The Non‐psychoactive Phytocannabinoid, Cannabidiol (CBD), and the Synthetic Derivatives, HU308 and CBD‐DMH, Reduces Hyperalgesia and Inflammation in a Mouse Model of Corneal injury.

Background and Purpose Damage to corneal tissue results in intense ocular pain, dysfunction in nociceptive signaling and release of inflammatory mediators. Current treatments for corneal pain and inflammation are frequently ineffective. The endocannabinoid system (ECS) is an emerging therapeutic target in the modulation of pain and inflammation. The ECS consists of endogenous cannabinoid ligands that mediate their actions via G‐protein coupled receptors, cannabinoid 1 receptor (CB 1 R) and cannabinoid 2 receptor (CB 2 R). Cannabinoids that bind to CB 1 R, like tetrahydrocannabinol (THC), have shown utility in treating pain, however, their therapeutic applications are limited by CB 1 R‐mediated behavioral side‐effects. The non‐psychoactive phytocannabinoid, cannabidiol (CBD), and CBD derivatives, CBD‐DMH and HU‐308, have reported anti‐inflammatory effects, which may be mediated independent of CB 1 R, and could offer an alternative to CB 1 R ligands in the treatment of ocular pain and inflammation. Therefore, the purpose of this research is to investigate the antinociceptive and anti‐inflammatory properties of CBD, CBD‐DMH and HU308 in a mouse model of corneal injury. Methods Experimental corneal hyperalgesia and inflammation were generated using chemical cauterization of the cornea in wildtype (WT) and CB 2 R knockout (CB 2 R −/− ) mice. Cauterized eyes were treated with topical cannabinoids (0.2–5% w/v) in the presence or absence of the CB 1 R antagonist, AM281 (2.5mg/kg ip). The ocular blink response, indicative of corneal hyperalgesia following chemical stimulation by capsaicin, was recorded 6 hours post‐injury. Mice were euthanized and eyes were enucleated at 12 hours and neutrophil infiltration into the cornea, a marker for inflammation, was analyzed using immunohistochemistry in the corneal sections. Results Corneal cauterization resulted in an increased blink response to capsaicin 6 hours post‐injury compared to sham control eyes (p < 0.0001). Application of 5% CBD, 5% CBD‐DMH and 1.5% HU308 reduced blinks in WT mice compared to vehicle‐treated eyes (p < 0.01). The antinociceptive effects of CBD and HU308 (p < 0.01 & p < 0.05, respectively), but not CBD‐DMH, were reduced in CB 2 R −/− mice. The antinociceptive effects of CBD‐DMH, but not CBD and HU308 (p < 0.0001), were blocked by the CB 1 R antagonist, AM281. Neutrophil infiltration into the cornea was increased 12 hours post injury, compared to non‐cauterized eyes in WT mice (p < 0.0001). Neutrophil infiltration was exacerbated in CB 2 R −/− mice compared to WT mice (p < 0.001). 5% CBD and 1.5% HU308 reduced neutrophil infiltration (p <0.001 & p <0.0001, respectively); these effects were reduced in CB 2 R −/− mice (p < 0.01 & p < 0.05, respectively). Conclusion CBD‐DMH had antinociceptive actions through CB 1 R, whereas, the antinociceptive and anti‐inflammatory actions of CBD and HU308 were independent of CB 1 R and mediated via CB 2 R activation. Therefore, the cannabinoids, CBD and HU308, could offer a novel therapy for ocular pain and inflammation with reduced CB 1 R mediated side‐effects. Support or Funding Information Canadian Institutes of Health Research (CIHR).