title: Stereospecific effects of a nonpeptidic NK1 selective antagonist, CP-96,345: antinociception in the absence of motor dysfunction.
abstract: CP-96,345 has been identified as being a highly selective, nonpeptidic agent with subnanomolar affinity for the NK1 receptor. In the present study, we observed that pre but not posttreatment with this agent will produce depression in the second, but not the first phase of the agitation behavior induced by the injection of formalin into a rat's hindpaw. This effect is monotonically dose dependent after intrathecal (10-200 micrograms/10 microliters) or systemic (1-15 mg/kg, ip) administration. Even at the highest dose examined (400 micrograms/10 microliters), there was only a transient motor weakness of the hindpaw. The stereoisomer CP-96,344 has no binding affinity, and has no effect on the formalin response, but shows the same dose profile for motor dysfunction at the highest dose. In contrast, Spantide, a peptidic sP ligand, had only a modest effect upon the formalin response at 1 microgram/10 microliters and produced a prominent, long-lasting motor dysfunction at 4 micrograms/10 microliters. These results provide the first suggestion of sP antagonists having prominent analgesic activity with a significant therapeutic index (analgesic to motor), and emphasizes the probable role of the NK1 class of receptors in the spinal cord in mediating at least one class of nociceptive afferent input.
authors.affiliation: Department of Anesthesiology, University of California, San Diego, La Jolla 92093.
authors.forename: T
authors.initials: T
authors.lastname: Yamamoto
authors.forename: T L
authors.initials: TL
authors.lastname: Yaksh
mesh_terms: D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007274:Injections, Intraperitoneal; D007278:Injections, Spinal; D007700:Kinetics; D009043:Motor Activity / Q000187:drug effects*; D010147:Pain Measurement; D051381:Rats; D011919:Rats, Inbred Strains; D018040:Receptors, Neurokinin-1; D017981:Receptors, Neurotransmitter / Q000187:drug effects*; D013116:Spinal Cord; D013237:Stereoisomerism; D013373:Substance P / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000494:pharmacology
chemical_list: D000700:Analgesics; D001713:Biphenyl Compounds; D018040:Receptors, Neurokinin-1; D017981:Receptors, Neurotransmitter; D013373:Substance P; C042867:spantide; C066892:CP 96345