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Long-term morphine delivery via slow release morphine pellets or osmotic pumps: Plasma concentration, analgesia, and naloxone-precipitated withdrawal.

ABSTRACT: 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.Male C57BL/6NCr mice (8weeksold) were implanted subcutaneously with slow-release pellets (25mg morphine sulfate) or osmotic pumps (64mg/mL, 1.0?L/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).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.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.

SUBMITTER: McLane VD

PROVIDER: S-EPMC5577921 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Long-term morphine delivery via slow release morphine pellets or osmotic pumps: Plasma concentration, analgesia, and naloxone-precipitated withdrawal.

McLane Virginia D VD Bergquist Ivy I Cormier James J Barlow Deborah J DJ Houseknecht Karen L KL Bilsky Edward J EJ Cao Ling L

Life sciences 20170716

<h4>Aims</h4>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.<h4>Main methods</h4>Male C57BL/6NCr mice (8weeksold) were implanted subcutaneously with slow-release pellets (25mg morphine sulfate) or osmotic pumps (64mg/mL, 1.0μL/h). Plasma ...[more]

PMID: 28723417

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Project description:The development of opioid dependence involves classical neuronal opioid receptor activation and is due in part to engagement of glia causing a proinflammatory response. Such opioid-induced glial activation occurs, at least in part, through a non-classical opioid mechanism involving Toll-like-receptor 4 (TLR4). Among the immune factors released following the opioid-glia-TLR4 interaction, interleukin-1? (IL-1?) plays a prominent role. Previous animal behavioral studies have demonstrated significant heterogeneity of chronic morphine-induced tolerance and dependence between different mouse strains. The aim of this study was to investigate whether the heterogeneity of chronic opioid-induced IL-1? expression contributes to differences in opioid tolerance and withdrawal behaviors. Chronic morphine-induced tolerance and dependence were assessed in 3 inbred wild-type mouse strains (Balb/c, CBA, and C57BL/6) and 2 knockout strains (TLR4 and MyD88). Analysis of brain nuclei (medial prefrontal cortex, cortex, brain stem, hippocampus, and midbrain and diencephalon regions combined) revealed that, of inbred wild-type mice, there are significant main effects of morphine treatment on IL-1? expression in the brain regions analyzed (p<0.02 for all regions analyzed). A significant increase in hippocampal IL-1? expression was found in C57BL/6 mice after morphine treatment, whilst, a significant decrease was found in the mPFC region of wild-type Balb/c mice. Furthermore, the results of wild-type inbred strains demonstrated that the elevated hippocampal IL-1? expression is associated with withdrawal jumping behavior. Interestingly, knockout of TLR4, but not MyD88 protected against the development of analgesic tolerance. Gene sequence differences of IL - 1? and TLR4 genes alone did not explain the heterogeneity of dependence behavior between mouse strains. Together, these data further support the involvement of opioid-induced CNS immune signaling in dependence development. Moreover, this study demonstrated the advantages of utilizing multiple mouse strains and indicates that appropriate choice of mouse strains could enhance future research outcomes.

Dataset Information

Long-term morphine delivery via slow release morphine pellets or osmotic pumps: Plasma concentration, analgesia, and naloxone-precipitated withdrawal.

Publications

Long-term morphine delivery via slow release morphine pellets or osmotic pumps: Plasma concentration, analgesia, and naloxone-precipitated withdrawal.

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