Interaction between nitric oxide and substance P on heat-induced inflammation in rat paw

To elucidate the interaction between nitric oxide (NO) and substance P (SP) in neurogenic inflammatory responses, we measured the change in the degree of Evans blue leakage and NO levels in perfusate from the subcutaneous space in the rat instep following noxious heat stimulation (47 degrees C for 30 min). Furthermore, the effects of drugs affecting nitric oxide synthase were examined. Noxious heat stimulation caused on an increase in NOx, or NO2- and NO3- into the perfusate in parallel with plasma extravasation. Nw-nitro-L-arginine methylester (L-NAME: 100 mg/kg once daily.) intraperitoneally (i.p.) given five times (chronic treatment) significantly suppressed the increase in Evans blue extravasation induced by heat stimulation, whereas acute treatments with L- and D-NAME (100 mg/kg once, i.p.) did not show any significant effect. NO release induced by heating also was significantly suppressed by chronic pretreatment with L-NAME, but not by acute treatment. SP (10(-5) M) applied into the perfusate caused a remarkable increase in the NOx release into the perfusate. Intra-arterial injection of RP67580 (1 mg/kg) on the perfused side, but not SR48968 (1 mg/kg), significantly attenuated the increases in Evans blue leakage and NOx release during heat stimulation. These results suggest that heat-induced SP release from the peripheral endings of small-diameter afferent fibers causes NO generation through NK-1R, and that this gas act to elicit or enhance inflammatory responses.