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

Paulina M Getsy; Walter J May; Alex P Young; Santhosh M Baby; Gregory A Coffee; James N Bates; Yee-Hsee Hsieh; Stephen J Lewis

doi:10.3389/fphar.2024.1405461

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

Front Pharmacol. 2024 Jun 24:15:1405461. doi: 10.3389/fphar.2024.1405461. eCollection 2024.

Authors

Paulina M Getsy¹, Walter J May², Alex P Young², Santhosh M Baby³, Gregory A Coffee¹, James N Bates⁴, Yee-Hsee Hsieh⁵, Stephen J Lewis^{1

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Affiliations

¹ Department of Pediatrics, Case Western Reserve University, Cleveland, OH, United States.
² Department of Pediatrics, University of Virginia, Charlottesville, VA, United States.
³ Galleon Pharmaceuticals, Inc., Horsham, PA, United States.
⁴ Department of Anesthesiology, University of Iowa Hospitals and Clinics Iowa, Iowa City, IA, United States.
⁵ Division of Pulmonary, Critical Care and Sleep Medicine, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH, United States.
⁶ Department of Pharmacology, Case Western Reserve University, Cleveland, OH, United States.
⁷ Functional Electrical Stimulation Center, Case Western Reserve University, Cleveland, OH, United States.

Abstract

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, pCO₂, pO₂, and sO₂), 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.

Keywords: analgesia; arterial blood-gas chemistry; fentanyl; male Sprague Dawley rats; tropine; ventilatory depression.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. These studies were supported in part by grants from Galleon Pharmaceuticals, Inc. (to SL) and from NIH/NIDA U01DA051373 (to SL). The authors declare that this study received funding from Galleon Pharmaceuticals, Inc. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.