Abstract
Cannabinoid receptor 1 (CB1) activation has been reported to reduce transient receptor potential cation channel subfamily V member 1 (TRPV1)-induced inflammatory responses and is anti-nociceptive and anti-inflammatory in corneal injury. We examined whether allosteric ligands, can modulate CB1 signaling to reduce pain and inflammation in corneal hyperalgesia. Corneal hyperalgesia was generated by chemical cauterization of cornea in wildtype and CB2 knockout (CB2−/−) mice. The novel racemic CB1 allosteric ligand GAT211 and its enantiomers GAT228 and GAT229 were examined alone or in combination with the orthosteric CB1 agonist Δ8-tetrahydrocannabinol (Δ8-THC). Pain responses were assessed following capsaicin (1 µM) stimulation of injured corneas at 6 h post-cauterization. Corneal neutrophil infiltration was also analyzed. GAT228, but not GAT229 or GAT211, reduced pain scores in response to capsaicin stimulation. Combination treatments of 0.5% GAT229 or 1% GAT211 with subthreshold Δ8-THC (0.4%) significantly reduced pain scores following capsaicin stimulation. The anti-nociceptive effects of both GAT229 and GAT228 were blocked with CB1 antagonist AM251, but remained unaffected in CB2−/− mice. Two percent GAT228, or the combination of 0.2% Δ8-THC with 0.5% GAT229 also significantly reduced corneal inflammation. CB1 allosteric ligands could offer a novel approach for treating corneal pain and inflammation.
Highlights
The cornea has one of the densest concentrations of unmyelinated sensory nerve endings in the body [1,2], which are highly sensitive to mechanical stimulation, temperature, and various chemicals mediators, through receptors such as the transient receptor potential family [3]
Stimulation of corneal nerves following damage can result in ocular pain, either to normally non-noxious stimuli and/or as a heightened pain response to noxious stimuli [9,11,12,13], which can result in sensitization and neuropathic pain over time [14]
This paper explored the potential for Cannabinoid receptor 1 (CB1) modulation by the CB1 allosteric ligands GAT211, GAT228 or GAT229, alone or in combination with the CB1 orthosteric agonist ∆8 -tetrahydrocannabinol
Summary
The cornea has one of the densest concentrations of unmyelinated sensory nerve endings in the body [1,2], which are highly sensitive to mechanical stimulation, temperature, and various chemicals mediators, through receptors such as the transient receptor potential family [3]. TRPV1-mediated corneal pain, was provided (THC), are able to reduce corneal hyperalgesia to a capsaicin challenge and, produce by a recent paper demonstrating that cannabinoids that act at CB1, such as tetrahydrocannabinol a reduction in corneal injury-induced inflammation [28]. In neuropathic and allosteric agonist activity, while the S-(−)-enantiomer GAT229 was shown to behave as a clean PAM inflammatory models of pain, GAT211 when delivered alone reduced allodynia without producing [34]. This paper explored the potential for CB1 modulation by the CB1 allosteric ligands GAT211, GAT228 or GAT229, alone or in combination with the CB1 orthosteric agonist ∆8 -tetrahydrocannabinol (∆8 -THC), in a mouse model of chemical injury-induced corneal hyperalgesia
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