Peripherally acting cannabinoid prevents migraine-like pain and sensitization of dural nociceptors
The 2024 MSC Emerging Science Contest for Early-Career Investigators took place on December 9, 2024. Below is a written summary of one of the presentations from the contest. (A recording of the event is available here).
Category: Pharmacology
Runner up: Yoshihiro Kitaoka, PhD, UCLA
Title: Peripherally acting cannabinoid prevents migraine-like pain and sensitization of dural nociceptors.
Hypothesis, methodology, findings and conclusions
Migraine sensitization of trigeminal dural afferents occurs in a mouse model of migraine, and we hypothesize that peripherally-restricted cannabinoids (PRCBs) may be useful in suppressing behavioral symptoms caused by this sensitization.
Anesthetized (isoflurane) female C57BL/6J mice (5-week-old) received supradural injections (at bregma) of pH-6.0 or pH-7.4 saline (5 μL). At 3 days post-injection, all mice were tested for latent sensitization by a second injection of pH-7.0 saline. Allodynia symptoms were assessed by withdrawal responses to stimulation of the periorbital region with calibrated von Frey hairs before and 1, 3, 5, 24, 48, and 72 hours after the 1st injection, and 1, 3, 5 and 24 hours after the 2nd injection. In separate groups of mice, the CB1R/CB2R agonist PRCB, PrNMI (5 μM), was co-applied with pH-6.0 saline with or without the peripherally-restricted selective CB1R inverse agonist, 18A (20 μM) or the brain permeant- selective CB2R inverse agonist, SR144528 (20 μM). Patch clamp recordings were obtained from fluorogold-labeled dural afferent trigeminal ganglion neurons (dTGs) acutely isolated 3-days after fluorogold co-injection with pH-7.4 or pH-6.0 saline. Behavioral tests and recordings were performed by investigators blinded to the treatments.
Supradural co-administration of pH-6.0 saline with PrNMI, prevented both the initial and latent symptoms of cutaneous allodynia. Co-administration of pH 6.0/PrNMI with 18A, or SR144528, abolished the preventative effects of PrNMI. Patch clamp recordings from dTGs revealed altered membrane properties and increased excitability of dTGs from pH-6.0-treated animals. These data suggest that the altered excitability and membrane properties of dTGs contribute to the development of latent sensitization and that the PRCB, PrNMI, effectively prevents behavioral symptoms of acid-mediated hyperalgesic priming and latent sensitization via activation of neuronal CB1 and non-neuronal CB2 receptors. This research on migraine-like pain in mice highlights new potential treatments, such as PRCBs, which could prevent migraines and reduce their severity. Understanding these mechanisms may lead to better, more personalized care for patients, offering new options for both prevention and symptom relief.
Implications for understanding migraine disease and/or its comorbidities, or how the research holds promise as a new avenue of future migraine study.
My research using a mouse model of migraine-like pain, created with a low-pH solution to simulate migraine conditions, provides insights into the mechanisms of trigeminal dural afferent sensitization, which plays a key role in migraine development. This model allowed us to assess the effectiveness of PrNMI as both a preventative and post-treatment option for reducing symptoms. Furthermore, by evaluating changes in the membrane properties of sensory neurons and the analgesic effects of PRCBs, the study points to the potential of PRCBs as a novel preventative treatment for migraine. Understanding these mechanisms and treatment effects may open new avenues for studying migraine comorbidities, such as chronic pain, and lead to more effective therapies for patients.