Attenuation of allodynia and microglial reactivity by inhibiting the degradation of 2-arachidonoylglycerol following injury to the trigeminal nerve in mice

Rantaro Kamimura; Mohammad Zakir Hossain; Kojiro Takahashi; Isao Saito; Junichi Kitagawa

doi:10.1016/j.heliyon.2022.e10034

Attenuation of allodynia and microglial reactivity by inhibiting the degradation of 2-arachidonoylglycerol following injury to the trigeminal nerve in mice

Heliyon. 2022 Jul 30;8(8):e10034. doi: 10.1016/j.heliyon.2022.e10034. eCollection 2022 Aug.

Authors

Rantaro Kamimura¹, Mohammad Zakir Hossain², Kojiro Takahashi¹, Isao Saito¹, Junichi Kitagawa²

Affiliations

¹ Division of Orthodontics, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University, 2-5274 Gakkocho-dori, Niigata 951-8514, Japan.
² Department of Oral Physiology, Matsumoto Dental University, 1780 Gobara Hirooka, Shiojiri, Nagano 399-0781, Japan.

Abstract

Endocannabinoids have an important role for the regulation of neuropathic pain. In our previous study, we observed that preventing the degradation of a endocannabinoid, 2-arachidonoylglycerol (2-AG), using an inhibitor of monoacylglycerol lipase (JZL184), attenuated neuropathic orofacial pain (NOP). The present study aimed to investigate mechanisms underlying JZL184-induced attenuation of NOP. We hypothesized that JZL184 may suppress microglial reactivity in the trigeminal spinal subnucleus caudalis (Vc) under NOP. The infraorbital nerve (ION) was hemisected to model NOP in mice, resulting in a significant reduction of mechanical head-withdrawal threshold (MHWT) on day 4 following the ION hemisection. Chronic systemic application of JZL184 at a concentration of 8 or 16 mg/kg/day for 4 days significantly attenuated the reduction of MHWT in mice exposed to NOP. Administering JZL184 at 4 mg/kg/day or its vehicle, however, did not attenuate the MHWT of mice with NOP. The reactivity of microglial cells in the Vc increased in mice with NOP compared to sham-operated controls. The application of JZL184 at 8 or 16 mg/kg/day for 4 days significantly reduced the increased microglial reactivity in the Vc. The changes of microglia under NOP were, by contrast, not reduced by application of the drug at 4 mg/kg/day or its vehicle. The results indicate that preventing 2-AG degradation may increase its accumulation in the Vc and normalize microglial reactivity under NOP, which may contribute to suppressing NOP.

Keywords: 2-Arachidonoylglycerol (2-AG); JZL184; Mice; Microglia; Monoacylglycerol lipase (MAGL); Orofacial neuropathic pain.