title: Analgesic antidepressants promote the responsiveness of locus coeruleus neurons to noxious stimulation: implications for neuropathic pain.
abstract: Antidepressants that block the reuptake of noradrenaline and/or serotonin are among the first-line treatments for neuropathic pain, although the mechanisms underlying this analgesia remain unclear. The noradrenergic locus coeruleus is an essential element of both the ascending and descending pain modulator systems regulated by these antidepressants. Hence, we investigated the effect of analgesic antidepressants on locus coeruleus activity in Sprague-Dawley rats subjected to chronic constriction injury (CCI), a model of neuropathic pain. In vivo extracellular recordings of locus coeruleus revealed that CCI did not modify the basal tonic activity of this nucleus, although its sensory-evoked response to noxious stimuli was significantly altered. Under normal conditions, noxious stimulation evokes an early response, corresponding to the activation of myelinated A fibers, which is followed by an inhibitory period and a subsequent late capsaicin-sensitive response, consistent with the activation of unmyelinated C fibers. CCI provokes an enhanced excitatory early response in the animals and the loss of the late response. Antidepressant administration over 7 days (desipramine, 10mg/kg/day or duloxetine, 5mg/kg/day, delivered by osmotic minipumps) decreased the excitatory firing rate of the early response in the CCI group. Moreover, in all animals, these antidepressants reduced the inhibitory period and augmented the late response. We propose that N-methyl-d-aspartate and alpha-2-adrenoceptors are involved in the analgesic effect of antidepressants. Antidepressant-mediated changes were correlated with behavioral effects indicative of analgesia in healthy and neuropathic rats.
authors.affiliation: Neuropsychopharmacology Research Group, Department of Neuroscience, University of Cadiz, Cadiz, Spain Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain Instituto Cajal CSIC, Madrid, Spain Neuropsychopharmacology Research Group, Psychobiology Area, Department of Psychology, University of Cadiz, Cadiz, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Alba-Delgado
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Mico
authors.forename: Pilar
authors.initials: P
authors.lastname: Sánchez-Blázquez
authors.forename: Esther
authors.initials: E
authors.lastname: Berrocoso
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D008125:Locus Coeruleus / Q000187:drug effects* / Q000502:physiology; D008297:Male; D016202:N-Methylaspartate / Q000502:physiology; D009437:Neuralgia / Q000503:physiopathology*; D009474:Neurons / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology; D013116:Spinal Cord / Q000473:pathology / Q000502:physiology
chemical_list: D000700:Analgesics; D000928:Antidepressive Agents; D018341:Receptors, Adrenergic, alpha-2; D016202:N-Methylaspartate