BACKGROUND: 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. METHODS: 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-alpha (TNF-alpha) 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. KEY RESULTS: In semi-chronic colitis, PSB-KK-1415 reduced macroscopic score (1.79 +/- 0.22 vs. 2.61 +/- 0.48), expression of TNF-alpha (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). CONCLUSIONS & INFERENCES: We showed that GPR18 is worth considering as a potential treatment target in intestinal inflammation and inflammatory pain.