PACAP-PAC1 receptor inhibition is effective in opioid induced hyperalgesia and medication overuse headache models

Zachariah Bertels; Elizaveta Mangutov; Kendra Siegersma; Haley C Cropper; Alycia Tipton; Amynah A Pradhan

doi:10.1016/j.isci.2023.105950

PACAP-PAC1 receptor inhibition is effective in opioid induced hyperalgesia and medication overuse headache models

iScience. 2023 Jan 10;26(2):105950. doi: 10.1016/j.isci.2023.105950. eCollection 2023 Feb 17.

Authors

Zachariah Bertels¹, Elizaveta Mangutov¹, Kendra Siegersma¹, Haley C Cropper¹, Alycia Tipton¹, Amynah A Pradhan¹

Affiliation

¹ Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA.

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. In situ 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.

Keywords: Cell biology; Neuroscience; Sensory neuroscience.