SR 48968 specifically depresses neurokinin A- 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 selective 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 stimulation has been shown to produce hyperalgesia via a substance P mechanism. SR 48968 given intrathecally had a dose-dependent inhibitory effect on both the behaviour and the hyperalgesia induced by neurokinin A but not on either of these effects produced by substance P. In addition, systemic administration of SR 48968 depressed the hyperalgesic effect of intrathecal administration of neurokinin A. First, this evidence indicates a unique role for neurokinin A in the spinal cord as distinct from that of its homologue, substance P. and confirms that neurokinin A acts via the tachykinin NK2 receptor, rather than non-specifically via the NK1 receptor. Second, the data indicate that in this model substance P does not express any of its effects non-selectively via activation of NK2 receptors. Third, SR 48968 appears to have access to the spinal cord upon systemic administration. Fourth, intrathecal administration of the NK1 receptor antagonist, CP-96,345 [(2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxy-phenyl)-methyl]-1- azabicyclo [2.2.2]-octan-3-amine], had no effect on the responses to intrathecal administration of neurokinin A. Finally, the hyperalgesia produced by sustained noxious thermal stimulation of the tip of the tail was unaffected 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.
Yashpal
K
K
Department of Psychiatry, McGill University, Montreal, Quebec, Canada.
Hui-Chan
C W
CW
Henry
J L
JL
D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006930:Hyperalgesia / Q000503:physiopathology*; D007278:Injections, Spinal; D008297:Male; D015288:Neurokinin A / Q000037:antagonists & inhibitors / Q000502:physiology*; D064729:Neurokinin-1 Receptor Antagonists; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000502:physiology; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors* / Q000502:physiology; D013373:Substance P / Q000037:antagonists & inhibitors / Q000502:physiology*
D001549:Benzamides; D001713:Biphenyl Compounds; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D013373:Substance P; C073839:SR 48968; D015288:Neurokinin A; C066892:CP 96345