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

Abstract

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.

Targeting Peripherally Restricted Cannabinoid Receptor 1, Cannabinoid Receptor 2, and Endocannabinoid-Degrading Enzymes for the Treatment of Neuropathic Pain Including Neuropathic Orofacial Pain

“…We also observed that MAGL immunoreactive neurons were increased in the Vc and upper cervical spinal cord (C1-C2) under the neuropathic pain condition, and this effect was reduced after administration of JZL184 [258]. These observations suggest that 2-AG may be increased in the Vc and C1-C2 areas under neuropathic pain conditions ( Figure 1) and rapidly degraded by MAGL, as indicated by the increased MAGL immunoreactivity [258]. 2-AG can be released from postsynaptic neurons by exaggerated presynaptic neuronal activity because of nerve injury [21,70,258] (Figure 1), which can be considered as the body's autoprotective/defense mechanism for pain control [21,61,68,69].…”

“…Trigeminal nerve injury was observed to induce neuropathic pain symptoms in the orofacial area [258,[263][264][265]. Systemic administration of the compound attenuated mechanical allodynia 2 h after administration [258]. We also observed that MAGL immunoreactive neurons were increased in the Vc and upper cervical spinal cord (C1-C2) under the neuropathic pain condition, and this effect was reduced after administration of JZL184 [258].…”

“…Systemic administration of the compound attenuated mechanical allodynia 2 h after administration [258]. We also observed that MAGL immunoreactive neurons were increased in the Vc and upper cervical spinal cord (C1-C2) under the neuropathic pain condition, and this effect was reduced after administration of JZL184 [258]. These observations suggest that 2-AG may be increased in the Vc and C1-C2 areas under neuropathic pain conditions ( Figure 1) and rapidly degraded by MAGL, as indicated by the increased MAGL immunoreactivity [258].…”

“…Recently, in a study, we observed that a selective MAGL inhibitor, JZL184, reduced NOP induced by injury to a branch of the trigeminal nerve in mice [258]. Trigeminal nerve injury was observed to induce neuropathic pain symptoms in the orofacial area [258,[263][264][265].…”

Potential for endocannabinoid system modulation in ocular pain and inflammation: filling the gaps in current pharmacological options

“…JZL184 acts as a MAGL-specific inhibitor [229], which allows differentiation from FAAH-inhibition mediated effects [231], and has been shown to produce analgesia in various pain assays [229,[232][233][234][235][236][237]. In a mouse model of orofacial neuropathic pain, induced via injury of the inferior orbital nerve, JZL184 reduced pain (increased threshold to mechanical stimulation) 2 h following administration [231].…”