Researchers Uncover Mechanism Behind Relationship of Migraine, Opioid-Induced Pain in Mice

The link between prolonged opioid treatment and an increased frequency, severity of migraines has been attributed to the discovery of a peptide confirmed in mice that distinguishes the relationship of migraine pain and opioid-induced hyperalgesia (OIH), according to study findings published yesterday in the journal Molecular & Cellular Proteomics.

For people suffering from migraines, opioids are often prescribed to provide temporary pain relief for episodic migraines. However, prolonged use has been shown to cause an increase in the frequency and severity of migraine. Despite prior studies seeking to uncover the catalyst behind this correlation, the underlying mechanism has remained unknown.

Researchers from the University of Illinois at Chicago (UIC) hypothesized that overlapping mechanisms between OIH and chronic migraine occur through neuropeptide dysregulation. To examine this hypothesis, researchers designed 2 animal models accounting for migraine pain and opioid overuse pain to determine if any neuropeptides were altered between the 2 conditions.

Researchers used a label-free, nonbiased liquid chromatography-mass spectrometry on mice to identify and measure changes in more than 1500 neuropeptides.

After conducting the analysis, 16 neuropeptides were shown to be altered between the 2 conditions, with known pro-migraine molecule, calcitonin-gene related peptide, among 7 peptides associated with chronic migraine and several pain-processing neuropeptides associated with the 9 other peptides affected in OIH. Composite peptide compliments pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal peptide, and secretogranin showed significant changes in both chronic migraine and OIH, which warranted a follow-up pharmacological study to confirm associations.

After follow-up, researchers confirmed the role of PACAP in both models, which validated the effectiveness of the study’s peptidomic approach and indicated PACAP as a mechanistic link between chronic migraine and OIH, noted the authors.

Senior study author Amynah Pradhan, PhD, associate professor of psychiatry at UIC College of Medicine, described the researchers’ excitement to find and confirm PACAP’s presence in both models. “This study validates prior work on PACAP's role in migraine pain and, more importantly, is the first to identify PACAP as a factor in opioid-induced pain,” said Pradhan.

In distinguishing PACAP as a mechanism through which opioids may exacerbate migraines, Pradhan highlighted that these findings can inform the development of real-world treatments. “There are clinical trials underway to test antibodies targeting PACAP and a PACAP-binding receptor. Based on our data, these therapies may be extremely effective for people that have used opioids to treat their migraines,” said Pradhan.

Reference

Anapindi KDB, Yang N, Romanova EV, et al. PACAP and other neuropeptides link chronic migraine and opioid-induced hyperalgesia mouse models. Mol Cell Proteomics. [published online October 24, 2019]. doi: 10.1074/mcp.RA119.001767.