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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number105950
JournaliScience
Volume26
Issue number2
DOIs
StatePublished - Feb 17 2023

Keywords

  • Cell biology
  • Neuroscience
  • Sensory neuroscience

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