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

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:


A recently deorphanized receptor, GPR18 showed to act with several endogenous cannaboinoid ligands. Among several potent functionalities the receptor activation also leads to the induction of anti‐infammatory and antinociceptive action. By using highly selective agonist of GPR18, PSB‐KK‐1415 we achieved an inflammation alleviation in two mouse models of colitis and a reduction in pain‐induced behaviors in mouse model of inflammatory pain.

Abstract

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‐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.

Key Results

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).

Conclusions & Inferences

We showed that GPR18 is worth considering as a potential treatment target in intestinal inflammation and inflammatory pain.

Key points

The aim of this study was to evaluate the role of GPR18 in intestinal inflammation and inflammatory pain. Selective agonist (PSB‐KK‐1415) and antagonist (PSB‐CB5) was utilized in the semi‐chronic and chronic mouse model of intestinal inflammation and mouse model of inflammatory pain.

PSB‐KK‐1415 presented the anti‐inflammatory activity in both models of intestinal inflammation. Moreover, GPR18 agonist presented pronounced anti‐nociceptive activity in animal model of inflammatory pain.

GPR18 appears as a promising target option in intestinal inflammation and inflammatory pain.