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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
Author(s) -
Fabisiak Adam,
Fabisiak Natalia,
Mokrowiecka Anna,
MaleckaPanas Ewa,
Jacenik Damian,
Kordek Radzislaw,
Zielińska Marta,
KiećKoowicz Katarzyna,
Fichna Jakub
Publication year - 2021
Publication title -
neurogastroenterology and motility
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.489
H-Index - 105
eISSN - 1365-2982
pISSN - 1350-1925
DOI - 10.1111/nmo.14003
Subject(s) - colitis , inflammation , agonist , myeloperoxidase , inflammatory bowel disease , pharmacology , tumor necrosis factor alpha , medicine , proinflammatory cytokine , nociception , receptor , immunology , disease
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.