The CannabinoidsΔTHC, CBD, and HU-308 Act via Distinct Receptors to Reduce Corneal Pain and Inflammation.
Cannabis Cannabinoid Res. 2018 ;3(1):11-20. Epub 2018 Feb 1. PMID: 29450258
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 (CBR) and cannabinoid 2 (CBR) receptors and/or noncannabinoid receptors in an experimental model of corneal hyperalgesia.Corneal hyperalgesia (increased pain response) was generated using chemical cauterization of the corneal epithelium in wild-type (WT) and CBR knockout (CBR) mice. Cauterized eyes were treated topically with the phytocannabinoidsΔ-tetrahydrocannabinol (ΔTHC) or cannabidiol (CBD), or the CBD derivative HU-308, in the presence or absence of the CBR antagonist AM251 (2.0 mg/kg i.p.), or the 5-HTreceptor 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.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 ΔTHC, CBD, and HU-308 reduced the pain score and neutrophil infiltration in WT mice. The antinociceptive and anti-inflammatory actions ofΔTHC, but not CBD, were blocked by the CBR antagonist AM251, but were still apparent, for both cannabinoids, in CBRmice. However, the antinociceptive and anti-inflammatory actions of HU-308 were absent in the CBRmice. The antinociceptive and anti-inflammatory effects of CBD were blocked by the 5-HTantagonist WAY100635.Topical cannabinoids reduce corneal hyperalgesia and inflammation. The antinociceptive and anti-inflammatory effects ofΔTHC are mediated primarily via CBR, whereas that of the cannabinoids CBD and HU-308, involve activation of 5-HTreceptors and CBRs, respectively. Cannabinoids could be a novel clinical therapy for corneal pain and inflammation resulting from ocular surface injury.