GR94839, A K-OPIOID AGONIST WITH LIMITED ACCESS TO THE CENTRAL-NERVOUS-SYSTEM, HAS ANTINOCICEPTIVE ACTIVITY

1 The pharmacological profile of GR94839, a kappa-opioid agonist with limited access to the central nervous system, has been investigated. Its antinociceptive activity has been compared with that of GR103545, a centrally-penetrating kappa-agonist and ICI204448, the previously described peripherally-selective kappa-agonist. 2 GR94839 was a potent agonist in the rabbit vas deferens in vitro assay for kappa-opioid receptors (IC50: 1.4 +/- 0.3 nM; n = 6), but had limited activity at mu- or delta-opioid receptors. 3 In the mouse abdominal constriction test, GR94839 was 238 fold more potent when given i.c.v. (ED50: 0.008 (0.004-0.029) mg kg-1; n = 18) than when s.c. (ED50: 1.9 (0.7-3.1) mg kg-1; n = 30). In comparison, GR103545 was equipotent when given i.c.v. or s.c. 4 After intravenous administration, the maximum plasma to brain concentration-ratio attained by GR94839 was 18 compared with 2 for GR85571, a structurally-related kappa-agonist that is centrally-penetrating. 5 GR94839 inhibited the 2nd phase of the rat formalin response at doses 7 fold lower than those required to inhibit the Ist phase (ED50 vs Ist phase: 10.2 (6.7-17.1) mg kg-1, s.c.; ED50 vs 2nd phase: 1.4 (1.0-1.8) mg kg-1, s.c.; n = 18). GR 103545 was equipotent against the two phases. 6 Intraplantar administration of the opioid antagonists, norbinaltorphimine (100-mu-g) or naltrexone (1-mu-g), reversed the antinociceptive effect of systemic GR94839 (3 mg kg-1, s.c.) against the 2nd phase of the formalin response and intraplantar injection of GR94839 (30-100-mu-g) selectively inhibited the 2nd phase. 7 GR94839 and ICI204448 reversed the hyperalgesia in the zymosan-inflamed rat paw at doses (ED50 GR94839: 2.0 (1.1-3.2) mg kg-1, s.c.; ED50 ICI204448: 1.2 (0.8-1.7) mg kg-1, s.c.), lower than those required to raise the noxious pressure threshold in the non-inflamed paw (ED50 GR94839: 16.4 (8.6-46.7) mg kg-1, s.c.; ED50 ICI204448: 68.0 (22.1-32000) mg kg-1, s.c.). GR103545 raised the noxious presure threshold in the inflamed and non-inflamed paws at the same doses. 8 GR94839 was sedative in the rat rotarod test (ED50: 35 (12-245) mg kg-1, s.c.) at doses higher than those required to inhibit the 2nd phase of the formalin response or reverse hyperalgesia in the zymosan-inflamed rat paw. The doses were comparable to those that inhibited the Ist phase of the formalin response and raised the noxious pressure threshold in the non-inflamed paw. 9 The results suggest that GR94839 is a selective kappa-agonist which has antinociceptive activity against inflammatory pain at doses that produce limited central effects. These antinociceptive effects are probably mediated at peripheral opioid receptors.