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. However, in the group given CP-96,345 (n = 6), the reaction time was 97.4 +/- 13.7% of the baseline reaction time, again indicating a block of the transient response and the involvement of NK-1 receptors. In the third paradigm, nociceptive scores were determined after subcutaneous injection of 50 mul of 2.5% formalin into one hind paw. The first phase of the response to this noxious chemical stimulus was similar in rats pretreated with saline, with CP-96,344 and with CP-96,345. The second phase was also unaffected in rats pretreated with saline (n = 10), with 20 mg/kg of CP-96,344 (n = 8) or with 5 mg/kg of CP-96,345 (n = 9). However, in the groups given 10 (n = 8) or 20 (n = 6) mg/kg of CP-96,345, there was a significant reduction in this second phase (P < 0.05-0.0 1), indicating an involvement of NK-1 receptors in evoking this second phase. The results indicate the efficacy of a systemically administered NK-1 receptor antagonist in blocking substance P-induced facilitation of a spinal nociceptive reflex and the stereospecificity of the actions of CP-96,345 in nociceptive tests. The data support the involvement of substance P or a related agent, acting via NK-1 receptors, in nociceptive responses to sustained noxious thermal and noxious chemical stimuli. NK-1 receptor antagonists may, therefore, be useful in the clinical treatment of pain originating from bums or lacerations of the skin or from inflamed tissue.