title: Age-dependent morphine tolerance development in the rat.
abstract: In all age groups, the use of opioids to treat chronic pain conditions has increased, yet the impact of age on opioid tolerance development has not been comprehensively addressed. In this study, we investigated age-related differences in morphine tolerance development in rats. Rats aged 3 wk, 3 mo, 6 mo, and 1 yr were used in the study. Morphine (8 mg/kg) was injected subcutaneously twice each day and its analgesic effect assessed by the change in tail-flick latency using a thermal stimulus 5 min before and 30 min after dosing. Tolerance was defined as a 75% reduction in morphine-induced analgesia compared to Day 1. Rats aged 3 wk, 3 mo, 6 mo, and 1 yr developed tolerance on the 4th, 10th, 14th, and 22nd days of morphine treatment, respectively. Plasma levels of morphine and its metabolites showed that pharmacokinetic differences among the groups did not correlate with the differences in tolerance development. This study demonstrates that morphine tolerance occurs more rapidly in younger rats than older rats and is unlikely to be the result of differences in drug metabolism or clearance. Aging may impact molecular processes involved in tolerance development and provide insight into novel therapeutic targets to delay opioid tolerance development.
authors.affiliation: Department of Anesthesia and Perioperative Care, University of California, San Francisco.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: James
authors.initials: J
authors.lastname: Mitchell
authors.forename: Kumi
authors.initials: K
authors.lastname: Moriyama
authors.forename: Ki-Jun
authors.initials: KJ
authors.lastname: Kim
authors.forename: Manohar
authors.initials: M
authors.lastname: Sharma
authors.forename: Guo-Xi
authors.initials: GX
authors.lastname: Xie
authors.forename: Pamela Pierce
authors.initials: PP
authors.lastname: Palmer
mesh_terms: D000375:Aging / Q000502:physiology*; D000701:Analgesics, Opioid / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004361:Drug Tolerance / Q000502:physiology*; D008297:Male; D013058:Mass Spectrometry; D009020:Morphine / Q000493:pharmacokinetics / Q000494:pharmacology*; D009022:Morphine Derivatives / Q000097:blood; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects
chemical_list: D000701:Analgesics, Opioid; D009022:Morphine Derivatives; C035349:morphine-6-glucuronide; D009020:Morphine; C018108:morphine-3-glucuronide