G-protein coupled receptor 35 (GPR35) activation and inflammatory pain: Studies on the antinociceptive effects of kynurenic acid and zaprinast.

G-protein coupled receptor 35 (GPR35) is a former "orphan receptor" expressed in brain and activated by either kynurenic acid or zaprinast. While zaprinast has been studied as a phosphodiesterase inhibitor, kynurenic acid (KYNA) is a tryptophan metabolite and has been proposed as the endogenous ligand for this receptor. In the present work, we showed that GPR35 is present in the dorsal root ganglia and in the spinal cord and in order to test the hypothesis that GPR35 activation could cause analgesia, we administered suitable doses of zaprinast or we increased the local concentration of KYNA by administering a precursor (kynurenine) or by inhibiting its disposal from the CNS (with probenecid). We used the "writhing test" induced by acetic acid i.p. injection in mice. KYNA and kynurenine plasma and spinal cord levels were measured with HPLC techniques. Kynurenine (30, 100, 300 mg/kg s.c.) increased plasma and spinal cord levels of KYNA and decreased the number of writhes in a dose dependent manner. Similarly, probenecid was able to increase KYNA levels in plasma and spinal cord, to reduce the number of writes and to amplify kynurenine effects. Furthermore, zaprinast had antinociceptive effects in the writhing test without affecting KYNA levels. In agreement with its affinity for GPR35 receptor (approximately 10 times higher than that of KYNA), zaprinast action occurred at relatively low doses. No additive actions were obtained when kynurenine and zaprinast were administered at maximally active doses. Our results suggest that GPR35 could be an interesting target for innovative pharmacological agents designed to reduce inflammatory pain. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.