Use of non-peptide tachykinin receptor antagonists to substantiate the involvement of NK 1 and NK 2 receptors in a spinal nociceptive reflex in the rat

Abstract

Non-peptide antagonists of the NK 1 and NK 2 receptors were tested as inhibitors of the reaction time in the rat tail-flick and on the decrease of reaction time induced by the intrathecal injection of the NK 1 receptor selective agonist [Sar 9,Met(O 2) 11]SP or of the NK 2 selective agonist NKA-(4–10). The decrease in reaction time produced by the NK 1 agonist lasted less than 11 min while that evoked by the NK 2 agonist persisted 26 min after injection. When given intrathecally, CP-96,345 and its chloro analog, Cl-CP, blocked dose-dependently both the behavioral responses and the decrease of reaction time induced by 6.5 nmol of [Sar 9,Met(O 2) 11]SP while they failed to modify the hyperalgesic response to 6.5 nmol NKA-(4–10); CP-96,345 was found more potent than Cl-CP and was also active as an antagonist when given intravenously. In contrast, SR 48968 (6.5 and 65 nmol) blocked the NKA-(4–10)-induced decreases in reaction time and was inactive against the hyperalgesic effect of [Sar 9,Met(O 2) 11]SP. The three antagonists blocked in a reversible manner, were inactive on their own on reaction time and non-toxic. The results indicate that the non-peptide CP-96,345 readily crosses the blood brain barrier and acts as a selective antagonist on spinal NK 1 receptors, while SR 48968 is selective on NK 2 receptors in the rat spinal cord. Hence, CP-96,345 and SR 48968 highlight a functional role for NK 1 and NK 2 receptors in spinal sensory neurotransmission.