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 inhibi tor 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 f irst paradigm, rats were lightly anaesthetized with a mixture of chlor al hydrate (120 mg/kg, i.p.) and sodium pentobarbital (20 mg/ kg, i.p. ). Tail flick reaction times were monitored and thermal hyperalgesia w as 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/k g 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 w ith 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 v alues respectively, indicating a block of the hyperalgesic responses s een 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 t o the action of endogenous substance P. In the second paradigm, tail f lick responses were monitored in the awake rat and thermal hyperalgesi a 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 va lue 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 indic ate that thermal hyperalgesia induced by endogenously released or exog enously administered substance P, are blocked by L-NAME but not by its enantiomer, D-NAME. Therefore an involvement of a nitric oxide syntha se mechanism in the hyperalgesic responses to substance P is suggested .