Virginia D McLane1, Ivy Bergquist2, James Cormier2, Deborah J Barlow2, Karen L Houseknecht3, Edward J Bilsky4, Ling Cao3. 1. University of Maine, Graduate School of Biomedical Science and Engineering, Orono, ME 04669, United States; University of New England, College of Osteopathic Medicine, Biddeford, ME 04005, United States. Electronic address: virginia.mclane@vcuhealth.org. 2. University of New England, College of Osteopathic Medicine, Biddeford, ME 04005, United States. 3. University of New England, College of Osteopathic Medicine, Biddeford, ME 04005, United States; University of New England, Center for Excellence in the Neurosciences, Biddeford, ME 04005, United States. 4. University of New England, College of Osteopathic Medicine, Biddeford, ME 04005, United States; University of New England, Center for Excellence in the Neurosciences, Biddeford, ME 04005, United States; Pacific Northwest University, Yakima, WA 98901, United States.
Abstract
AIMS: Slow-release morphine sulfate pellets and osmotic pumps are common routes of chronic morphine delivery in mouse models, but direct comparisons of these drug delivery systems are lacking. In this study, we assessed the efficacy of slow-release pellets versus osmotic pumps in delivering morphine to adult mice. MAIN METHODS: Male C57BL/6NCr mice (8weeksold) were implanted subcutaneously with slow-release pellets (25mg morphine sulfate) or osmotic pumps (64mg/mL, 1.0μL/h). Plasma morphine concentrations were quantified via LC-MS/MS, analgesic efficacy was determined by tail flick assay, and dependence was assessed with naloxone-precipitated withdrawal behaviors (jumping) and physiological effects (excretion, weight loss). KEY FINDINGS: Morphine pellets delivered significantly higher plasma drug concentrations compared to osmotic pumps, which were limited by the solubility of the morphine sulfate and pump volume/flow rate. Within 96h post-implantation, plasma morphine concentrations were indistinguishable in pellet vs. pump-treated samples. While osmotic pump did not have an antinociceptive effect in the tail flick assay, pumps and pellets induced comparable dependence symptoms (naloxone-precipitated jumping behavior) from 24-72h post-implantation. SIGNIFICANCE: In this study, we compared slow-release morphine pellets to osmotic minipumps for morphine delivery in mice. We found that osmotic pumps and subcutaneous morphine sulfate pellets yielded significantly different pharmacokinetics over a 7-day period, and as a result significantly different antinociceptive efficacy. Nonetheless, both delivery methods induced dependence as measured by naloxone-precipitated withdrawal.
AIMS: Slow-release morphine sulfate pellets and osmotic pumps are common routes of chronic morphine delivery in mouse models, but direct comparisons of these drug delivery systems are lacking. In this study, we assessed the efficacy of slow-release pellets versus osmotic pumps in delivering morphine to adult mice. MAIN METHODS: Male C57BL/6NCr mice (8weeksold) were implanted subcutaneously with slow-release pellets (25mg morphine sulfate) or osmotic pumps (64mg/mL, 1.0μL/h). Plasma morphine concentrations were quantified via LC-MS/MS, analgesic efficacy was determined by tail flick assay, and dependence was assessed with naloxone-precipitated withdrawal behaviors (jumping) and physiological effects (excretion, weight loss). KEY FINDINGS:Morphine pellets delivered significantly higher plasma drug concentrations compared to osmotic pumps, which were limited by the solubility of the morphine sulfate and pump volume/flow rate. Within 96h post-implantation, plasma morphine concentrations were indistinguishable in pellet vs. pump-treated samples. While osmotic pump did not have an antinociceptive effect in the tail flick assay, pumps and pellets induced comparable dependence symptoms (naloxone-precipitated jumping behavior) from 24-72h post-implantation. SIGNIFICANCE: In this study, we compared slow-release morphine pellets to osmotic minipumps for morphine delivery in mice. We found that osmotic pumps and subcutaneous morphine sulfate pellets yielded significantly different pharmacokinetics over a 7-day period, and as a result significantly different antinociceptive efficacy. Nonetheless, both delivery methods induced dependence as measured by naloxone-precipitated withdrawal.
Authors: U Arvidsson; M Riedl; S Chakrabarti; J H Lee; A H Nakano; R J Dado; H H Loh; P Y Law; M W Wessendorf; R Elde Journal: J Neurosci Date: 1995-05 Impact factor: 6.167
Authors: Gregory Corder; Vivianne L Tawfik; Dong Wang; Elizabeth I Sypek; Sarah A Low; Jasmine R Dickinson; Chaudy Sotoudeh; J David Clark; Ben A Barres; Christopher J Bohlen; Grégory Scherrer Journal: Nat Med Date: 2017-01-16 Impact factor: 53.440