Novel selective agonist of GPR18, PSB-KK-1415 exerts potent anti-inflammatory and anti-nociceptive activities in animal models of intestinal inflammation and inflammatory pain.

Abstract

GPR18 is a recently deorphanized receptor which was reported to act with several endogenous cannabinoid ligands. Here, we aimed to describe the role of GPR18 in intestinal inflammation and inflammatory pain. The anti-inflammatory activity of selective GPR18 agonist, PSB-KK-1415, and antagonist, PSB-CB5, was characterized in semi-chronic and chronic mouse models of colitis induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS). The extent of inflammation was evaluated based on the macroscopic and microscopic scores, quantification of myeloperoxidase (MPO) activity, and Western blot analyses of tumor necrosis factor-α (TNF-α) and interleukin-6 in colonic tissue. The expression of GPR18 in colonic samples from patients with Crohn's disease (CD) was quantified using real-time PCR. The anti-nociceptive potential of the agonist in intestinal inflammation was evaluated in the mouse model of inflammatory pain. In semi-chronic colitis, PSB-KK-1415 reduced macroscopic score (1.79±0.22 vs. 2.61±0.48), expression of TNF-α (1.89±0.36 vs. 2.83±0.64), and microscopic score (5.00±0.33 vs. 6.45±0.40), all compared to mice with colitis. In chronic colitis, PSB-KK-1415 decreased macroscopic score (3.33±1.26 vs. 4.00±1.32) and MPO activity (32.23±8.51 vs. 41.33±11.64) compared to inflamed mice. In the mouse model of inflammatory pain, PSB-KK-1415 decreased the number of pain-induced behaviors in both, controls (32.60±2.54 vs. 58.00±6.24) and inflamed mice (60.83±2.85 vs. 85.00±5.77) compared to animals without treatment with PSB-KK-1415 (P<0.005 for both). Lastly, we showed an increased expression of GPR18 in CD patients compared to healthy controls (3.77±1.46 vs. 2.38±0.66, p=0.87). We showed that GPR18 is worth considering as a potential treatment target in intestinal inflammation and inflammatory pain.