title: NPYFa, A Chimeric Peptide of Met-Enkephalin, and NPFF Induces Tolerance-Free Analgesia.
abstract: 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 NPYFa (YGGFMKKKPQRFamide), having the Met-enkephalin (opioid) and PQRFamide 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 NPYFa 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-γS 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 NPYFa. Moreover, chronic (6 days) treatment with NPYFa exhibited an absence of tolerance development subsequent to its analgesia. The current study proposes NPYFa 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.
authors.affiliation: Peptide Synthesis Laboratory, CSIR-Institute of Genomics and Integrative Biology (CSIR-IGIB), New Delhi, India.|Academy of Scientific and Innovative Research (AcSIR), CSIR-IGIB Campus, New Delhi, India.
authors.forename: Annu
authors.initials: A
authors.lastname: Mudgal
authors.affiliation: Peptide Synthesis Laboratory, CSIR-Institute of Genomics and Integrative Biology (CSIR-IGIB), New Delhi, India.|Department of Chemistry, Motilal Nehru College, University of Delhi, Delhi, 110021, India.
authors.forename: Krishan
authors.initials: K
authors.lastname: Kumar
authors.affiliation: Institut de Pharmacologie et Biologie Structurale, Toulouse Cedex, France.|Laboratoire Anthropologie Moléculaire et Imagerie de Synthèse, Toulouse Cedex, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Mollereau
authors.affiliation: Peptide Synthesis Laboratory, CSIR-Institute of Genomics and Integrative Biology (CSIR-IGIB), New Delhi, India.|Academy of Scientific and Innovative Research (AcSIR), CSIR-IGIB Campus, New Delhi, India.
authors.forename: Santosh
authors.identifier: 0000-0002-1276-8784
authors.initials: S
authors.lastname: Pasha
mesh_terms: D000698:Analgesia; D000700:Analgesics / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004744:Enkephalin, Methionine / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D009842:Oligopeptides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018013:Receptors, Neuropeptide / Q000819:agonists / Q000378:metabolism; D011957:Receptors, Opioid / Q000819:agonists / Q000378:metabolism; D013997:Time Factors
chemical_list: D000700:Analgesics; D009842:Oligopeptides; D018013:Receptors, Neuropeptide; D011957:Receptors, Opioid; C083929:neuropeptide FF receptor; D004744:Enkephalin, Methionine; C053651:phenylalanyl-leucyl-phenylalanyl-glutaminyl-prolyl-glutaminyl-arginyl-phenylalaninamide
keywords: chimeric peptide; neuropeptide FF; opiate tolerance; tolerance-free antinociception