IMPLICATION OF A NITRIC-OXIDE SYNTHASE MECHANISM IN THE ACTION OF SUBSTANCE-P - L-NAME BLOCKS THERMAL HYPERALGESIA INDUCED BY ENDOGENOUS AND EXOGENOUS SUBSTANCE-P IN THE RAT

The effects of i.p. administration of the nitric oxide synthase inhibitor N-G-nitro-L-arginine methylester (L-NAME) and its inactive isomer, D-NAME, were tested in two nociceptive paradigms in the rat. In the first paradigm, rats were lightly anaesthetized with a mixture of chloral hydrate (120 mg/kg, i.p.) and sodium pentobarbital (20 mg/ kg, i.p.). Tail flick reaction times were monitored and thermal hyperalgesia was induced by immersion of the tail in hot water at 55 degrees C for 1.5 min. In the groups of rats pretreated with saline (n = 5), 100 mg/kg D-NAME (n = 6), 10 (n = 5) or 25 (n = 6) mg/kg L-NAME, this thermal injury induced a transient reduction in the reaction time that was 54-59% of the baseline value. However, in the groups of rats pretreated with 50 (n = 6) or 100 (n = 7) mg/kg L-NAME the reaction times were 73.9 +/- 2.7% (P < 0.05) and 102.3 +/- 0.9% (P < 0.001) of the baseline values respectively, indicating a block of the hyperalgesic responses seen in the other groups. As this hyperalgesia has been reported to be blocked by NK-1 receptor antagonists, it is suggested that it is due to the action of endogenous substance P. In the second paradigm, tail flick responses were monitored in the awake rat and thermal hyperalgesia was induced by intrathecal administration of substance P (6.5 nmol) via a chronically implanted catheter. In the group of rats pretreated with saline (n = 5) or D-NAME (n = 5; 100 mg/kg), substance P reduced the reaction time to 39.1 +/- 9.9 and 45.5 +/- 2.1% of the baseline value respectively. However, in the rats pretreated with L-NAME (n = 6; 100 mg/kg), the reaction time following substance P administration was 108.8 +/-: 8.8% of the baseline value (P < 0.001), indicating a block of the hyperalgesic response induced by substance P. These data indicate that thermal hyperalgesia induced by endogenously released or exogenously administered substance P, are blocked by L-NAME but not by its enantiomer, D-NAME. Therefore an involvement of a nitric oxide synthase mechanism in the hyperalgesic responses to substance P is suggested.