Antinociceptive activity of the tachykinin NK1 receptor antagonist, CP-99,994, in conscious gerbils.

1. The ability of CP-99,994, and its less active enantiomer, CP-100,263, to inhibit spontaneous behaviours and hyperalgesia induced by central infusion of the NK1 receptor agonist, GR73632 or intraplantar injection of formalin was investigated in rats and gerbils. 2. GR73632 (3 pmol, i.c.v.)-induced foot tapping in gerbils was dose-dependently inhibited by CP-99,994 (0.1-1 mg kg-1, s.c.), but not by CP-100,263 (10 mg kg-1, s.c.) using pretreatment times up to 60 min. The centrally active dose-range for CP-99,994 was increased to 1-10 mg kg-1 s.c. with a higher challenge dose of GR73632 (30 pmol, i.c.v.). 3. In gerbils, intrathecal (i.t.) injection of GR73632 (30 pmol) elicited behaviours (licking, foot tapping or flinching and face washing) which closely resembled, but which was less specifically localized than, behaviours seen in animals injected with formalin (0.1-5%) into one hindpaw. 4. In rats, CP-100,263, but not CP-99,994 (up to 30 mg kg-1), inhibited the early phase response to intraplantar injection of 5% formalin (ID50 = 13.9 mg kg-1). The late phase was inhibited by both compounds (ID50 values 36.3 and 20.9 mg kg-1, respectively). In gerbils, there was marginal evidence for enantioselective inhibition of the early phase induced by formalin (2%). The ID50 values were 6.2 mg kg-1 for CP-99,994 and 13.4 mg kg-1 for CP-100,263. 5. Intrathecal injection of GR73632 (30 pmol) caused thermal hyperalgesia in igerbils which was inhibited enantioselectively by s.c. administration of CP-99,994 (ID50= 2.46 mg kg-1), but not by CP-100,263 (30 mg kg-1).6. In gerbils, intraplantar injection of formalin (0.1%) caused thermal hyperalgesia which was inhibited by CP-99,994 (ID50= 1.1 mg kg-1, s.c.). There was a nonsignificant trend for an anti-algesic effect of CP-100,236 (estimated ID50 = 8.2 mg kg-1, s.c.).7 These findings support the proposal that NK1 receptor antagonists may be useful in the clinical management of pain and reinforce the need to dissociate specific and nonspecific antinociceptive effects of available compounds.