Nitric oxide mediates long-term hyperalgesic and antinociceptive effects of the N-terminus of substance P in the formalin assay in mice

Abstract

Conditions such as hyperalgesia can occur days or months after the noxious insult. Substance P (SP) is released in response to noxious stimuli. Given the long-term effects of the N-terminus of SP on putative nociceptive transmitters, we investigated changes in formalin-induced nociception following an accumulation of SP N-terminal metabolites in mice. Pre-treatment with the N-terminal metabolite of SP, SP(1–7), was without effect when injected intrahecally (i.t.) 5 or 30 min before formalin. 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, Nω-nitro- l-arginine methyl ester HCl ( l-NAME), blocked both hyperalgesic and antinociceptive effects when co-injected with SP(1–7). Consistent with 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) antagonist. Thus, SP(1–7) modulates nociception via two distinct NO-mediated pathways. When injected for 7 days, tolerance developed to the antinociceptive effect of SP(1–7) on Phase 2, but not to the hyperalgesic effect on Phase 1. Intraperitoneally injected SP(1–7) also produced hyperalgesia 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 within the spinal cord area, is sufficient for long-term modulation of multiple types of nociception with hyperalgesic responses being most persistent.