The Cannabinoids Δ⁸THC, CBD, and HU-308 Act via Distinct Receptors to Reduce Corneal Pain and Inflammation

Background and Purpose: Corneal injury can result in dysfunction of corneal nociceptive signaling and corneal sensitization. Activation of the endocannabinoid system has been reported to be analgesic and anti-inflammatory. The purpose of this research was to investigate the antinociceptive and anti-inflammatory effects of cannabinoids with reported actions at cannabinoid 1 (CB₁R) and cannabinoid 2 (CB₂R) receptors and/or noncannabinoid receptors in an experimental model of corneal hyperalgesia. Methods: Corneal hyperalgesia (increased pain response) was generated using chemical cauterization of the corneal epithelium in wild-type (WT) and CB₂R knockout (CB₂R^-/-) mice. Cauterized eyes were treated topically with the phytocannabinoids Δ⁸-tetrahydrocannabinol (Δ⁸THC) or cannabidiol (CBD), or the CBD derivative HU-308, in the presence or absence of the CB₁R antagonist AM251 (2.0 mg/kg i.p.), or the 5-HT_1A receptor antagonist WAY100635 (1 mg/kg i.p.). Behavioral pain responses to a topical capsaicin challenge at 6 h postinjury were quantified from video recordings. Mice were euthanized at 6 and 12 h postcorneal injury for immunohistochemical analysis to quantify corneal neutrophil infiltration. Results: Corneal cauterization resulted in hyperalgesia to capsaicin at 6 h postinjury compared to sham control eyes. Neutrophil infiltration, indicative of inflammation, was apparent at 6 and 12 h postinjury in WT mice. Application of Δ⁸THC, CBD, and HU-308 reduced the pain score and neutrophil infiltration in WT mice. The antinociceptive and anti-inflammatory actions of Δ⁸THC, but not CBD, were blocked by the CB₁R antagonist AM251, but were still apparent, for both cannabinoids, in CB₂R^-/- mice. However, the antinociceptive and anti-inflammatory actions of HU-308 were absent in the CB₂R^-/- mice. The antinociceptive and anti-inflammatory effects of CBD were blocked by the 5-HT_1A antagonist WAY100635. Conclusion: Topical cannabinoids reduce corneal hyperalgesia and inflammation. The antinociceptive and anti-inflammatory effects of Δ⁸THC are mediated primarily via CB₁R, whereas that of the cannabinoids CBD and HU-308, involve activation of 5-HT_1A receptors and CB₂Rs, respectively. Cannabinoids could be a novel clinical therapy for corneal pain and inflammation resulting from ocular surface injury.