Conference Coverage

Harold G. Wolff Lecture Award: DOR Deletion From PAC1-Expressing Cells Increased Migraine-Associated Symptoms in Mice

Edited by:
Anthony Calabro, MA

Key Highlights

  • Researchers evaluated whether deletion of delta opioid receptors (DOR) from PAC1-expressing cells altered migraine-associated symptoms and response to DOR agonism.
  • PAC1-DOR mice showed reduced DOR expression in migraine-processing regions, including the somatosensory cortex, thalamus, and trigeminal nucleus caudalis.
  • DOR deletion from PAC1-expressing cells enhanced cephalic allodynia after acute nitroglycerin exposure and increased cortical spreading depression events.
  • The DOR agonist SNC80 did not produce anti-migraine or analgesic effects in PAC1-DOR mice across nitroglycerin-induced migraine-associated pain, medication overuse headache, and inflammatory pain models.

The deletion of delta opioid receptors (DORs) from pituitary adenylate cyclase-activating polypeptide receptor type 1 (PAC1)-expressing cells increased susceptibility to migraine-associated symptoms, and it abolished responses to a DOR agonist in a conditional knockout mouse model, according to findings by Yaseen Agbaria, PhD, Harold G. Wolff Lecture Award winner for the best new paper on headache or facial pain. Dr. Agbaria presented his findings at the American Headache Society 68th Annual Scientific Meeting in Orlando, FL.

In their paper, “Delta-Opioid Receptors in PAC1-Expressing Cells Regulate Endogenous and Pharmacological Responses to Migraine-Associated Symptoms,” Agbaria and colleagues noted that DOR is a novel target for the treatment of migraine and headache disorders and is highly co-expressed with the PAC1 in key migraine-processing regions, including the trigeminal nucleus caudalis and somatosensory cortex.

The researchers generated a conditional knockout mouse in which DOR was selectively deleted from PAC1-expressing cells by crossing a PAC1-Cre line with a DOR floxed line. They characterized DOR expression in the central and peripheral nervous systems of this mouse line.

PAC1-DOR mice and LoxP control littermates were evaluated in nitroglycerin-induced migraine-associated pain and potassium chloride-induced cortical spreading depression models. The investigators also assessed whether DOR deletion from PAC1-expressing cells altered DOR agonist-induced convulsions, hyperlocomotion, anxiolytic-like behavior, and anti-allodynic effects in nitroglycerin-induced migraine-associated pain, opioid-induced medication overuse headache, and complete Freund adjuvant inflammatory pain models.

Study Findings

PAC1-DOR mice showed robust reductions in DOR expression in migraine-processing regions, including approximately 75% in the somatosensory cortex, 71% in the thalamus, and 84% in the trigeminal nucleus caudalis. DOR expression was reduced by approximately 10% in the trigeminal ganglion.

Naïve PAC1-DOR mice had cephalic and peripheral mechanical thresholds similar to those of LoxP controls. However, PAC1-DOR mice developed enhanced cephalic allodynia after acute nitroglycerin exposure at multiple tested doses. They also had an increased number of cortical spreading depression events compared with LoxP controls.

The DOR agonist SNC80 failed to induce convulsions, hyperlocomotion, and anxiolytic-like effects in PAC1-DOR mice. In addition, the anti-migraine and analgesic effects of SNC80 were abolished in nitroglycerin-induced migraine-associated pain, opioid-induced medication overuse headache, and inflammatory pain models.

Clinical Implications

According to the study authors, the findings suggest that endogenous activation of DOR in PAC1-expressing cells is essential for modulating migraine-associated symptoms. The authors also stated that the anti-allodynic effects of DOR agonists are mediated by DOR activation in PAC1-expressing cells.

Expert Commentary

“Our findings revealed a novel aspect of DOR function within PAC1-cells in regulating migraine-associated symptoms and mediating the anti-migraine effects of DOR agonist,” the researchers concluded.

Reference
Awad-Igbaria Y, Zhang Y, Macklin-Jackson D, Franke E, Mangutov E, Pradhan AA. Harold G. Wolff Lecture Award: δ-opioid receptors in pac1-expressing cells regulate endogenous and pharmacological responses to migraine-associated symptoms. Presented at: 68th Annual Scientific Meeting of the American Headache Society; June 4-7, 2026; Orlando, FL.