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Spinal antinociceptive effects of the novel NOP receptor agonist PWT2 ‐nociceptin/orphanin FQ in mice and monkeys
Author(s) -
Rizzi A,
Sukhtankar D D,
Ding H,
Hayashida K,
Ruzza C,
Guerrini R,
Calò G,
Ko M C
Publication year - 2015
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/bph.13150
Subject(s) - nociceptin receptor , nop , nociception , pharmacology , agonist , chemistry , neuropathic pain , receptor , antagonist , in vivo , opioid , medicine , opioid peptide , biology , biochemistry , microbiology and biotechnology
Background and purpose Using an innovative chemical approach, peptide welding technology ( PWT ), a tetrabranched derivative of nociceptin/orphanin FQ ( N / OFQ ) has been generated and pharmacologically characterized. Both in vitro and in vivo PWT 2‐ N / OFQ displayed the same pharmacological profile to the natural ligand. It was more potent and produced longer‐lasting effects. The aim of the present study was to investigate the spinal effects of PWT 2‐ N / OFQ in nociceptive and neuropathic pain models in mice and non‐human primates. Experimental Approach Tail withdrawal assay in mice and monkeys was used as a nociceptive pain model and mechanical threshold in mice subjected to chronic constriction injury was used as a neuropathic pain model. The antinociceptive effects of spinally administered N / OFQ and PWT2 ‐ N / OFQ were assessed in these models. Key Results PWT2 ‐ N / OFQ mimicked the spinal antinociceptive effects of N / OFQ both in nociceptive and neuropathic pain models in mice as well as in non‐human primates displaying 40‐fold higher potency and a markedly prolonged duration of action. The effects of N / OFQ and PWT2 ‐ N / OFQ were sensitive to the N / OFQ receptor ( NOP ) antagonist SB ‐612111, but not to opioid receptor antagonists. Conclusions and Implications The present study has demonstrated that PWT2 ‐ N / OFQ mimicked the antinociceptive effects of the natural peptide in rodents and non‐human primates acting as a potent and longer‐lasting NOP ‐selective agonist. More generally, PWT derivatives of biologically active peptides can be viewed as innovative pharmacological tools for investigating those conditions and states in which selective and prolonged receptor stimulation promotes beneficial effects.