Sophia Jalilvand

Program: Neurosciences

Current advisor: Jose A. Moron-Concepcion, PhD

Undergraduate university: University of Texas-Dallas, 2023

Enrollment year: 2023

Research summary
Peripherally acting μ-opioid receptor antagonists and naloxone may differentially modulate opioid seeking following a simulated overdose in fentanyl self-administering rats

Drug overdose is the leading cause of injury mortality in the United States, with most fatalities resulting from opioid-induced respiratory depression (OIRD) primarily driven by the synthetic opioid fentanyl. Naloxone (NLX) is the most widely used antidote to reverse opioid overdoses through its fast-acting, broad μ-opioid receptor (MOR) antagonism, significantly reducing overdose mortality. However, NLX also precipitates severe acute withdrawal that frequently drives immediate return-to-use, which highlights the need for alternative pharmacological strategies that reverse OIRD without precipitating withdrawal. Our lab recently demonstrated that selective antagonism of peripherally located MOR reverses respiratory depression induced by non-contingent intravenous fentanyl administration without producing aversive behavior in rats, suggesting that peripherally acting μ-opioid receptor antagonists (PAMORAs) may represent a novel overdose rescue strategy.

While these findings establish the feasibility of implementing PAMORAs for OIRD reversal, the behavioral consequences of PAMORA-mediated rescue in voluntary opioid users remain unknown. To address this gap, we developed a modified fentanyl intravenous self-administration (IVSA) paradigm in which overdose and reversal are modeled as a consequence of the animal’s own behavior. After three weeks of fixed ratio 1 (FR1) training during which each active lever press delivers a fentanyl infusion (5 μg/kg), rats undergo a simulated overdose session in which the first active lever press yields a single intravenous fentanyl bolus (100 μg/kg) followed five minutes later by NLX, a PAMORA, or saline control. After four additional FR1 sessions, motivation for fentanyl is assessed with a progressive ratio (PR) session. By uniquely enabling rats to self-initiate both daily fentanyl intake and an overdose-like event, the reversal experience can be linked to addiction-relevant behavioral outcomes.

Our preliminary data suggests that fentanyl self-administering rats which underwent a simulated overdose reversed with the FDA-approved PAMORA Naloxegol exhibited reduced drug-seeking behavior compared to NLX-treated rats, as evidenced by fewer active lever presses immediately following reversal, lower intake across post-overdose FR1 sessions, and lower PR breakpoint. These early findings support the novel paradigm and suggest that PAMORAs may attenuate relapse-relevant behavior following opioid overdose. Ultimately, this work may inform the design of early-phase clinical trials aimed at testing behavioral tolerability and relapse outcomes following PAMORA-mediated opioid overdose reversal in humans.

Graduate publications