title: S-Methadone augments R-methadone induced respiratory depression in the neonatal guinea pig.
abstract: Methadone is administered as a racemic mixture, although its analgesic and respiratory effects are attributed to R-isomer activity at the mu opioid receptor (MOP). Recently, we observed a four-fold increase in inspiratory time in 3-day-old guinea pigs following an injection of racemic methadone. We hypothesized that this effect was due to augmentation of R-methadone induced respiratory depression by the S-methadone isomer. In the current longitudinal study, we injected 3-, 7-, and 14-day-old neonatal guinea pigs with saline, R-methadone, S-methadone, or R- plus S-methadone in order to characterize the roles of the individual isomers, as well as the synergistic effects of co-administration. Using plethysmography, we measured respiratory parameters while breathing room air and during a 5% CO(2) challenge. S-Methadone alone had no respiratory effects. However, the R- plus S-methadone group showed greater respiratory depression and increased inspiratory time than the R-methadone group in the youngest animals, suggesting that the respiratory effects of R-methadone are augmented by S-methadone in early development.
authors.affiliation: Department of Physiology & Pharmacology, L334, School of Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239-3098, USA.
authors.forename: Daniel A N
authors.initials: DA
authors.lastname: Silverman
authors.forename: Rosemary T
authors.initials: RT
authors.lastname: Nettleton
authors.forename: Katherine B
authors.initials: KB
authors.lastname: Spencer
authors.forename: Michael
authors.initials: M
authors.lastname: Wallisch
authors.forename: George D
authors.initials: GD
authors.lastname: Olsen
mesh_terms: D000367:Age Factors; D000701:Analgesics, Opioid / Q000737:chemistry* / Q000633:toxicity*; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006168:Guinea Pigs; D008297:Male; D008691:Methadone / Q000737:chemistry* / Q000633:toxicity*; D009043:Motor Activity / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D010991:Plethysmography; D011247:Pregnancy; D012123:Pulmonary Ventilation / Q000187:drug effects; D012131:Respiratory Insufficiency / Q000139:chemically induced* / Q000503:physiopathology; D015656:Respiratory Mechanics / Q000187:drug effects; D013237:Stereoisomerism; D013990:Tidal Volume / Q000187:drug effects; D013997:Time Factors
chemical_list: D000701:Analgesics, Opioid; D008691:Methadone