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 intrathecally (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,
N omega-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.