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.
Authors: Thapa Dinesh , Toguri James Thomas , Szczesniak Anna Maria , Kelly Melanie EM 
Published: November 2023

Background and PurposeDamage 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 (CB1R) and cannabinoid 2 receptor (CB2R). Cannabinoids that bind to CB1R, like tetrahydrocannabinol (THC), have shown utility in treating pain, however, their therapeutic applications are limited by CB1R‐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 CB1R, and could offer an alternative to CB1R 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.MethodsExperimental corneal hyperalgesia and inflammation were generated using chemical cauterization of the cornea in wildtype (WT) and CB2R knockout (CB2R−/−) mice. Cauterized eyes were treated with topical cannabinoids (0.2–5% w/v) in the presence or absence of the CB1R 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.ResultsCorneal 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 CB2R−/− mice. The antinociceptive effects of CBD‐DMH, but not CBD and HU308 (p < 0.0001), were blocked by the CB1R 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 CB2R−/− 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 CB2R−/− mice (p < 0.01 & p < 0.05, respectively).ConclusionCBD‐DMH had antinociceptive actions through CB1R, whereas, the antinociceptive and anti‐inflammatory actions of CBD and HU308 were independent of CB1R and mediated via CB2R activation. Therefore, the cannabinoids, CBD and HU308, could offer a novel therapy for ocular pain and inflammation with reduced CB1R mediated side‐effects.Support or Funding InformationCanadian Institutes of Health Research (CIHR).