title: Differential respiratory effects of [Dmt1]DALDA and morphine in mice.
abstract: H-Dmt-D-Arg-Phe-Lys-NH(2) ([Dmt(1)]DALDA, dDAL), a highly selective mu-opioid peptide, produces potent analgesia without respiratory depression after intrathecal administration. Despite carrying 3+ net charge, dDAL is also a potent analgesic after systemic administration. We compared the respiratory effects of dDAL and morphine after subcutaneous administration in mice using whole body plethysmography. Analgesic doses of 3 and 10 times ED(50) were examined. Both drugs dose-dependently decreased respiratory frequency and minute volume in room air. Tidal volume was increased by the lower dose of morphine, while it was decreased by the higher dose of dDAL. The decrease in minute volume by dDAL and morphine was completely reversed by naloxone. No difference in ventilatory response to CO(2) was observed between dDAL and morphine at three times ED(50). Ventilatory response to hypoxia was significantly diminished by dDAL compared to morphine and saline, and this effect of dDAL was naloxone-irreversible. Thus dDAL likely reduces the sensitivity of the peripheral chemoreflex loop through a non-opioid action.
authors.affiliation: Department of Autonomic Physiology, Chiba University Graduate School of Medicine, Chuo-ku, Chiba 260-8670, Japan. shimoyama@faculty.chiba-u.jp
authors.forename: Megumi
authors.initials: M
authors.lastname: Shimoyama
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Kuwaki
authors.forename: Akira
authors.initials: A
authors.lastname: Nakamura
authors.forename: Yasuichiro
authors.initials: Y
authors.lastname: Fukuda
authors.forename: Naohito
authors.initials: N
authors.lastname: Shimoyama
authors.forename: Peter W
authors.initials: PW
authors.lastname: Schiller
authors.forename: Hazel H
authors.initials: HH
authors.lastname: Szeto
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006935:Hypercapnia / Q000503:physiopathology; D000860:Hypoxia / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000494:pharmacology*; D009270:Naloxone / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology*; D012119:Respiration / Q000187:drug effects*; D013990:Tidal Volume / Q000187:drug effects; D013997:Time Factors
chemical_list: C424424:2',6'-dimethyltyrosyl-arginyl-phenylalanyl-lysinamide; D009842:Oligopeptides; D009270:Naloxone; D009020:Morphine