Intranasal Treatment with Cannabinoid 2 Receptor Agonist HU-308 Ameliorates Cold Sensitivity in Mice with Traumatic Trigeminal Neuropathic Pain.

Post-traumatic trigeminal neuropathy (PTTN) is a sensory abnormality caused by injury to the trigeminal nerve during orofacial surgery. However, existing analgesics are ineffective against PTTN. Abnormal microglial activation in the caudal part of the spinal trigeminal nucleus caudal part (Sp5C), where the central trigeminal nerve terminals reside, plays an important role in PTTN pathogenesis. Therefore, regulating microglial activity in Sp5C appears to be an important approach to controlling pain in PTTN. Cannabinoid receptor 2 (CB₂) is expressed in immune cells including microglia, and its activation has anti-inflammatory effects. The current study demonstrates that the repeated intranasal administration of CB₂ agonist HU-308 ameliorates the infraorbital nerve cut (IONC)-induced hyperresponsiveness to acetone (cutaneous cooling). The therapeutic efficacy of oral HU-308 was found to be less pronounced in alleviating cold hypersensitivity in IONC mice compared to intranasal administration, indicating the potential advantages of the intranasal route. Furthermore, repeated intranasal administration of HU-308 suppressed the activation of Sp5C microglia in IONC mice. Additionally, pretreatment with the CB₂ antagonist, SR 144528, significantly blocked the anti-nociceptive effect of repeated intranasal administration of HU-308 on cold hypersensitization in IONC mice. These data suggest that the continuous stimulation of CB₂ ameliorates PTTN-induced pain via the inhibition of microglial activation. Thus, CB₂ agonists are potential candidates for novel therapeutic agents against PTTN.