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NPYF a, A Chimeric Peptide of Met‐Enkephalin, and NPFF Induces Tolerance‐Free Analgesia
Author(s) -
Mudgal Annu,
Kumar Krishan,
Mollereau Catherine,
Pasha Santosh
Publication year - 2016
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12721
Subject(s) - neuropeptide , receptor , enkephalin , opioid peptide , chemistry , opioid , peptide , pharmacology , met enkephalin , biochemistry , biology
Methionine‐enkephalin‐Arg‐Phe is an endogenous amphiactive analgesic peptide. Neuropeptide FF, on the other hand, is reported for its role in opioid modulation and tolerance development. Based on these reports, in the present study we designed a chimeric peptide NPYF a ( YGGFMKKKPQRF amide), having the Met‐enkephalin (opioid) and PQRF amide sequence of neuropeptide FF, which can then target both the opioid and neuropeptide FF receptors. We hypothesized that the chimeric peptide so designed would have both analgesic properties and further aid in understanding of the role of neuropeptide FF in the development of opiate tolerance. Our studies indicated that NPYF a induced an early onset, potent, dose‐dependent and prolonged antinociception. Additionally, antagonists ( MOR , KOR , and DOR ) pretreatment studies determined a KOR ‐mediated antinociception activity of the ligand. Further, in vitro binding studies using the Eu‐ GTP ‐ γ S binding assay on cell lines expressing opioid and NPFF receptors showed binding to both the opioid and neuropeptide FF receptors suggesting a multiple receptor binding character of NPYF a. Moreover, chronic (6 days) treatment with NPYF a exhibited an absence of tolerance development subsequent to its analgesia. The current study proposes NPYF a as a potent, long‐acting antinociceptor lacking tolerance development as well as a probe to study opioid analgesia and the associated complex mechanisms of tolerance development.