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.
Keywords: Buprenorphine; Metabolism; Mouse; Mu-opioid receptor; Refinement; Strain specific.
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
Reduced supraspinal nociceptive responses and distinct gene expression profile in CXBH recombinant inbred mice.J Pain. 2013 Jun;14(6):648-61. doi: 10.1016/j.jpain.2013.01.773. Epub 2013 Apr 12. J Pain. 2013. PMID: 23583704
Liver lobe and strain differences in the activity of murine cytochrome P450 enzymes.Toxicology. 2018 Jul 1;404-405:76-85. doi: 10.1016/j.tox.2018.06.001. Epub 2018 Jun 4. Toxicology. 2018. PMID: 29879457
Metabolomic analysis of normal (C57BL/6J, 129S1/SvImJ) mice by gas chromatography-mass spectrometry: detection of strain and gender differences.Talanta. 2011 Jul 15;85(1):718-24. doi: 10.1016/j.talanta.2011.04.060. Epub 2011 May 5. Talanta. 2011. PMID: 21645764
Opioids and the management of chronic severe pain in the elderly: consensus statement of an International Expert Panel with focus on the six clinically most often used World Health Organization Step III opioids (buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone).Pain Pract. 2008 Jul-Aug;8(4):287-313. doi: 10.1111/j.1533-2500.2008.00204.x. Epub 2008 May 23. Pain Pract. 2008. PMID: 18503626
Opioids.2019 Apr 25. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012–. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. 2012–. PMID: 31643200 Free Books & Documents. Review.
Cited by 1 article
Repeatability analysis improves the reliability of behavioral data.PLoS One. 2020 Apr 2;15(4):e0230900. doi: 10.1371/journal.pone.0230900. eCollection 2020. PLoS One. 2020. PMID: 32240211 Free PMC article.