In vivo signal transduction of nociceptive response by kyotorphin (tyrosine-arginine) through G(αi)- and inositol trisphosphate-mediated Ca2+ influx

Hiroshi Ueda, Makoto Inoue

Research output: Contribution to journalArticlepeer-review

Abstract

Kyotorphin is a dipeptidic neuropeptide (tyrosine-arginine) that has specific receptor coupled to G(i) and phospholipase C and elicits Met- enkephalin release. Here, we attempted to demonstrate the in vivo evidence for the presynaptic mechanism by analyzing its nociceptive responses after peripheral application. Kyotorphin elicited potent nociceptive flexor responses at extremely low doses between 0.1 and 100 fmol after the intraplantar injection into the hind-limb of mice. The site of action of kyotorphin-induced responses was identified to be on nociceptor endings, because the responses were markedly attenuated by intrathecal pretreatments with Gα(i1) or Gα(12) antisense-oligodeoxynucleotides. Similar mechanisms were observed with histamine-induced nociceptive responses, except for the use of different antagonist and Gα(q/11) antisense-oligodeoxynucleotide. Both responses were characterized to be mediated through inositol trisphosphate receptor-gated Ca2+ influx, because they were blocked by xestospongin C, an allosteric antagonist for inositol trisphosphate receptor and EGTA, but not thapsigargin. Because the nociceptive responses by compound 48/80 through histamine-release from mast cells were completely abolished by thapsigargin, it is unlikely that the dose of thapsigargin is not sufficient to block both responses. All of these in vivo findings strongly support our previous view that kyotorphin elicits Ca2+ influx through inositol trisphosphate receptor located at presynaptic plasma membranes.

Original languageEnglish (US)
Pages (from-to)108-115
Number of pages8
JournalMolecular Pharmacology
Volume57
Issue number1
StatePublished - Jan 18 2000
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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