PACAP and Other Neuropeptide Targets Link Chronic Migraine and Opioid-induced Hyperalgesia in Mouse Models

Chronic use of opioids can produce opioid-induced hyperalgesia (OIH), and when used to treat migraine, these drugs can result in increased pain and headache chronicity. We hypothesized that overlapping mechanisms between OIH and chronic migraine occur through neuropeptide dysregulation. Using label-free, non-biased liquid chromatography-mass spectrometry to identify and measure changes in more than 1500 neuropeptides under these two conditions, we observed only 16 neuropeptides that were altered between the two conditions. The known pro-migraine molecule, calcitonin-gene related peptide, was among seven peptides associated with chronic migraine, with several pain-processing neuropeptides among the nine other peptides affected in OIH. Further, composite peptide complements Pituitary adenylate cyclase-activating polypeptide (PACAP), Vasoactive intestinal peptide (VIP) and Secretogranin (SCG) showed significant changes in both chronic migraine and OIH. In a follow-up pharmacological study, we confirmed the role of PACAP in models of these two disorders, validating the effectiveness of our peptidomic approach, and identifying PACAP as a mechanistic link between chronic migraine and OIH. Data are available via ProteomeXchange with identifier PXD013362. The neuropeptides within seven nervous system regions involved in relaying pain signals have been identified and quantified in mouse models of chronic migraine and opioid-induced hyperalgesia using label-free peptidomics. Of the >1500 peptides identified, only a few neuropeptides were significantly altered between the two conditions, including the known pro-migraine molecule, calcitonin-gene related peptide. As pituitary adenylate cyclase activating enzyme (PACAP)-related peptides were similarly altered in both groups, we validated PACAP as an overlapping mechanism of chronic migraine-associated pain and opioid-induced hyperalgesia.