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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.
AuthorsV M Goettl, A A Larson
JournalPain (Pain) Vol. 67 Issue 2-3 Pg. 435-41 (Oct 1996) ISSN: 0304-3959 [Print] NETHERLANDS
PMID8951939 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Analgesics
  • Enzyme Inhibitors
  • Peptide Fragments
  • Formaldehyde
  • Nitric Oxide
  • Substance P
  • substance P (1-7)
  • Arginine
  • NG-Nitroarginine Methyl Ester
Topics
  • Analgesics (pharmacology)
  • Animals
  • Arginine (pharmacology)
  • Enzyme Inhibitors (pharmacology)
  • Formaldehyde
  • Hyperalgesia (chemically induced, physiopathology)
  • Injections, Intraperitoneal
  • Injections, Spinal
  • Male
  • Mice
  • Mice, Inbred Strains
  • NG-Nitroarginine Methyl Ester (pharmacology)
  • Nitric Oxide (physiology)
  • Pain Measurement
  • Peptide Fragments (pharmacology)
  • Stereoisomerism
  • Substance P (pharmacology)
  • Time Factors

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