Developmental Programming of Cardiovascular Disease due to Prenatal Fentanyl Exposure

About This Grant

PROJECT SUMMARY U.S. statistics from 2022 showed an alarming increase in opioid use disorder diagnoses during pregnancy in a 5-year period, resulting in an 87% surge in cases of neonatal opioid withdrawal syndrome (NOWS), characterized by the acute overactivation of the sympathetic tone. Opioid misuse and abuse are linked to increased mental and physical comorbidities such as cardiovascular disease (CVD) risk, resulting from major hemodynamic, vascular, and autonomic derangements. Yet, the lack of follow-up studies in individuals with prenatal fentanyl exposure (PFE) hinders the fine-tuning of therapeutic approaches and the prevention of adverse health outcomes in this vulnerable population. We developed a rat model of PFE during preconception until mid-pregnancy by training dams to self-administer fentanyl, a potent mu opioid receptor (µ-OR) agonist. Our preliminary data show that neonates with PFE undergo somatic signs of withdrawal, while later in life display sympathetic activation, hypertension, and exacerbated pressor response to acute stress. We found that PFE exacerbates the density of noradrenergic neurons of the locus coeruleus (LC), the primary site for brain norepinephrine (NE) synthesis and release. In further studies, we determined that adult offspring with PFE show neuronal activation (cFos+cells) in the posterior paraventricular nucleus of the hypothalamus (PVN), a key region regulating blood pressure by modulating sympathoexcitatory, preautonomic neurons, and a major site for LC projections. Notably, we found that a chronic naltrexone treatment, a non-selective opioid antagonist with a high affinity for µ-OR, reduced blood pressure in adult offspring with PFE but not in normotensive counterparts. Buprenorphine is a weak partial µ-OR agonist that reduces maternal opioid craving and neonatal withdrawal syndrome. More recently, the α2 adrenoceptor (α2-AR) agonist lofexidine has been approved as the first non-opioid treatment for OUD in adults, administered alone or as a co-adjuvant. Using our model of PFE, we treated neonates with saline, buprenorphine, or buprenorphine+lofexidine during the first week of life. Our data shows that only the combined pharmacotherapy was effective in reducing somatic signs of withdrawal and abolishing the development of hypertension. This proposal will investigate 1) whether the hypothesis that PFE exacerbates blood pressure by increasing LC excitatory inputs to PVN, thereby mediating the µ-OR- dependent activation of pre-autonomic neurons in PVN, and 2) whether neonatal withdrawal programs sympathetic activation by increasing LC-NE synthesis and release in adult offspring with PFE.