Abstract
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 Gαs (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.
Footnotes
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Parts of this study were supported by Special Coordination Funds of the Science and Technology Agency of the Japanese Government; a research grant from the Environmental Agency, Government of Japan; grants-in-aid from the Ministry of Education, Science, Culture and Sports of Japan; and a grant from the Human Frontier Science Program.
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DOI: 10.1124/jpet.103.049361.
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ABBREVIATIONS: N/OFQ, nociceptin/orphanin FQ; NOP, nociceptin/orphanin FQ receptor; ANF, algogenic-induced nociceptive flexion; AS-ODN, antisense oligodeoxynucleotide; MS-ODN, missense oligodeoxynucleotide; i.pl., intraplantar; NMDA, N-methyl-d-aspartate; PKA, protein kinase A; CP-99994, (+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine; MK-801, (–)-5-methyl-10,11-dihydro-5H-dibenzo[a.d]cyclohepten-5.10-imine maleate; KT5720, [9R,10S,12S]-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3,2,1-kl]pyrrolo[3,4-l][1,6]benzodiazocine-10-carboxylic acid hexyl ester.
- Received January 21, 2003.
- Accepted March 27, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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