Dussol Manon, da Silva Borges Gisela, Beaulieu Claudie, Ghorbel Hadir, Descheemaeker Amélie, Herault Karine, Voisin Daniel, Luccarini Philippe, Gendron Louis, Dallel Radhouane
Université Clermont Auvergne, CHU Clermont-Ferrand, Inserm, Neuro-Dol, Clermont-Ferrand, France.
Département de Pharmacologie-Physiologie, Faculté de médecine et des sciences de la santé, Centre de recherche du CHU de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, Canada.
Br J Pharmacol. 2025 Sep;182(18):4380-4399. doi: 10.1111/bph.70098. Epub 2025 Jun 2.
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.
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.
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.
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.
小鼠的临床前研究表明，δ阿片受体（DOPs）是一种潜在的偏头痛治疗靶点。在此，我们研究了其在大鼠偏头痛模型中两性的作用。
我们使用RNAscope评估三叉神经节（TG）中DOP的分布，使用von Frey毛发评估DOP激动剂SNC80对面部机械敏感性的作用，并使用体内电生理学方法评估三叉神经尾侧核宽动态范围（WDR）神经元在生理条件下以及由硝酸异山梨酯（ISDN）注射诱导的偏头痛模型中的反应。
在未处理的大鼠中，DOP mRNA主要由大直径有髓鞘的NF200阳性TG神经元以及一些降钙素基因相关肽（CGRP）肽能神经元表达，但很少由IB4结合的非肽能无髓鞘神经元表达，且无性别差异。静脉注射SNC80对两性中WDR神经元对有害机械刺激的反应具有同等程度的抑制作用。在急性条件下，SNC80通过外周和中枢DOPs对两性中ISDN诱导的硬脑膜肥大（MH）均具有同等程度的剂量依赖性抑制作用。在慢性给予ISDN后，DOP mRNA的分布仅在雌性大鼠的TG中增加，特别是在NF200阳性神经元中。皮下注射SNC80可通过作用于雌性大鼠的外周DOPs以及雄性大鼠的中枢DOPs，逆转发作间期以及慢性发作期的头部机械性超敏反应，且雌性大鼠的逆转作用比雄性大鼠更强。
DOP介导的抗偏头痛作用在雌性大鼠中比雄性大鼠更强，并且在慢性条件下似乎分别通过雌性大鼠的外周DOPs和雄性大鼠的中枢DOPs介导。这些结果强化了使用DOP激动剂治疗偏头痛的相关性。
