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[Dmt 1 ]N/OFQ(1–13)‐NH 2 : a potent nociceptin/orphanin FQ and opioid receptor universal agonist
Author(s) -
Molinari S,
Camarda V,
Rizzi A,
Marzola G,
Salvadori S,
Marzola E,
Molinari P,
McDonald J,
Ko MC,
Lambert DG,
Calo' G,
Guerrini R
Publication year - 2013
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2012.02115.x
Subject(s) - nociceptin receptor , nop , chemistry , agonist , receptor , opioid , gtpgammas , opioid receptor , pharmacology , opioid peptide , biochemistry , biology
Background and Purpose Intrathecally (i.t.) administered nociceptin/orphanin FQ ( N/OFQ ) evokes antinociceptive effects in rodents. Recent studies in monkeys demonstrated that i.t. co‐application of N/OFQ and morphine elicits synergistic antinociceptive actions suggesting mixed N/OFQ peptide ( NOP ) and μ opioid receptor agonists as innovative spinal analgesics. Thus, novel N/OFQ related peptides were synthesized in order to identify and pharmacologically characterize a mixed NOP / μ opioid receptor agonist. Experimental Approach The following in vitro assays were used: calcium mobilization in cells expressing the human NOP or classical opioid receptors and chimeric G proteins, receptor and [ 35 S]‐GTPγS binding, [ 35 S]‐GTPγS binding in rat spinal cord membranes, guinea pig ileum bioassay. In vivo experiments were performed in monkeys using the tail withdrawal assay. Key Results From calcium mobilization studies [Dmt 1 ]N/OFQ(1–13)‐NH 2 was selected as the most potent and least selective compound. The mixed NOP /opioid full agonist activity and high affinity of [Dmt 1 ]N/OFQ(1–13)‐NH 2 was confirmed at human recombinant receptors in receptor binding, calcium mobilization and/or [ 35 S]‐GTPγS binding studies, at rat spinal cord receptors in [ 35 S]‐GTPγS binding experiments, and at guinea pig receptors inhibiting neurogenic contractions in the ileum. In vivo in the tail withdrawal assay in monkeys i.t. [Dmt 1 ]N/OFQ(1–13)‐NH 2 was able to elicit robust and long‐lasting antinociceptive effects. Conclusions and Implications Collectively, these results demonstrate that [Dmt 1 ]N/OFQ(1–13)‐NH 2 behaves as NOP /opioid receptor universal agonist and substantiate the suggestion that such mixed ligands are worthy of development as innovative spinal analgesics.