCI [chronic constriction nerve injury]) etiologies, we investigated the antihypersensitivity effect of acute and repeated agomelatine administration. We then determined the influence of melatonergic, 5-HT2C, α-2 and β-1/2 adrenergic receptor antagonists in the antihypersensitivity effect of agomelatine. The effect of the combination of agomelatine + gabapentin was evaluated using an isobolographic approach. In STZ and CCI models, single doses of agomelatine significantly and dose dependently reduced mechanical hypersensitivity. After daily administrations for 2 weeks, this effect was confirmed in the CCI model and agomelatine also displayed a marked antihypersensitivity effect in the OXA model. The antihypersensitivity effect of agomelatine involved melatonergic, 5-HT2C, and α-2 adrenergic receptors but not beta adrenoceptors. The isobolographic analysis demonstrated that the combination of agomelatine + gabapentin had additive effects. Agomelatine exerts a clear-cut antihypersensitivity effect in 3 different neuropathic pain models. Its effect is mediated by melatonergic and 5-HT2C receptors and, although agomelatine has no affinity, also by α-2 adrenergic receptors. Finally, agomelatine combined with gabapentin produces an additive antihypersensitivity effect.

Antidepressants remain one of the first line treatments prescribed to neuropathic pain patients despite their limited efficacy and/or their numerous side effects. More and more, pharmacotherapy for neuropathic pain has evolved towards the use of therapeutic combinations. The goal of the present study was to assess the efficacy of the combination of antidepressants - selective serotonin reuptake inhibitors and serotonin-noradrenaline reuptake inhibitors-with a peptide (TAT-2ASCV) able to disrupt the interaction between serotonin type 2A (5-HT2A) receptors and associated PDZ proteins. Mechanical hypersensitivity was assessed in sciatic nerve ligation-induced neuropathic pain in rats using paw pressure test after acute treatment with TAT-2ASCV alone or in combination with repeated treatment with fluoxetine or duloxetine or clomipramine. First, we validated the anti-hyperalgesic effect of TAT-2ASCV on mechanical hypersensitivity at the dose of 100 ng/rat (single i.t. injection). Second, using selective receptor antagonists, we found that the effect of TAT-2ASCV on mechanical hypersensitivity involves 5-HT2A as well as GABAA receptors. Finally, we showed that the association of TAT-2ASCV (100 ng, single i.t. injection) with fluoxetine (10 mg/kg, five i.p. injections) reveals its anti-hyperalgesic effect, while the association with duloxetine (1 mg/kg, five i.p. injections) or clomipramine (2.5 mg/kg, five i.p. injections) is only additive. Those results further accentuate the interest to develop small molecules acting like TAT-2ASCV in order to treat neuropathic pain as a monotherapy or in combination with antidepressants.