A Dual Noradrenergic Mechanism for the Relief of Neuropathic Allodynia by the Antidepressant Drugs Duloxetine and Amitriptyline.

In addition to treating depression, antidepressant drugs are also a first-line treatment for neuropathic pain, which is pain secondary to lesion or pathology of the nervous system. Despite the widespread use of these drugs, the mechanism underlying their therapeutic action in this pain context remains partly elusive. The present study combined data collected in male and female mice from a model of neuropathic pain and data from the clinical setting to understand how antidepressant drugs act. We show two distinct mechanisms by which the selective inhibitor of serotonin and noradrenaline reuptake duloxetine and the tricyclic antidepressant amitriptyline relieve neuropathic allodynia. One of these mechanisms is acute, central, and requires descending noradrenergic inhibitory controls and α2A adrenoceptors, as well as the mu and delta opioid receptors. The second mechanism is delayed, peripheral, and requires noradrenaline from peripheral sympathetic endings and ß2 adrenoceptors, as well as the delta opioid receptors. We then conducted a transcriptomic analysis in dorsal root ganglia, which suggested that the peripheral component of duloxetine action involves the inhibition of neuroimmune mechanisms accompanying nerve injury, including the downregulation of the TNF-α-NF-κB signaling pathway. Accordingly, immunotherapies against either TNF-α or Toll-like receptor 2 (TLR2) provided allodynia relief. We also compared duloxetine plasma levels in the animal model and in patients and we observed that patients' drug concentrations were compatible with those measured in animals under chronic treatment involving the peripheral mechanism. Our study highlights a peripheral neuroimmune component of antidepressant drugs that is relevant to their delayed therapeutic action against neuropathic pain.SIGNIFICANCE STATEMENT In addition to treating depression, antidepressant drugs are also a first-line treatment for neuropathic pain, which is pain secondary to lesion or pathology of the nervous system. However, the mechanism by which antidepressant drugs can relieve neuropathic pain remained in part elusive. Indeed, preclinical studies led to contradictions concerning the anatomical and molecular substrates of this action. In the present work, we overcame these apparent contradictions by highlighting the existence of two independent mechanisms. One is rapid and centrally mediated by descending controls from the brain to the spinal cord and the other is delayed, peripheral, and relies on the anti-neuroimmune action of chronic antidepressant treatment.

The antiallodynic action of pregabalin in neuropathic pain is independent from the opioid system.

BACKGROUND: Clinical management of neuropathic pain, which is pain arising as a consequence of a lesion or a disease affecting the somatosensory system, partly relies on the use of anticonvulsant drugs such as gabapentinoids. Therapeutic action of gabapentinoids such as gabapentin and pregabalin, which act by the inhibition of calcium currents through interaction with the α2δ-1 subunit of voltage-dependent calcium channels, is well documented. However, some aspects of the downstream mechanisms are still to be uncovered. Using behavioral, genetic, and pharmacological approaches, we tested whether opioid receptors are necessary for the antiallodynic action of acute and/or long-term pregabalin treatment in the specific context of neuropathic pain. RESULTS: Using the cuff model of neuropathic pain in mice, we show that acute pregabalin administration at high dose has a transitory antiallodynic action, while prolonged oral pregabalin treatment leads to sustained antiallodynic action, consistent with clinical observations. We show that pregabalin remains fully effective in µ-opioid receptor, in δ-opioid receptor and in κ-opioid receptor deficient mice, either female or male, and its antiallodynic action is not affected by acute naloxone. Our work also shows that long-term pregabalin treatment suppresses tumor necrosis factor-α overproduction induced by sciatic nerve constriction in the lumbar dorsal root ganglia. CONCLUSIONS: We demonstrate that neither acute nor long-term antiallodynic effect of pregabalin in a context of neuropathic pain is mediated by the endogenous opioid system, which differs from opioid treatment of pain and antidepressant treatment of neuropathic pain. Our data are also supportive of an impact of gabapentinoid treatment on the neuroimmune aspect of neuropathic pain.

Glucocorticoid-mediated nycthemeral and photoperiodic regulation of tph2 expression.

In the Syrian hamster dorsal and median raphé nuclei, the tryptophan hydroxylase 2 gene (tph2), which codes the rate-limiting enzyme of serotonin synthesis, displays daily variations in its expression in animals entrained to a long but not to a short photoperiod. The present study aimed to assess the role of glucocorticoids in the nycthemeral and photoperiodic regulation of daily tph2 expression. In hamsters held in long photoperiod from birth, after adrenalectomy and glucocorticoid implants the suppression of glucocorticoid rhythms induced an abolition of the daily variations in tph2-mRNA concentrations, a decrease in the amplitude of body temperature rhythms and an increase in testosterone levels. All these effects were reversed after experimental restoration of a clear daily rhythm in the plasma glucocorticoid concentrations. We conclude that the photoperiod-dependent rhythm of glucocorticoids is the main regulator of tph2 daily expression.

Complex regional influence of photoperiod on the nycthemeral functioning of the dorsal and median raphé serotoninergic system in the Syrian hamster.

The Syrian hamster (Mesocricetus auratus) is a widely used species for the study of biological clock synchronization and photoperiodism. The serotoninergic system arising from the median (MnR) and the dorsal raphé (DR) is a major actor in circadian clock synchronization. This serotoninergic system is also associated with functions and behaviours influenced by seasonal changes. The aim of the present study was to assess the influence of photoperiod on the daily functioning of the MnR and DR serotoninergic system. The morphology of both raphé nuclei was analysed in hamsters kept under long and short photoperiod by immunocytochemical detection of two markers of the serotoninergic system, serotonin and tryptophan hydroxylase (TPH, the rate-limiting enzyme of serotonin synthesis). The morphological analysis revealed a fairly complex morphological organization of the DR and MnR along their caudo-rostral extent. This morphological organisation was similar in the two photoperiods. However, quantification of several markers of serotonin (5-HT) synthesis in the DR and MnR revealed a time-dependent functioning of serotoninergic cells that was locally influenced by photoperiod. In particular, the significant daily variations of tph2-mRNA and TPH levels in the rostral MnR, and of the 5-HT/5-HIAA (5-hydroxyindoleacetic acid) ratio within the suprachiasmatic nuclei, were abolished under short photoperiod. The results are discussed with regard to the known physiological role of the serotoninergic system on the biological clock.