Fentanyl disrupts autoregulation and leads to exacerbated vasodilation in resistance arteries independent of mu-opioid receptor activation
Authors: Townsend Jr Paul , Pernomian Laena , Moura Kawane , Waigi Emily , Wilson Emily , McCarthy Cameron , Wenceslau Camilla 
Published: May 2023

According to the CDC, 107,375 people in the United States died of drug overdoses and poisonings in the 12-month period ending in January 2022 with 67% involving synthetic opioids like fentanyl. Recent studies have implicated the use of prescription opioids as a risk factor for cardiovascular diseases (CVD), with reported associations including myocardial infarction, coronary artery disease and vascular deterioration. With small doses of fentanyl being particularly dangerous to those who have little to no tolerance, our primary hypothesis was that acute exposure to fentanyl will abolish myogenic activity and induce exacerbated vasodilation. While the mu-opioid receptor (MOR) serves as the primary target for exogenous opioids, it has been shown that the endogenous opioids like spinorphin can induce calcium flux in neutrophils via the N-formyl peptide receptor (FPR-1). With this premise, our second hypothesis was that the vasodilatory effects of fentanyl were in part contributed by inhibition of FPR1. To test these hypotheses, mesenteric resistance arteries were isolated from 12-13-week-old male C57BL/6J mice and vascular function evaluated. Myogenic tone was evaluated via a pressure-response curve (10-140 mmHg) after a 30-minute incubation with fentanyl 10-6M. Contractility was evaluated via concentration-response curves to phenylephrine (Phe) in arteries pretreated with: Fentanyl 10-6M (Fen), Naloxone 10-5M (Nal, MOR antagonist), Naloxone 10-5M+Fentanyl 10-6M (Nal+Fen), Cyclosporin H 10-5M (Cyclo, FPR-1 antagonist), or Cyclosporin H 10-5M+Fentanyl 10-6M (Cyclo+Fen). Arteries were incubated with antagonists 15 minutes prior to a 30-minute fentanyl incubation. Control (Cont) levels were established prior to any incubations. Pressure data were analyzed using student t test and contractility data using one way anova (p<0.05* vs Cont). Fen abolished myogenic tone in arteries when compared to Cont at 40 mmHg (Cont 7.8±2.2 vs Fen 1.5±1.5*, %, n=3). Further, Fen significantly decreased contraction when compared to Cont [Area under the curve (AUC): Cont 54±5 vs. Fen 15±3 n=4*]. However, the presence of the antagonists for FPR-1 [AUC: Fen 15±3 vs. Cyclo+Fen 12 ±2, n=4, p>0.05) or mu-opioid receptor (AUC: Fen 15±3, vs. Nal+Fen 13±2, n=4, p>0.05) did not change these responses. The presence of the antagonists alone decreased contraction. This suggests a constitutive effect of FPR-1 or mu-opioid receptor on Phe-induced contractility (AUC: Cont 54±5 vs. Nal 32±10* vs. Cyclo 17±2*). Overall, our data suggest that acute treatments of Fentanyl lead to a significant disruption of autoregulation and exacerbated vasodilation in resistance arteries independent of mu and FPR-1 receptors. Therefore, chronic exposure to this opioid may lead to dysfunction and loss of myogenic tone and, subsequently, CVD. R00GM118885, R01HL149762, R00HL151889, and NHLBI (R00HL151889) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.