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[Dmt1]N/OFQ(1‐13)‐NH2, a potent NOP/MOP receptor mixed agonist
Author(s) -
Calo’ Girolamo,
Molinari Stefano,
Camarda Valeria,
Rizzi Anna,
Marzola Giuliano,
Salvadori Severo,
Marzola Erika,
Molinari Paola,
McDonald John,
Ko Mei-Chuan,
Lambert David,
Guerrini Remo
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.836.1
Subject(s) - nop , nociceptin receptor , chemistry , receptor , agonist , pharmacology , in vivo , nociception , morphine , opioid , biochemistry , opioid peptide , biology , microbiology and biotechnology
i.t. nociceptin/orphanin FQ (N/OFQ) evokes antinociceptive effects in rodents. Studies in monkeys demonstrated that i.t. coapplication of N/OFQ and morphine elicits synergistic antinociceptive actions. Novel N/OFQ related peptides were synthesised in order to identify and characterize mixed NOP/MOP agonists. The following in vitro assays were used: Ca2+ mobilization in cells expressing hNOP or hMOP receptors and the chimeric protein Gαqi5, receptor and [35S]GTPS binding, guinea pig ileum bioassay. In vivo experiments were performed in mice and monkeys using the tail withdrawal assay. From Ca2+ mobilization studies [Dmt1]N/OFQ(1‐13)NH2 was selected as the most potent and least selective compound. The mixed NOP/MOP full agonist activity and high affinity of [Dmt1]N/OFQ(1‐13)NH2 was confirmed at recombinant receptors in receptor and [35S]GTPS binding studies, at rat spinal cord receptors in [35S]GTPS binding experiments, and in the guinea pig ileum. In vivo in mice and monkeys i.t. morphine and N/OFQ evoked similar antinociceptive effects. [Dmt1]N/OFQ(1‐13)NH2 was also able to elicit a robust antinociceptive action being more potent than N/OFQ (by 30 fold) and morphine (by 3 fold). These results demonstrate that [Dmt1]N/OFQ(1‐13)NH2 behaves as mixed NOP/MOP agonist and substantiate the proposal that such mixed ligands are worthy of development as spinal analgesics.