Tropine exacerbates the ventilatory depressant actions of fentanyl in freely-moving rats.

Autor: Getsy PM; Department of Pediatrics, Case Western Reserve University, Cleveland, OH, United States., May WJ; Department of Pediatrics, University of Virginia, Charlottesville, VA, United States., Young AP; Department of Pediatrics, University of Virginia, Charlottesville, VA, United States., Baby SM; Galleon Pharmaceuticals, Inc., Horsham, PA, United States., Coffee GA; Department of Pediatrics, Case Western Reserve University, Cleveland, OH, United States., Bates JN; Department of Anesthesiology, University of Iowa Hospitals and Clinics Iowa, Iowa City, IA, United States., Hsieh YH; Division of Pulmonary, Critical Care and Sleep Medicine, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH, United States., Lewis SJ; Department of Pediatrics, Case Western Reserve University, Cleveland, OH, United States.; Department of Pharmacology, Case Western Reserve University, Cleveland, OH, United States.; Functional Electrical Stimulation Center, Case Western Reserve University, Cleveland, OH, United States.
Jazyk: angličtina
Zdroj: Frontiers in pharmacology [Front Pharmacol] 2024 Jun 24; Vol. 15, pp. 1405461. Date of Electronic Publication: 2024 Jun 24 (Print Publication: 2024).
DOI: 10.3389/fphar.2024.1405461
Abstrakt: Our lab is investigating the efficacy profiles of tropine analogs against opioid-induced respiratory depression. The companion manuscript reports that the cell-permeant tropeine, tropine ester (Ibutropin), produces a rapid and sustained reversal of the deleterious actions of fentanyl on breathing, alveolar-arterial (A-a) gradient (i.e., index of alveolar gas exchange), and arterial blood-gas (ABG) chemistry in freely-moving male Sprague Dawley rats, while not compromising fentanyl analgesia. We report here that in contrast to Ibutropin, the injection of the parent molecule, tropine (200 μmol/kg, IV), worsens the adverse actions of fentanyl (75 μg/kg, IV) on ventilatory parameters (e.g., frequency of breathing, tidal volume, minute ventilation, peak inspiratory and expiratory flows, and inspiratory and expiratory drives), A-a gradient, ABG chemistry (e.g., pH, pCO 2 , pO 2 , and sO 2 ), and sedation (i.e., the righting reflex), while not affecting fentanyl antinociception (i.e., the tail-flick latency) in freely-moving male Sprague Dawley rats. These data suggest that tropine augments opioid receptor-induced signaling events that mediate the actions of fentanyl on breathing and alveolar gas exchange. The opposite effects of Ibutropin and tropine may result from the ability of Ibutropin to readily enter peripheral and central cells. Of direct relevance is that tropine, resulting from the hydrolysis of Ibutropin, would combat the Ibutropin-induced reversal of the adverse effects of fentanyl. Because numerous drug classes, such as cocaine, atropine, and neuromuscular blocking drugs contain a tropine moiety, it is possible that their hydrolysis to tropine has unexpected/unintended consequences. Indeed, others have found that tropine exerts the same behavioral profile as cocaine upon central administration. Together, these data add valuable information about the pharmacological properties of tropine.
Competing Interests: Author SB was employed by Galleon Pharmaceuticals, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers at the time of submission. This had no impact on the peer review process and the final decision.
(Copyright © 2024 Getsy, May, Young, Baby, Coffee, Bates, Hsieh and Lewis.)
Databáze: MEDLINE
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