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Morphine analgesia in male inbred genetic diversity mice recapitulates the among-individual variance in response to morphine in humans.

ABSTRACT: Morphine is a widely used analgesic, but its use in clinical precision medicine is limited by the variance in response among individuals. Although previous studies have shown that individual differences in morphine can be explained in terms of pharmacodynamics and pharmacokinetics, genetic polymorphisms also play an important role. However, the genetic basis of different sensitivity and tolerance susceptibility to morphine remains ambiguous. Using 15 strains of inbred Genetic Diversity (GD) mice, a new resource with wide genetic and phenotypic variation, we demonstrated great variance in sensitivity to morphine analgesia and susceptibility to morphine tolerance between different GD strains. Among-individual variance in response to morphine analgesia in the population can be modeled in GD mice. Two loci respectively may be associated with the among-individual variance in morphine sensitivity and tolerance, confirming the role of genetic factors in among-individual different responses to morphine. These results indicate that GD mice may be a potential tool for the identification of new biomarkers to improve the clinical administration of morphine.

SUBMITTER: Yang Y

PROVIDER: S-EPMC9240740 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Morphine analgesia in male inbred genetic diversity mice recapitulates the among-individual variance in response to morphine in humans.

Yang Yin Y Guan Bowen B Wei Qiang Q Wang Wei W Meng Aimin A

Animal models and experimental medicine 20220603 3

Morphine is a widely used analgesic, but its use in clinical precision medicine is limited by the variance in response among individuals. Although previous studies have shown that individual differences in morphine can be explained in terms of pharmacodynamics and pharmacokinetics, genetic polymorphisms also play an important role. However, the genetic basis of different sensitivity and tolerance susceptibility to morphine remains ambiguous. Using 15 strains of inbred Genetic Diversity (GD) mice ...[more]

PMID: 35656737

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Project description:Hemorrhage is a leading cause of preventable battlefield and civilian trauma deaths. Ketamine, fentanyl, and morphine are recommended analgesics for use in the prehospital (i.e., field) setting to reduce pain. However, it is unknown whether any of these analgesics reduce hemorrhagic tolerance in humans. We tested the hypothesis that fentanyl (75 µg) and morphine (5 mg), but not ketamine (20 mg), would reduce tolerance to simulated hemorrhage in conscious humans. Each of the three analgesics was evaluated independently among different cohorts of healthy adults in a randomized, crossover (within drug/placebo comparison), placebo-controlled fashion using doses derived from the Tactical Combat Casualty Care Guidelines for Medical Personnel. One minute after an intravenous infusion of the analgesic or placebo (saline), we employed a pre-syncopal limited progressive lower-body negative pressure (LBNP) protocol to determine hemorrhagic tolerance. Hemorrhagic tolerance was quantified as a cumulative stress index (CSI), which is the sum of products of the LBNP and the duration (e.g., [40 mmHg x 3 min] + [50 mmHg x 3 min] …). Compared with ketamine (p = 0.002 post hoc result) and fentanyl (p = 0.02 post hoc result), morphine reduced the CSI (ketamine (n = 30): 99 [73-139], fentanyl (n = 28): 95 [68-130], morphine (n = 30): 62 [35-85]; values expressed as a % of the respective placebo trial's CSI; median [IQR]; Kruskal-Wallis test p = 0.002). Morphine-induced reductions in tolerance to central hypovolemia were not well explained by a prediction model including biological sex, body mass, and age (R2=0.05, p = 0.74). These experimental data demonstrate that morphine reduces tolerance to simulated hemorrhage while fentanyl and ketamine do not affect tolerance. Thus, these laboratory-based data, captured via simulated hemorrhage, suggest that morphine should not be used for a hemorrhaging individual in the prehospital setting.

Dataset Information

Morphine analgesia in male inbred genetic diversity mice recapitulates the among-individual variance in response to morphine in humans.

Publications

Morphine analgesia in male inbred genetic diversity mice recapitulates the among-individual variance in response to morphine in humans.

Similar Datasets

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