Peripheral delta opioid receptors mediate duloxetine antiallodynic effect in a mouse model of neuropathic pain

• Published in: The European journal of neuroscience Vol. 48; no. 5; pp. 2231 - 2246
• Main Authors: Ceredig, Rhian Alice, Pierre, Florian, Doridot, Stéphane, Alduntzin, Unai, Salvat, Eric, Yalcin, Ipek, Gaveriaux‐Ruff, Claire, Barrot, Michel, Massotte, Dominique
• Format: Journal Article
• Language: English
• Published: France Wiley Subscription Services, Inc 01-09-2018; Wiley
• Subjects: Animals; antidepressant; Antidepressive Agents, Tricyclic - pharmacology; cuff model; Disease Models, Animal; Duloxetine Hydrochloride - pharmacology; Female; G protein‐coupled receptor; Ganglia, Spinal - metabolism; Hyperalgesia - drug therapy; Hyperalgesia - metabolism; Life Sciences; Male; mechanical allodynia; Mice, Transgenic; Narcotics; Neuralgia - drug therapy; Neuralgia - metabolism; Neurobiology; Neurons and Cognition; Nortriptyline - pharmacology; Pain Measurement - drug effects; Pain Measurement - methods; peripheral nerve injury; Receptors, Opioid, delta - drug effects; Receptors, Opioid, delta - metabolism; Sciatic Nerve - drug effects; Sciatic Nerve - metabolism; G protein-coupled receptor; mechanical allodynia; peripheral nerve injury; cuff model; antidepressant
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/ejn.14093

Peripheral delta opioid (DOP) receptors are essential for the antiallodynic effect of the tricyclic antidepressant nortriptyline. However, the population of DOP‐expressing cells affected in neuropathic conditions or underlying the antiallodynic activity of antidepressants remains unknown. Using a mouse line in which DOP receptors were selectively ablated in cells expressing Nav1.8 sodium channels (DOP cKO), we established that these DOP peripheral receptors were mandatory for duloxetine to alleviate mechanical allodynia in a neuropathic pain model based on sciatic nerve cuffing. We then examined the impact of nerve cuffing and duloxetine treatment on DOP‐positive populations using a knock‐in mouse line expressing a fluorescent version of the DOP receptor fused with the enhanced green fluorescent protein (DOPeGFP). Eight weeks postsurgery, we observed a reduced proportion of DOPeGFP‐positive small peptidergic sensory neurons (calcitonin gene‐related peptide (CGRP) positive) in dorsal root ganglia and a lower density of DOPeGFP‐positive free nerve endings in the skin. These changes were not present in nerve‐injured mice chronically treated with oral duloxetine. In addition, increased DOPeGFP translocation to the plasma membrane was observed in neuropathic conditions but not in duloxetine‐treated neuropathic mice, which may represent an additional level of control of the neuronal activity by DOP receptors. Our results therefore established a parallel between changes in the expression profile of peripheral DOP receptors and mechanical allodynia induced by sciatic nerve cuffing.
Peripheral delta opioid receptors are mandatory for duloxetine antiallodynic effect after sciatic nerve cuffing. The characterization of the neuropathic condition using fluorescent DOPeGFP knock‐in mice revealed less DOPeGFP‐positive small peptidergic sensory neurons in dorsal root ganglia, lower density of DOPeGFP‐positive free nerve endings in the skin and increased DOPeGFP translocation to the plasma membrane. These changes were absent in duloxetine‐treated neuropathic mice.