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.
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 nocistatin- and C-peptide-induced pronociceptive responses in a novel algogenic-induced nociceptive flexion test in mice. The intraplantar (i.pl.) 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) (i.pl.), 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 i.pl. 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 pretreatment (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 Galphas (i.t.) and with KT-5720 (i.pl.), 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.
Inoue
Makoto
M
Division of Molecular Pharmacology and Neuroscience, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8521, Japan.
Kawashima
Toshiko
T
Allen
Richard G
RG
Ueda
Hiroshi
H
D000701:Analgesics, Opioid / Q000627:therapeutic use; D000818:Animals; D002096:C-Peptide / Q000494:pharmacology*; D002211:Capsaicin / Q000494:pharmacology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology*; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000502:physiology*; D008297:Male; D051379:Mice; D009619:Nociceptors / Q000502:physiology*; D018847:Opioid Peptides / Q000494:pharmacology*; D010146:Pain / Q000139:chemically induced*; D010147:Pain Measurement; D010446:Peptide Fragments / Q000627:therapeutic use; D015398:Signal Transduction; D014665:Vasodilator Agents / Q000627:therapeutic use; D000097629:Nociceptin
D000701:Analgesics, Opioid; D002096:C-Peptide; D002211:Capsaicin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D019205:GTP-Binding Protein alpha Subunits, Gs; D018847:Opioid Peptides; D010446:Peptide Fragments; D014665:Vasodilator Agents; D000097629:Nociceptin; C111148:nocistatin