With a three-year K23 grant from the NIH National Institute on Drug Abuse entitled "Sex-specific impact of prenatal opioids on brain reward signaling and neonatal feeding regulation," MIRI Principal Investigator and neonatologist, Dr. Elizabeth Yen continues her research on understanding how prenatal opioid exposure affects infant feeding, childhood growth and metabolic risk factors in a sex-specific manner.
Dr. Yen's research has assumed increased significance and urgency during the opioid epidemic: the number of babies born with prenatal opioid exposure suffering from the withdrawal signs called Neonatal Abstinence Syndrome (NAS), or Neonatal Opioid Withdrawal Syndrome (NOWS) has increased more than five-fold over the past 10 years.
New study expands on preliminary findings
With the overall goal of understanding changes in reward and inflammatory gene expression during the first year of life in infants with prenatal opioid exposure, the NIH-funded study will expand on Dr. Yen's initial findings in her pilot study. In the pilot, she demonstrated that opioid-exposed infants had greater expression of a key dopamine/reward gene (DRD2) that correlated significantly with dysregulated, or abnormal, feeding habits, such as difficulty feeding and hyperphagia (excessive eating) and greater caloric intake, even more so in males than females.
Another pilot study finding that will be examined in the newly funded grant was a higher expression of inflammatory genes, particularly in female subjects. Inflammation plays an important role in opioid addiction. "Opioid binding to specific opioid receptors in the brain is the classical pathway that induces opioid reward signaling," Dr. Yen explained. "However, emerging animal data demonstrate that activating an alternative pathway triggers inflammatory cascades that enhance the impact of opioids on brain reward circuitry and precipitate its drug reinforcement properties. In other words, opioids may lead to inflammation, further enhancing opioid potency."
Research focus + study design of the K23 study
The K23-funded study will test the hypothesis that prenatal opioids dysregulate brain reward signaling and upregulate pro-inflammatory pathways with increased sex-specific risks for hyperphagia and associated long-term metabolic disorders. Saliva will be analyzed to evaluate the expression of reward and inflammation genes in 56 pairs of opioid-exposed and non-exposed newborns matched for sex and age. Serial saliva analysis will also be performed post-hospital discharge up to one year of age. Early metabolic risk will be assessed using serum lipid panels at one year of age, along with growth and nutritional data. Results will be analyzed by sex.
Possible ramifications of reward signaling dysregulation in opioid-exposed infants
Based on the finding that prenatal opioid exposure may heighten brain reward signaling that dysregulates feeding behavior, Dr. Yen speculates that these infants may be predisposed to future reward-seeking behaviors later in life. The imbalance in the feeding center that controls hunger and reward signaling, or an overabundance of signals that drive the urge to seek pleasurable or rewarding experiences, may initially predispose these infants to hyperphagia and metabolic challenges. But over time, they may seek drugs or engage in other addictive behaviors. In other words, prenatal opioid exposure may propagate a vicious addiction cycle through the reprogrammed brain reward signaling.
Future collaborations
Dr. Yen looks forward to collaborating with other scientists. "Through this novel research supported by adult and animal data, I strive to inspire and join forces with others to ensure that more research is done to understand the impact of prenatal opioid exposure on the developing brain and to break the vicious addiction cycle," she said. "Knowing that prenatal opioid exposure may heighten the expression of a key dopamine/reward gene and if this gene indeed leads to future opioid use disorder, we could alter the pathway of this gene and its downstream regulation to halt the vicious addiction cycle. Similarly, studying the inflammatory roles of prenatal opioid exposure may provide novel interventions, such as anti-inflammatory agents, to manage infants with NAS. Although for ethical considerations this would never be possible in research involving babies, it could be tried in animal models."
A strategic opportunity
Intrigued as she is by the science, Dr. Yen's fundamental calling is as a physician. "As a neonatologist caring for ill infants, my goal is to be a steward and gatekeeper who ensures not only a healthy beginning but a life course primed for optimal long-term health outcomes," she said. "The short hospital encounter with these babies and their families provides me a strategic opportunity to engage in a lifelong dialogue that will advance the science and health outcomes for this vulnerable population."
