Inhibition of 2-arachydonoylgycerol degradation attenuates orofacial neuropathic pain in trigeminal nerve-injured mice

• Published in: Journal of Oral Science Vol. 60; no. 1; pp. 37 - 44
• Main Authors: Kamimura, Rantaro, Hossain, Mohammad Z., Unno, Shumpei, Ando, Hiroshi, Masuda, Yuji, Takahashi, Kojiro, Otake, Masanori, Saito, Isao, Kitagawa, Junichi
• Format: Journal Article
• Language: English
• Published: Japan Nihon University School of Dentistry 2018
• Subjects: 2-arachydonoylglycerol (2-AG); Dentistry; JZL184; monoacylglycerol lipase (MAGL); orofacial neuropathic pain; orofacial neuropathic pain; 2-arachydonoylglycerol (2-AG); monoacylglycerol lipase (MAGL); JZL184
• ISSN: 1343-4934; 1880-4926
• DOI: 10.2334/josnusd.17-0005

Current therapeutics are not effective for orofacial neuropathic pain, and better options are needed. The present study used inferior orbital nerve (ION)-injured mice to investigate the effect of inhibiting monoacylglycerol lipase (MAGL), an enzyme that degrades the major endocannabinoid 2-arachydonoylgycerol (2-AG) in orofacial neuropathic pain. The head-withdrawal threshold to mechanical stimulation of the whisker pad was reduced on days 3, 5, and 7 after ION injury. Injection of JZL184, a selective inhibitor of MAGL, on day 7 after ION injury attenuated the reduction in head-withdrawal threshold at 2 h after administration. Moreover, the numbers of MAGL-immunoreactive neurons in the trigeminal subnucleus caudalis (Vc) and upper cervical spinal cord (C1-C2) were significantly greater in ION-injured mice than in sham-operated mice but were reduced after administration of JZL184. The increase in MAGL immunoreactivity suggests that increased 2-AG production is followed by rapid enzymatic degradation of 2-AG. JZL184 inhibited this degradation and thus increased 2-AG concentration in the brain, particularly in the Vc and C1-C2 regions, thus attenuating pain. Our findings suggest that inhibition of 2-AG degradation by MAGL inhibitors is a promising therapeutic option for treatment of orofacial neuropathic pain.