PACAP-PAC1 Receptor Inhibition is Effective in Opioid Induced Hyperalgesia and Medication Overuse Headache Models

Overview

Journal iScience

Publisher Cell Press

Date 2023 Feb 9

PMID 36756376

Authors

Zachariah Bertels

Elizaveta Mangutov

Kendra Siegersma

Haley C Cropper

Alycia Tipton

Amynah A Pradhan

Affiliations

Soon will be listed here.

Abstract

Opioids prescribed for pain and migraine can produce opioid-induced hyperalgesia (OIH) or medication overuse headache (MOH). We previously demonstrated that pituitary adenylate cyclase activating polypeptide (PACAP) is upregulated in OIH and chronic migraine models. Here we determined if PACAP acts as a bridge between opioids and pain chronification. We tested PACAP-PAC1 receptor inhibition in novel models of opioid-exacerbated trigeminovascular pain. The PAC1 antagonist, M65, reversed chronic allodynia in a model which combines morphine with the migraine trigger, nitroglycerin. Chronic opioids also exacerbated cortical spreading depression, a correlate of migraine aura; and M65 inhibited this augmentation. hybridization showed MOR and PACAP co-expression in trigeminal ganglia, and near complete overlap between MOR and PAC1 in the trigeminal nucleus caudalis and periaqueductal gray. PACAPergic mechanisms appear to facilitate the transition to chronic headache following opioid use, and strategies targeting this system may be particularly beneficial for OIH and MOH.

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