Spinal nitric oxide synthesis inhibition blocks NMDA-induced thermal hyperalgesia and produces antinociception in the formalin test in rats

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Abstract
To assess the possible role of spinal nitric oxide (NO) synthesis in nociceptive processing, we examined the effect of intrathecal (i.t.) injection of arginine analogs that act as alternate substrates for NO synthase and thus inhibit NO production. NG-nitro-L-arginine ester (r-NAME) and NG-monomethyl-L-arginine (L-NMMA) produced a dose-dependent, stereospecific inhibition of the second phase (10-60 min; ED50, 135 and 246 nmol) of the formalin test with minimal effect on the first phase (0-9 min; ED50 > 1.1 mumol). The inhibitory action of L-NAME was dose-dependently reversed by i.t. L-arginine (ID50, 4.9 mumol) but not by D-arginine (ID50 > 14 mumol). The suppression of the second-phase formalin response by L-NAME was similar whether administered before or after formalin injection into the rat paw. Spinal administration of L-NAME (370 nmol), but not D-NAME (3.7 mumol), also blocked thermal hyperalgesia induced by i.t. injection of N-methyl-D-aspartate (NMDA; 6.8 nmol). The effect of L-NAME was reversed by L-arginine (4.7 mumol) but not with D-arginine (14 mumol). None of the compounds, L-NAME, D-NAME or L-arginine, when injected alone, had any effect on normal thermal response latencies or on the 52.5 degrees C hot plate. These studies indicate that modulation of spinal NO synthesis can diminish the facilitated processing of afferent activity which is induced by a continued afferent barrage (second phase of the formalin test). This hyperalgesic component appears initiated by the activation of a spinal NMDA receptor that, through the generation of NO, leads to the observed augmented processing of afferent input and the associated hyperalgesic component of the subsequent pain behavior.