TARGETING THE ENDOCANNABINOID SYSTEM WITH ORTHOSTERIC AND ALLOSTERIC CANNABINOID LIGANDS TO REDUCE CORNEAL PAIN AND INFLAMMATION

Abstract

The endocannabinoid system, including cannabinoid 1 (CB1R) and cannabinoid 2 (CB2R) receptor, is an emerging target for treating pain and inflammation. This research investigated the effects of orthosteric and allosteric cannabinoid receptor ligands using a mouse model of corneal hyperalgesia. Behavioral pain responses were quantified 6 h after corneal chemical injury. Neutrophil infiltration was assessed by immunohistochemistry in post-mortem corneas 6-12 h post-injury. Tetrahydrocannabinol (∆8THC) mediated its anti-nociceptive and anti-inflammatory effects via CB1R whereas, cannabidiol (CBD) mediated anti-nociceptive and anti-inflammatory actions via 5-HT1A receptor. Anti-nociceptive and anti-inflammatory effects of the CBD-derivative, HU-308, were mediated via CB2R. Allosteric ligands can minimize side-effects associated with orthosteric receptor activation. The CB1R positive allosteric modulator (PAM), GAT229, and the ago-PAM, GAT211 (plus ∆8THC), or the CB1R allosteric agonist, GAT228, were anti-nociceptive and anti-inflammatory in cornea. Cannabinoids, together with allosteric ligands, could be a novel therapy for corneal pain and inflammation.