Lisa K. Brents, Ph.D.
Ph.D. – University of Arkansas for Medical Sciences, 2013
Neonatal abstinence syndrome (NAS) often occurs in newborns with chronic prenatal exposure to substances that induce physical dependence, such as opioids like heroin, oxycodone, and fentanyl. Newborns with opioid-induced NAS often exhibit inconsolable high-pitched crying, tremor, vomiting, diarrhea, hypersensitivity, and sleep disturbances. Like opioid abuse, NAS has increased almost 5-fold in the US since 2000, and the aggregate costs of treating NAS in the US are now approximately $1.5 billion.
The overall goal of my work is to develop interventions to prevent and diminish NAS. My work is focused on understanding why some newborns develop NAS while others with similar maternal opioid use do not. More specifically, I am investigating the involvement of norbuprenorphine (NorBUP) in the development of opioid dependence in babies born to buprenorphine (BUP)-treated mothers. NorBUP is a major active metabolite of BUP, which is a partial agonist at the mu opioid receptor that is often used in medication assisted treatment of opioid use disorder. NorBUP exhibits much greater efficacy at the opioid receptors than BUP, suggesting that prolonged in utero exposure to NorBUP could induce physical dependence in the fetus and lead to NAS in the newborn. Differences in maternal-fetal BUP pharmacokinetics across the patient population may lead to large inter-patient variance in fetal exposure levels to NorBUP, which may promote the observed BUP dose-independent individual differences in NAS development. Therefore, I am investigating NorBUP as a major driver of NAS in BUP-exposed neonates. I am collaborating with a cross-disciplinary team of preclinical and clinical investigators that includes Drs. Bill Fantegrossi, Mike Owens, and Jeff Moran of the UAMS Department of Pharmacology and Toxicology and Dr. Zachary Stowe of the UAMS Women’s Mental Health Program in the Department of Psychiatry. Future directions of our research include early identification of patient dyads that are most susceptible to NAS and the development of new therapeutics that minimize fetal exposure to opioids.
Recent Research Support
UAMS Fellow-to-Faculty Award (07/01/16 – 06/30/18)
“Maternofetal buprenorphine pharmacokinetics in the development of neonatal abstinence syndrome (NAS)”
732 DA022981 NIH/NIDA (01/13/13 – 01/13/16)
“Translational Training in Addiction”
Brents LK, Zimmerman SM, Saffell AR, Fantegrossi WE, Prather PL, Differential Drug-Drug Interactions of the Synthetic Cannabinoids JWH-018 and JWH-073: Implications for Drug Abuse Liability and Pain Therapy. Journal of Pharmacology and Experimental Therapeutics. 346(3): 350-61, 2013 (PMID: 23801678).
Rajasekaran M, Brents LK, Franks LN, Moran JH, Prather PL, Human metabolites of synthetic cannabinoids JWH-018 and JWH-073 in K2/Spice Retain CB2 affinity and exhibit properties predicted to enhance receptor signaling. Toxicology and Applied Pharmacology. 269(2): 100-8, 2013 (PMID: 23537664).
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 Metabolism and Disposition. 40(11):2174-84, 2012 (PMID: 22904561).
Seely KA, Brents LK, Franks LN, Rajasekaran M, Zimmerman SM, Fantegrossi WE, Prather PL, AM-251 Exhibits Direct Antagonist/Inverse Agonist Activity at Mu-Opioid Receptors: Implications for Opioid/Cannabinoid Interaction Studies. Neuropharmacology. 63(5): 905-15, 2012 (PMID: 22771770).
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. Chemical Research in Toxicology. 25(4): 825-7, 2012 (PMID: 22404317).
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. Biochemical Pharmacology. 83(7):952-61, 2012 (PMID: 22266354).
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. 6(7): e21917, 2011 (PMID: 21755008).