SR-48968 SPECIFICALLY DEPRESSES NEUROKININ-A-INDUCED VS SUBSTANCE-P-INDUCED HYPERALGESIA IN A NOCICEPTIVE WITHDRAWAL REFLEX

To determine the role of neurokinin A and tachykinin NK2 receptors in processing of nociceptive information at the spinal level, the selecti ve NK2 receptor antagonist, SR 48968 (S)-N-methyl-N[4-(4-acetylamino-4 -[phenyl piperidino)-2-(3,4-dichlorophenyl)butyl]benzamide, was tested for its effects on the hyperalgesia produced in the tail flick reflex by intrathecal administration of neurokinin A and of substance P. SR 48968 was also tested in a model in which noxious peripheral stimulati on has been shown to produce hyperalgesia via a substance P mechanism. SR 48968 given intrathecally had a dose-dependent inhibitory effect o n both the behaviour and the hyperalgesia induced by neurokinin A but not on either of these effects produced by substance P. In addition, s ystemic administration of SR 48968 depressed the hyperalgesic effect o f intrathecal administration of neurokinin A. First, this evidence ind icates a unique role for neurokinin A in the spinal cord as distinct f rom that of its homologue, substance P, and confirms that neurokinin A acts via the tachykinin NK2 receptor, rather than non-specifically vi a the NK1 receptor. Second, the data indicate that in this model subst ance P does not express any of its effects non-selectively via activat ion of NK2 receptors. Third, SR 48968 appears to have access to the sp inal cord upon systemic administration. Fourth, intrathecal administra tion of the NK1 receptor antagonist, CP-96,345 henyl)-methyl]-1-azabic yclo[2.2.2]-octan-3-amine], had no effect on the responses to intrathe cal administration of neurokinin A. Finally, the hyperalgesia produced by sustained noxious thermal stimulation of the tip of the tail was u naffected by intrathecal administration of SR 48968; thus, it remains to find a physiological response in which endogenous neurokinin A and NK2 receptors at the spinal level are involved in the rat in vivo.