CP-96,345, but not its stereoisomer, CP-96,344, blocks the nociceptive responses to intrathecally administered substance P and to noxious thermal and chemical stimuli in the rat.
The effects of subcutaneous administration of the non-peptide NK-1 (substance P) receptor antagonist, CP-96,345, and its stereoisomer, CP-96,344, were tested in three nociceptive paradigms in the rat. In the first paradigm, tail flick responses were monitored before and after intrathecal administration of substance P (6.5 nmol) in rats pretreated subcutaneously with saline, CP-96,344 (5 mg/kg) or CP-96,345 (5 mg/kg). In the control groups, pretreated with saline (n = 6) or with CP-96,344 (n = 5), substance P reduced the tail flick reaction time at 1 min after administration to 38.3 +/- 5.1 (mean +/- S.E.M.) and 32.1 +/- 7.7% of the mean baseline value, respectively. In contrast, in the group pretreated with CP-96,345 (n = 6) the reaction time following administration of substance P was 98.8 +/- 3.3% of the baseline reaction time; this value was not significantly different from the baseline value of this group, indicating a block (P < 0.01) of the substance P-induced facilitation of the tail flick response. In the second paradigm, rats were anesthetized with a mixture of chloral hydrate (120 mg/kg, i.p.) and sodium pentobarbital (20 mg/kg, i.p.), and the effects were determined on tail flick reaction time of a sustained noxious cutaneous stimulation, immersing the tip of the tail in hot water at 55 degrees C. In the groups of rats pretreated with saline (n = 4) or with CP-96,344 (n = 7), this noxious stimulus produced a transient decrease in reaction time to 62-74% of the baseline value.(ABSTRACT TRUNCATED AT 250 WORDS)
Yashpal
K
K
Department of Psychiatry, McGill University, Montreal, Quebec, Canada.
Radhakrishnan
V
V
Coderre
T J
TJ
Henry
J L
JL
D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D005557:Formaldehyde; D006339:Heart Rate / Q000187:drug effects; D006358:Hot Temperature; D007278:Injections, Spinal; D008297:Male; D010146:Pain / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time; D018040:Receptors, Neurokinin-1; D017981:Receptors, Neurotransmitter / Q000037:antagonists & inhibitors*; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology*; D013237:Stereoisomerism; D013373:Substance P / Q000008:administration & dosage / Q000494:pharmacology*
D001713:Biphenyl Compounds; D018040:Receptors, Neurokinin-1; D017981:Receptors, Neurotransmitter; D005557:Formaldehyde; D013373:Substance P; C066892:CP 96345