Nocistatin and prepro-nociceptin/orphanin FQ 160-187 cause nociception through activation of Gi/o in capsaicin-sensitive and of Gs in capsaicin-insensitive nociceptors, respectively

Makoto Inoue, Toshiko Kawashima, Richard G. Allen, Hiroshi Ueda

Research output: Contribution to journalArticlepeer-review


Nociceptin/orphanin FQ (N/OFQ), nocistatin, and prepro-N/OFQ 160-187 (C-peptide) are all derived from the same precursor protein. We examine the pharmacological mechanisms of nocistatinand C-peptide-induced pronociceptive responses in a novel algogenic-induced nociceptive flexion test in mice. The intraplantar ( injection of nocistatin- and C-peptide induced pronociceptive responses in a range of 0.01 to 10 or 1 pmol, respectively, which showed 100- to 1000-fold less potent effects than the N/OFQ. The nociceptive effects of both peptides were not affected by 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1, 3-dihydro-2H-benzimidazole-2-one (J-113397) (, an N/OFQ receptor antagonist, indicating that they are mediated by a novel mechanism independent of activation of N/OFQ receptor. Like N/OFQ, nocistatin-induced nociception was abolished by injection of pertussis toxin, phospholipase C inhibitor, or CP-99994, a neurokinin 1 receptor antagonist, indicating that nocistatin may elicit nociception through a substance P release from nociceptor endings via activation of Gi/o and phospholipase C. The nociception was abolished by neonatal pre-treatment (s.c.) with capsaicin or by i.t. pretreatment with CP-99994, but not MK-801 (i.t.), an N-methyl-D-aspartate receptor antagonist. In contrast, C-peptide-induced nociception was attenuated by the pretreatment with antisense oligodeoxynucleotide for Gαs (i.t.) and with KT-5720 (, a cyclic AMP-dependent protein kinase inhibitor, but not with pertussis toxin. The nociception was neither attenuated by neonatal capsaicin nor by i.t. injection with CP-99994, but it was attenuated by i.t. injection with MK-801. These results suggest that nocistatin and C-peptide derived from prepro-N/OFQ stimulate distinct nociceptive fibers through different in vivo signaling mechanisms.

Original languageEnglish (US)
Pages (from-to)141-146
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number1
StatePublished - Jul 1 2003
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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