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

J Oral Sci. 2018 Mar 24;60(1):37-44. doi: 10.2334/josnusd.17-0005. Epub 2018 Mar 2.


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.

Keywords: 2-arachydonoylglycerol (2-AG); JZL184; monoacylglycerol lipase (MAGL); orofacial neuropathic pain.

MeSH terms

  • Animals
  • Arachidonic Acids / antagonists & inhibitors*
  • Arachidonic Acids / metabolism
  • Behavior, Animal
  • Benzodioxoles / pharmacology
  • Endocannabinoids / antagonists & inhibitors*
  • Endocannabinoids / metabolism
  • Enzyme Inhibitors / pharmacology
  • Facial Pain / etiology
  • Facial Pain / prevention & control*
  • Glycerides / antagonists & inhibitors*
  • Glycerides / metabolism
  • Male
  • Mice, Inbred C57BL
  • Monoacylglycerol Lipases / antagonists & inhibitors
  • Monoacylglycerol Lipases / metabolism
  • Neuralgia / etiology
  • Neuralgia / prevention & control*
  • Piperidines / pharmacology
  • Trigeminal Nerve Injuries / complications*


  • Arachidonic Acids
  • Benzodioxoles
  • Endocannabinoids
  • Enzyme Inhibitors
  • Glycerides
  • JZL 184
  • Piperidines
  • glyceryl 2-arachidonate
  • Monoacylglycerol Lipases