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Analgesic treatment with buprenorphine should be adapted to the mouse strain.
Pharmacology Biochemistry and Behavior ( IF 3.3 ) Pub Date : 2020-02-20 , DOI: 10.1016/j.pbb.2020.172877
Juliane Rudeck 1 , Silvia Vogl 1 , Céline Heinl 1 , Matthias Steinfath 1 , Sebastian Fritzwanker 2 , Andrea Kliewer 2 , Stefan Schulz 2 , Gilbert Schönfelder 3 , Bettina Bert 1
Affiliation  

Buprenorphine is a commonly used opioid to treat moderate to severe pain in mice. Although strain differences regarding basal pain sensitivity and the analgesic effect of other opioids have been described for mice, the data for buprenorphine is incomplete. Hence, we investigated basal pain sensitivity and the analgesic effect of buprenorphine (0.42, 4.0 mg·kg−1) in male C57BL/6J, Balb/cJ and 129S1/SvImJ mice using the incremental hot plate. Additionally, we verified single nucleotide polymorphisms in Cytochrome P450 3a (Cyp3a) genes, which encode for enzymes that are relevant for buprenorphine metabolism, and analyzed serum and brain concentrations of buprenorphine and its metabolites. Finally, in a pilot survey we determined μ-opioid receptor (MOR) protein expression in whole brain lysates.

Basal pain sensitivity differed significantly between the mouse strains (Balb/cJ > C57BL/6J > 129S1/SvImJ). Additionally, buprenorphine showed a dose- and strain-dependent effect: at a higher dose it led to increased antinociception in C57BL/6J and Balb/cJ mice, whereas in 129S1/SvImJ mice this effect was diminished. Serum and brain concentrations of buprenorphine and its metabolites dose-dependently increased and differed slightly between the strains at the high dose. However, these slight strain differences did not correlate with pain behavior. Furthermore, serum buprenorphine metabolic ratio and distribution of buprenorphine and its metabolites between brain and blood showed no dose- and only some strain-dependent differences independent from nociceptive behavior. Western blot analysis revealed no strain difference in the basal MOR protein expression in brain lysates.

Our results indicate that buprenorphine dosing should be determined in a pilot study for the respective mouse strain to optimize pain treatment and to avoid unwanted side effects. The present pharmacokinetic data and the coarse determination of MOR expression do not explain the strain differences in the analgesic effect of buprenorphine. However, follow-up studies focusing on more specific pharmacodynamic factors could further elucidate the reasons.



中文翻译:

丁丙诺啡的镇痛治疗应适应小鼠品系。

丁丙诺啡是治疗小鼠中度至重度疼痛的常用阿片类药物。尽管已经描述了小鼠对基础疼痛敏感性和其他阿片类药物的镇痛作用的差异,但是丁丙诺啡的数据并不完整。因此,我们使用增量热板研究了雄性C57BL / 6J,Balb / cJ和129S1 / SvImJ小鼠的基础疼痛敏感性和丁丙诺啡(0.42,4.0 mg·kg -1)的镇痛作用。此外,我们验证了细胞色素P450 3aCyp3a)中的单核苷酸多态性)基因编码与丁丙诺啡代谢相关的酶,并分析了丁丙诺啡及其代谢产物的血清和脑中浓度。最后,在一项初步调查中,我们确定了全脑裂解液中的μ阿片受体(MOR)蛋白表达。

小鼠品系之间的基础疼痛敏感性显着不同(Balb / cJ> C57BL / 6J> 129S1 / SvImJ)。此外,丁丙诺啡显示出剂量依赖性和品系依赖性:在较高剂量下,它会导致C57BL / 6J和Balb / cJ小鼠的抗伤害作用增强,而在129S1 / SvImJ小鼠中这种作用减弱。高剂量时,丁丙诺啡及其代谢产物的血清和脑中浓度呈剂量依赖性增加,并且在菌株之间略有不同。但是,这些轻微的应变差异与疼痛行为无关。此外,血清丁丙诺啡的代谢率以及丁丙诺啡及其代谢产物在脑和血液之间的分布没有剂量依赖性,并且仅存在一些依赖于伤害感受行为的菌株依赖性差异。

我们的结果表明,应在有关小鼠品系的初步研究中确定丁丙诺啡的剂量,以优化疼痛治疗并避免不良副作用。目前的药代动力学数据和MOR表达的粗略确定不能解释丁丙诺啡镇痛作用中的菌株差异。但是,针对更具体的药效学因素的后续研究可以进一步阐明原因。

更新日期:2020-02-20
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