Lisa Brents, Ph.D.

BrentsPositions

Assistant Professor, Department of Pharmacology and Toxicology

Contacts

E-mail: LBRENTS@uams.edu

Research Experience

The objective of my laboratory is to develop treatment strategies for opioid use disorder that can be administered to pregnant women without negatively affecting fetuses. Current pharmacological treatments for opioid use disorder during pregnancy include the opioids methadone and buprenorphine, to which the fetus can become physically dependent. This physical dependence leads to neonatal abstinence syndrome (NAS) during the first days and weeks of life. NAS is a potentially life-threatening withdrawal syndrome that is characterized by inconsolable high-pitched crying, tremor, vomiting, diarrhea, sleep disturbances, and hypersensitivity to stimuli that are normally well tolerated by newborns. Additionally, the life-long effects of in utero opioid exposure or experiencing NAS are poorly understood. Although methadone and buprenorphine often cause NAS, maternal and neonatal outcomes following treatment with the medications are substantially improved relative to no treatment; thus methadone and buprenorphine represent the current best treatments for opioid use disorder during pregnancy.

Buprenorphine treatment is associated with less severe NAS than methadone; therefore, my laboratory is focused on understanding the factors that drive buprenorphine-associated NAS so that we can develop strategies to combat it. Our active projects are examining the contributions of an active metabolite of buprenorphine, called norbuprenorphine, to NAS. Evidence suggests that this metabolite is not important for maternal treatment but is associated with NAS. We envision that reducing fetal exposure to norbuprenorphine during maternal buprenorphine treatment will improve neonatal and life-long outcomes for the offspring. Potential methods to accomplish this goal that we are investigating include shunting buprenorphine metabolism from norbuprenorphine to minor, inactive metabolites, and increasing placental transport of norbuprenorphine from fetal to maternal circulation by p-glycoprotein.

Recent Publications

Griffin BA, Caperton CO, Russell LN, Cabanlong CV, Wilson CD, Urquhart KR, Martins BS, Zita MD, Patton AL, Alund AW, Owens SM, Fantegrossi WE, Moran JH, Brents LK. In Utero Exposure to Norbuprenorphine, a Major Metabolite of Buprenorphine, Induces Fetal Opioid Dependence and Leads to Neonatal Opioid Withdrawal Syndrome. J Pharmacol Exp Ther. 2019 Jul;370(1):9-17. doi: 10.1124/jpet.118.254219. Epub 2019 Apr 26. PubMed PMID: 31028107; PubMed Central PMCID: PMC6538887.

Brents LK, James GA, Cisler JM, Kilts CD. Personality variables modify the relationship between childhood maltreatment history and poor functional outcomes. Psychiatry Res. 2018 Oct;268:229-237. doi: 10.1016/j.psychres.2018.07.010. Epub 2018 Jul 6. PubMed PMID: 30064070; PubMed Central PMCID: PMC6455924.

Brents LK. Correlates and Consequences of Prenatal Cannabis Exposure (PCE): Identifying and Characterizing Vulnerable Maternal Populations and Determining Outcomes for Exposed Offspring . In: Handbook of Cannabis and Related Pathologies. 1st ed. Preedy VR, editor. London, UK: Academic Press; 2017. Chapter 17; p.160-170. 1170p.

Brents LK. Marijuana, the Endocannabinoid System and the Female Reproductive System. Yale J Biol Med. 2016 Jun;89(2):175-91. eCollection 2016 Jun. Review. PubMed PMID: 27354844; PubMed Central PMCID: PMC4918871.

Tai S, Hyatt WS, Gu C, Franks LN, Vasiljevik T, Brents LK, Prather PL, Fantegrossi WE. Repeated administration of phytocannabinoid Δ(9)-THC or synthetic cannabinoids JWH-018 and JWH-073 induces tolerance to hypothermia but not locomotor suppression in mice, and reduces CB1 receptor expression and function in a brain region-specific manner. Pharmacol Res. 2015 Dec;102:22-32. doi: 10.1016/j.phrs.2015.09.006. Epub 2015 Sep 8. PubMed PMID: 26361728; PubMed Central PMCID: PMC4684449.

Brents LK, Tripathi SP, Young J, James GA, Kilts CD. The role of childhood maltreatment in the altered trait and global expression of personality in cocaine addiction. J Psychiatr Res. 2015 May;64:23-31. doi: 10.1016/j.jpsychires.2015.02.015. Epub 2015 Mar 12. PubMed PMID: 25805246; PubMed Central PMCID: PMC4404225.

Marshell R, Kearney-Ramos T, Brents LK, Hyatt WS, Tai S, Prather PL, Fantegrossi WE. In vivo effects of synthetic cannabinoids JWH-018 and JWH-073 and phytocannabinoid Δ9-THC in mice: inhalation versus intraperitoneal injection. Pharmacol Biochem Behav. 2014 Sep;124:40-7. doi: 10.1016/j.pbb.2014.05.010. Epub 2014 May 21. PubMed PMID: 24857780; PubMed Central PMCID: PMC4340656.

Brents LK, Prather PL. The K2/Spice phenomenon: emergence, identification, legislation and metabolic characterization of synthetic cannabinoids in herbal incense products. Drug Metab Rev. 2014 Feb;46(1):72-85. doi: 10.3109/03602532.2013.839700. Epub 2013 Sep 24. Review. PubMed PMID: 24063277; PubMed Central PMCID: PMC4100246.

Brents LK, Zimmerman SM, Saffell AR, Prather PL, Fantegrossi WE. Differential drug-drug interactions of the synthetic Cannabinoids JWH-018 and JWH-073: implications for drug abuse liability and pain therapy. J Pharmacol Exp Ther. 2013 Sep;346(3):350-61. doi: 10.1124/jpet.113.206003. Epub 2013 Jun 25. PubMed PMID: 23801678; PubMed Central PMCID: PMC3920092.

