Mu and delta opioid receptors play opposite nociceptive and behavioural roles on nerve-injured mice.

TitleMu and delta opioid receptors play opposite nociceptive and behavioural roles on nerve-injured mice.
Publication TypeJournal Article
Year of Publication2019
AuthorsMartínez-Navarro M, Cabañero D, Wawrzczak-Bargiela A, Robé A, Gaveriaux-Ruff C, Kieffer BL, Przewlocki R, Baños JE, Maldonado R
JournalBr J Pharmacol
Date Published2019 Oct 26

BACKGROUND AND PURPOSE: Mu and delta opioid receptors (MOP, DOP) limit pain perception in physiological conditions, but their relative contribution to the manifestations of pathological pain is not completely understood. Here we used a genetic approach to investigate the opioid mechanisms modulating neuropathic pain and its comorbid manifestations.EXPERIMENTAL APPROACH: We generated conditional knockout mice with MOP or DOP deletion in sensory Nav1.8-positive neurons (Nav1.8), in GABAergic forebrain neurons (DLX5/6) or constitutively (CMV). Mutant mice and wild-type littermates were subjected to partial sciatic nerve ligation (PSNL) or sham surgery, and their nociceptive responses were compared. Anxiety-, depressive-like behaviour and cognitive performance were also measured. Opioid receptor mRNA expression, microgliosis and astrocytosis were assessed in the dorsal root ganglia and/or the spinal cord.KEY RESULTS: Constitutive CMV-MOP knockouts showed heat hyperalgesia under naïve conditions. Following PSNL, CMV-MOP mice displayed reduced mechanical allodynia and enhanced heat hyperalgesia. This phenotype was accompanied by increased DOP expression in dorsal root ganglia and spinal cord, and reduced microgliosis and astrocytosis in deep dorsal horn laminae. Conditional MOP knockouts and control mice developed similar hypersensitivity after PSNL, except for an enhanced heat hyperalgesia shown by DLX5/6-MOP male mice. Anxiety-like manifestations of neuropathic pain were aggravated in CMV-MOP and DLX5/6-MOP knockouts. Conversely, nerve-injured CMV-DOP mice showed increased mechanical allodynia, whereas Nav1.8-DOP and DLX5/6-DOP mice had partial nociceptive enhancement. Interestingly, CMV-DOP and DLX5/6-DOP mutants showed increased depressive-like behaviour after PSNL or sham-surgery.CONCLUSIONS AND IMPLICATIONS: This work reveals adverse consequences of MOP activity after nerve injury, including increased anxiety-like responses involving forebrain GABAergic neurons and enhanced mechanical pain sensitivity related with repression of DOP expression and spinal cord gliosis. In contrast, DOP shows a protective function limiting nociceptive and affective manifestations of neuropathic pain.

Alternate JournalBr. J. Pharmacol.
PubMed ID31655493