Contribution of peripheral and central delta opioid receptors in the relief of migraine-like headache in female and male rats.

BACKGROUND AND PURPOSE

Preclinical studies in mice highlight delta opioid receptors (DOPs) as a potential migraine treatment. Here, we examined their role in a rat model of migraine in both sexes.

EXPERIMENTAL APPROACH

We assessed DOP distribution in the trigeminal ganglion (TG) using RNAscope, the action of the DOP agonist SNC80 on facial mechanical sensitivity using von Frey hairs and responses of trigeminal nucleus caudalis wide dynamic range (WDR) neurons using in vivo electrophysiology, in physiological conditions and a migraine model induced by isosorbide dinitrate (ISDN) injections.

KEY RESULTS

In naive rats, DOP mRNA was expressed by large-diameter myelinated NF200-positive TG neurons predominantly and by some CGRP peptidergic neurons, but rarely by IB4-binding nonpeptidergic unmyelinated neurons, with no sex difference. Intravenous SNC80 inhibited WDR neuron responses to noxious mechanical stimuli equally in both sexes. In acute conditions, SNC80 inhibited ISDN-induced MH in a dose-dependent manner equally in both sexes, through peripheral and central DOPs. After chronic administration of ISDN, the distribution of DOP mRNA increased in the TG of females only, specifically in NF200-positive neurons. Subcutaneous SNC80 reversed the interictal and, more in females than in males, the chronic ictal cephalic mechanical hypersensitivity, by acting through peripheral DOPs in females and through central DOPs in males.

CONCLUSION AND IMPLICATIONS

DOP-mediated antimigraine effect is stronger in female than male rats and appears to be mediated in chronic conditions through peripheral DOPs in females and central DOPs in males. The results strengthen the relevance of using DOP agonists to treat migraine.