Rajasekaran M, Brents LK, Franks LN, Moran JH, Prather PL. Human metabolites of synthetic cannabinoids JWH-018 and JWH-073 bind with high affinity and act as potent agonists at cannabinoid type-2 receptors. Toxicol Appl Pharmacol. 2013 Jun 1;269(2):100-8. doi: 10.1016/j.taap.2013.03.012. Epub 2013 Mar 26. PubMed PMID: 23537664; PubMed Central PMCID: PMC3685885.

Madadi NR, Penthala NR, Brents LK, Ford BM, Prather PL, Crooks PA. Evaluation of (Z)-2-((1-benzyl-1H-indol-3-yl)methylene)-quinuclidin-3-one analogues as novel, high affinity ligands for CB1 and CB2 cannabinoid receptors. Bioorg Med Chem Lett. 2013 Apr 1;23(7):2019-21. doi: 10.1016/j.bmcl.2013.02.025. Epub 2013 Feb 14. PubMed PMID: 23466226; PubMed Central PMCID: PMC4167632.

Safe SH, Prather PL, Brents LK, Chadalapaka G, Jutooru I. Unifying mechanisms of action of the anticancer activities of triterpenoids and synthetic analogs. Anticancer Agents Med Chem. 2012 Dec;12(10):1211-20. Review. PubMed PMID: 22583404; PubMed Central PMCID: PMC3532564.

Chimalakonda KC, Seely KA, Bratton SM, Brents LK, Moran CL, Endres GW, James LP, Hollenberg PF, Prather PL, Radominska-Pandya A, Moran JH. Cytochrome P450-mediated oxidative metabolism of abused synthetic cannabinoids found in K2/Spice: identification of novel cannabinoid receptor ligands. Drug Metab Dispos. 2012 Nov;40(11):2174-84. doi: 10.1124/dmd.112.047530. Epub 2012 Aug 17. PubMed PMID: 22904561; PubMed Central PMCID: PMC3477201.

Seely KA, Brents LK, Franks LN, Rajasekaran M, Zimmerman SM, Fantegrossi WE, Prather PL. AM-251 and rimonabant act as direct antagonists at mu-opioid receptors: implications for opioid/cannabinoid interaction studies. Neuropharmacology. 2012 Oct;63(5):905-15. doi: 10.1016/j.neuropharm.2012.06.046. Epub 2012 Jul 4. PubMed PMID: 22771770; PubMed Central PMCID: PMC3408547.

Liu X, Jutooru I, Lei P, Kim K, Lee SO, Brents LK, Prather PL, Safe S. Betulinic acid targets YY1 and ErbB2 through cannabinoid receptor-dependent disruption of microRNA-27a:ZBTB10 in breast cancer. Mol Cancer Ther. 2012 Jul;11(7):1421-31. doi: 10.1158/1535-7163.MCT-12-0026. Epub 2012 May 2. PubMed PMID: 22553354; PubMed Central PMCID: PMC4924623.

Seely KA, Brents LK, Radominska-Pandya A, Endres GW, Keyes GS, Moran JH, Prather PL. A major glucuronidated metabolite of JWH-018 is a neutral antagonist at CB1 receptors. Chem Res Toxicol. 2012 Apr 16;25(4):825-7. doi: 10.1021/tx3000472. Epub 2012 Mar 15. PubMed PMID: 22404317; PubMed Central PMCID: PMC3921679.

Brents LK, Gallus-Zawada A, Radominska-Pandya A, Vasiljevik T, Prisinzano TE, Fantegrossi WE, Moran JH, Prather PL. Monohydroxylated metabolites of the K2 synthetic cannabinoid JWH-073 retain intermediate to high cannabinoid 1 receptor (CB1R) affinity and exhibit neutral antagonist to partial agonist activity. Biochem Pharmacol. 2012 Apr 1;83(7):952-61. doi: 10.1016/j.bcp.2012.01.004. Epub 2012 Jan 18. PubMed PMID: 22266354; PubMed Central PMCID: PMC3288656.

Brents LK, Medina-Bolivar F, Seely KA, Nair V, Bratton SM, Nopo-Olazabal L, Patel RY, Liu H, Doerksen RJ, Prather PL, Radominska-Pandya A. Natural prenylated resveratrol analogs arachidin-1 and -3 demonstrate improved glucuronidation profiles and have affinity for cannabinoid receptors. Xenobiotica. 2012 Feb;42(2):139-56. doi: 10.3109/00498254.2011.609570. Epub 2011 Oct 4. PubMed PMID: 21970716; PubMed Central PMCID: PMC3608422.

Koryakina Y, Jones SM, Cornett LE, Seely K, Brents L, Prather PL, Kofman A, Kurten RC. Effects of the β-agonist, isoprenaline, on the down-regulation, functional responsiveness and trafficking of β2-adrenergic receptors with N-terminal polymorphisms. Cell Biol Int. 2012;36(12):1171-83. doi: 10.1042/CBI20120134. PubMed PMID: 22938397; PubMed Central PMCID: PMC4018189.

Brents LK, Reichard EE, Zimmerman SM, Moran JH, Fantegrossi WE, Prather PL. Phase I hydroxylated metabolites of the K2 synthetic cannabinoid JWH-018 retain in vitro and in vivo cannabinoid 1 receptor affinity and activity. PLoS One. 2011;6(7):e21917. doi: 10.1371/journal.pone.0021917. Epub 2011 Jul 6. PubMed PMID: 21755008; PubMed Central PMCID: PMC3130777.