title: 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 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.
authors.affiliation: Department of Veterinary Pathobiology, University of Minnesota, St. Paul 55108, USA.
authors.forename: V M
authors.initials: VM
authors.lastname: Goettl
authors.forename: A A
authors.initials: AA
authors.lastname: Larson
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005557:Formaldehyde; D006930:Hyperalgesia / Q000139:chemically induced* / Q000503:physiopathology*; D007274:Injections, Intraperitoneal; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D010147:Pain Measurement; D010446:Peptide Fragments / Q000494:pharmacology*; D013237:Stereoisomerism; D013373:Substance P / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000700:Analgesics; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D005557:Formaldehyde; D009569:Nitric Oxide; D013373:Substance P; C036877:substance P (1-7); D001120:Arginine; D019331:NG-Nitroarginine Methyl Ester