Enhancement of the endocannabinoid system through monoacylglycerol lipase inhibition relieves migraine-associated pain in mice

Background: Migraine affects over 1 billion people worldwide and is a leading cause of disability. Targeting the cannabinoid system offers a promising approach for pain and migraine relief. This study evaluated a novel monoacylglycerol lipase (MAGL) inhibitor to prolong endocannabinoid action in acute and chronic mouse models of migraine. It also examined MAGL and cannabinoid receptor 1 (CB₁) mRNA expression in key head pain-processing regions. Methods: C57BL6/J male and female mice received the human migraine trigger nitroglycerin (NTG) acutely or every other day for 9 days. Allodynia was assessed by von Frey hair stimulation of the periorbital area. A single dose of MAGL inhibitor (ABD-1970) was tested in acute and chronic NTG models. Additionally, ABD-1970 was given daily for 5 days to assess tolerance. In situ hybridization measured transcript expression of MAGL, CB₁, and neuronal marker Rbfox3 in trigeminal ganglia (TG) and trigeminal nucleus caudalis (TNC). Results: A single injection of ABD-1970 blocked cephalic allodynia induced by acute NTG. ABD-1970 also blocked chronic allodynia established by chronic intermittent NTG. Repeated administration did not induce tolerance, and ABD-1970 continued to block NTG-induced allodynia after 5 days of administration. There was high expression of MAGL and CB₁ in the TG and TNC, present in Rbfox3 positive and negative cells. Conclusion: MAGL inhibitor effectively blocked acute and chronic migraine-associated pain, likely through prolonged endocannabinoid action. This effect may be mediated through action at peripheral or central sites considering the high MAGL and CB₁ expression in the TG and TNC, respectively. The endocannabinoid system appears to modulate migraine mechanisms, and MAGL may be a promising target for this disorder.