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Allosteric Cannabinoid Receptor 1 (CB1) Ligands Reduce Ocular Pain and Inflammation

Department of Pharmacology, Dalhousie University, Halifax, NS B3H 4R2, Canada
Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA
Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN 47405, USA
Department of Anesthesia, Pain Management & Perioperative Medicine, Dalhousie University, Halifax, NS B3H 4R2, Canada
Author to whom correspondence should be addressed.
Academic Editor: Spyros P. Nikas
Molecules 2020, 25(2), 417;
Received: 18 November 2019 / Accepted: 16 January 2020 / Published: 20 January 2020
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. View Full-Text
Keywords: cannabinoids; allosteric ligands; cornea; pain; inflammation cannabinoids; allosteric ligands; cornea; pain; inflammation
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MDPI and ACS Style

Thapa, D.; Cairns, E.A.; Szczesniak, A.-M.; Kulkarni, P.M.; Straiker, A.J.; Thakur, G.A.; Kelly, M.E.M. Allosteric Cannabinoid Receptor 1 (CB1) Ligands Reduce Ocular Pain and Inflammation. Molecules 2020, 25, 417.

AMA Style

Thapa D, Cairns EA, Szczesniak A-M, Kulkarni PM, Straiker AJ, Thakur GA, Kelly MEM. Allosteric Cannabinoid Receptor 1 (CB1) Ligands Reduce Ocular Pain and Inflammation. Molecules. 2020; 25(2):417.

Chicago/Turabian Style

Thapa, Dinesh, Elizabeth A. Cairns, Anna-Maria Szczesniak, Pushkar M. Kulkarni, Alex J. Straiker, Ganesh A. Thakur, and Melanie E.M. Kelly 2020. "Allosteric Cannabinoid Receptor 1 (CB1) Ligands Reduce Ocular Pain and Inflammation" Molecules 25, no. 2: 417.

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