UCLA

Chronic migraine is debilitating and greatly diminishes individual’s quality of life. Moreover, repeated use of current abortive medications leads to rebound headaches and latent sensitization of trigeminal ganglion (TG) neurons. Emerging evidence indicates that cannabinoids may be effective in reducing the frequency of migraine attacks. However, their widespread use is limited by their psychotropic side effects. We recently developed peripherally-restricted cannabinoids (PRCBs), demonstrating their effectiveness in several preclinical models of neuropathic and cancer pain, without psychotropic side effects. We investigated the efficacy of our lead PRCB in a mouse model of medication overuse headache and latent sensitization, assessed changes in protein expression of select ion channels and enzymes involved in the pathogenesis of these headaches, and examined the cellular mechanisms by which peripheral cannabinoid 1 receptor (CB1R) activation exerts its effects on TG neurons. Pre-treatment with a PRCB prevented chronic triptan-induced hypersensitivity, latent sensitization, and increases in phosphorylated protein kinase A, neuronal nitric oxide synthase, and transient receptor ankyrin 1 protein levels compared to vehicle-treated mice. PRCB reversibly suppressed low pH- and allyl isothiocyanate-evoked currents in TG neurons in a CB1R-dependent manner. PRCB effectiveness in preventing triptan-induced latent sensitization points to its potential as a preventative treatment for rebound headaches.