Elsevier

Peptides

Volume 11, Issue 4, July–August 1990, Pages 817-825
Peptides

Article
Correlation of substance P-induced desensitization with substance P amino terminal metabolites in the mouse spinal cord

https://doi.org/10.1016/0196-9781(90)90199-FGet rights and content

Abstract

Intrathecal injection of mice with substance P (SP) or its C-terminal fragments results in a behavioral syndrome characterized by reciprocal caudally directed biting and scratching. Repeated injection of SP, but not SP C-terminal fragments, results in a decrease in the intensity of, or desensitization to, these SP-induced behaviors. Peptidase inhibitors, phosphoramidon (PH), bacitracin (BAC), diprotin A (DPA) and angiotensin converting enzyme inhibitor (ACEI OR SQ20881), together with [3H]SP, were used to investigate the possible accumulation of tritiated N-terminal metabolites in the mouse spinal cord in vivo during the development of desensitization to SP. SP N-terminal metabolites in the spinal cord were quantified by reverse-phase HPLC. The magnitude of SP-induced desensitization correlated well (r=.95) with total SP N-terminal metabolites recovered from the spinal cords of the same mice studied in vivo. The magnitude of SP-induced desensitization was also found to be negatively correlated (r=.95) with total recovered intact [3H]SP. The rank order of potency of the peptidase inhibitors in decreasing the magnitude of SP-induced desensitization was BAC = PH >> ACEI > DPA. The order of potency for in vitro inhibition of SP metabolism using synaptic membrane-derived peptidases was BAC > PH >> ACEI. These results support the hypothesis that desensitization to SP-induced behaviors depends, at least in part, on the concentration of SP N-terminal metabolites in the spinal cord.

References (64)

  • B. Horsthemke et al.

    Degradation of substance P by neurones and glial cells

    Biochem. Biophys. Res. Commun.

    (1984)
  • J.L. Hylden et al.

    Intrathecal substance P elicits a caudally directed biting and scratching behavior in mice

    Brain Res.

    (1981)
  • O.J. Igwe et al.

    Optimization of HPLC-RIA protocols for the analyses of substance P and some of its metabolic fragments

    J. Chromatogr.

    (1988)
  • D.H. Jones et al.

    Isolation of synaptic plasma membrane from brain by combined flotation-sedimentation density gradient centrifugation

    Biochim. Biophys. Acta

    (1974)
  • S.A. Krumins et al.

    Modulation of [3H]-DAGO binding by substance P (SP) and SP fragments in the mouse brain and spinal cord via μt interactions

    Neuropeptides

    (1989)
  • A.A. Larson

    Desensitization to intrathecal substance P in mice; possible involvement of opioids

    Pain

    (1988)
  • J.R. Naranjo et al.

    Antinociceptive and Met-enkephalin releasing effects of tachykinins and substance P fragments

    Peptides

    (1986)
  • J.R. Naranjo et al.

    Analgesic activity of substance P in rats: Apparent mediation by met-enkaphalin release

    Life Sci.

    (1982)
  • J.R. Naranjo et al.

    Blockade by met-enkephalin antiserum of analgesia induced by substance P in mice

    Neuropharmacology

    (1982)
  • A. Oblin et al.

    Degradation of substance P by membrane peptidases in the rat substantia nigra: Effect of selective inhibitors

    Neurosci. Lett.

    (1988)
  • A. Oblin et al.

    Metalloendopeptidase (EC 3.4.24.11) but not angiotensin converting enzyme is involved in the inactivation of substance P by synaptic membranes of the rat substantia nigra

    Life Sci.

    (1989)
  • M.S. Orloff et al.

    Catabolism of substance P and neurotensin in the rat stomach wall is susceptible to inhibitors of angiotensin converting enzyme

    Regul. Pept.

    (1986)
  • M.F. Piercey et al.

    Use of substance P partial fragments to characterize substance P receptors of cat dorsal horn neurons

    Brain Res.

    (1980)
  • M. Randić et al.

    Effects of substance P in cat dorsal horn neurons activated by noxious stimuli

    Brain Res.

    (1977)
  • I. Rollandy et al.

    Importance of the presence of the N-terminal tripeptide of SP for the stimulation of phosphatidylinositol metabolism in rat parotid gland: A possible activation of phospholipases C and D

    Neuropeptides

    (1989)
  • T. Segawa et al.

    Further observation of the lack of active uptake system for substance P in the central nervous system

    Jpn. J. Pharmacol.

    (1977)
  • P.K. Smith et al.

    Measurement of protein using bicinchoninic acid

    Anal. Biochem.

    (1985)
  • J. Stewart et al.

    A fragment of substance P with specific central activity: SP(1–7)

    Peptides

    (1982)
  • E.A. Thiele et al.

    Substance K and substance P as possible endogenous substrates of angiotensin converting enzyme in the brain

    Biochem. Biophys. Res. Commun.

    (1985)
  • K. Yashpal et al.

    Substance P given intrathecally at the spinal T-9 level increases adrenal output of adrenaline and noradrenaline in the rat

    Neuroscience

    (1985)
  • A.J. Abbott et al.

    The collisional limit: An important consideration for membrane-associated enzymes and receptors

    FASEB J.

    (1988)
  • W.A. Banks et al.

    Peptides and the blood brain barrier: Lipophilicity as a predictor of permeability

    Brain Res. Bull.

    (1985)
  • Cited by (0)

    View full text