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-HT1A 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-HT1A 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-HT1A receptors and CB2Rs, respectively.
Cannabinoids could be a novel clinical
therapy for corneal
pain and
inflammation resulting from ocular surface injury.