The 2023 MSC Emerging Science Contest for Early-Career Investigators took place on December 13, 2023. Below is a written summary of one of the presentations from the contest. Read about other presentations from the event in our Early-Career Science Library.
Category: Trigeminal pain and headache
Winner: Elizaveta Mangutov, PhD candidate, Washington University in St. Louis, US
Title: Delta opioid receptor activation inhibits PACAP-induced cephalic allodynia
Hypothesis, methodology, findings and conclusions.
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a known human migraine trigger and antibodies against the peptide and its receptor (PAC1) are being tested for the treatment of migraine. We have previously identified the delta opioid receptor (DOR) as a novel therapeutic target for headache disorders. However, it is still unclear how DORs regulate migraine-associated symptoms. Our hypothesis is that chronic intermittent PACAP will induce chronic cephalic allodynia in mice, and that known and developing migraine therapeutics will be able to acutely block the PACAP-induced allodynia.
One of the aims of this study was to develop a mouse model of PACAP-induced headache, and to determine the effect of DOR agonist in this model. A further goal was to investigate co-expression of DOR with PACAP and PAC1 receptor. To develop the PACAP model in mice, the effect of increasing doses of acute and chronic PACAP was assessed on mechanical responses measured by manual von Frey hair stimulation of the periorbital region. We also tested established headache therapies in this model, including the acute treatment sumatriptan, and a calcitonin gene-related peptide (CGRP) antagonist, as well as the DOR agonist, SNC80. Expression of DOR and the PACAPergic system was determined using in situ hybridization to identify co-expression of PACAP, its receptor PAC1, and DOR mRNA. The somatosensory cortex, hippocampus, trigeminal nucleus caudalis, and trigeminal ganglia were analyzed.
PACAP caused acute and chronic dose-dependent cephalic allodynia. Our maximum dose of PACAP was blocked by sumatriptan and DOR agonist SNC80, but not olcegepant. Correspondingly, in a model of chronic CGRP-induced allodynia, the PAC1 antagonist M65 was ineffective. There was some co-expression of PACAP and DOR in all brain regions but it was relatively low. In contrast, there was very high co-expression (>75%) of PAC1 and DOR in the somatosensory cortex, hippocampus, and trigeminal nucleus caudalis.
We have developed a mouse model of PACAP-induced allodynia that responds to known migraine therapeutics. DOR agonists showed efficacy in this model, and a strong co-expression between PAC1 and DOR was observed in specific brain regions. This evidence supports further clinical trials into DOR as a future therapeutic for patient care. Further investigations will determine the functional relationship between DOR and PACAP-PAC1.
Implications for understanding migraine disease and/or its comorbidities, or how the research holds promise as a new avenue of future migraine study.
This study contributes to our understanding of migraine by providing new insights into PACAP as a trigger for allodynia in mice. It also reveals the role of DOR agonists in mitigating PACAP-induced behaviors, offering a potential mechanism for relieving symptoms associated with migraine. Notably, while sumatriptan effectively blocked chronic PACAP-induced allodynia, the CGRP antagonist olcegepant did not. Sumatriptan appears to have a broader impact, possibly acting through various pathways and methods. On the other hand, CGRP antagonists are more targeted, suggesting that PACAP may induce migraine-like symptoms through a different pathway than CGRP. This study underscores the potential functional relationship between DOR and PACAP, prompting further investigation. And it supports further clinical trials into DOR as a future therapeutic for migraine.