NITRIC-OXIDE MEDIATES LONG-TERM HYPERALGESIC AND ANTINOCICEPTIVE EFFECTS OF THE N-TERMINUS OF SUBSTANCE-P IN THE FORMALIN ASSAY IN MICE

Conditions such as hyperalgesia can occur days or months after the nox ious insult. Substance P (SP) is released in response to noxious stimu li. Given the long-term effects of the N-terminus of SP on putative no ciceptive transmitters, we investigated changes in formalin-induced no ciception following an accumulation of SP N-terminal metabolites in mi ce. Pre-treatment with the N-terminal metabolite of SP, SP(1-7), was w ithout effect when injected intrathecally (i.t.) 5 or 30 min before fo rmalin. However, at 24 h, SP(1-7) increased behaviors during Phase 1, indicating hyperalgesia, and attenuated Phase 2 responses, consistent with antinociception. The nitric oxide (NO) synthase inhibitor, Nw-nit ro-L-arginine methyl ester HCl (L-NAME), blocked both hyperalgesic and antinociceptive effects when co-injected with SP(1-7). Consistent wit h a NO-mediated pathway, L-arginine (L-arg), the N-terminal amino acid of SP and precursor to NO, mimicked the antinociceptive effect of SP( 1-7) on Phase 2. The hyperalgesic effect of SP(1-7) in Phase 1, which was not mimicked by L-arg, was prevented by D-SP(1-7), a SP(1-7) antag onist. Thus, SP(1-7) modulates nociception via two distinct NO-mediate d pathways. When injected for 7 days, tolerance developed to the antin ociceptive effect of SP(1-7) on Phase 2, but not to the hyperalgesic e ffect on Phase 1. Intraperitoneally injected SP(1-7) also produced hyp eralgesia during Phase 1, to which tolerance developed following seven daily injections. Together, these data support the hypothesis that an accumulation of SP N-terminal metabolites, either peripherally or wit hin the spinal cord area, is sufficient for long-term modulation of mu ltiple types of nociception with hyperalgesic responses being most per sistent.