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. 2025 Nov 1.
doi: 10.1007/s00213-025-06945-1. Online ahead of print.

Effects of TPA023B, an α2/3/5GABAA subtype-selective partial allosteric modulator, on fentanyl-induced respiratory depression in male rats: comparison with the non-selective benzodiazepine midazolam

Loc M Pham  1 , Andria B Nanney  1 , Jordan Hasting  1 , Daniela Rüedi-Bettschen  1 , Kevin B Freeman  1 , James K Rowlett  2
Affiliations

Effects of TPA023B, an α2/3/5GABAA subtype-selective partial allosteric modulator, on fentanyl-induced respiratory depression in male rats: comparison with the non-selective benzodiazepine midazolam

Loc M Pham et al. Psychopharmacology (Berl). .

Abstract

Rationale: Opioid-related overdose deaths involving benzodiazepines have increased in recent years, and prior studies have reported that clinically used benzodiazepines can enhance the respiratory-depressant effects of mu opioid receptor (MOR) agonists. TPA023B is an α1-sparing GABAA positive allosteric modulator developed as a potential anxiolytic with fewer benzodiazepine-typical side effects. However, it is unknown if and to what degree TPA023B can affect MOR-agonist induced respiratory depression.

Objectives: The current study compared the effects of either TPA023B or midazolam, alone and combined with fentanyl, on respiratory depression in rats, using whole-body plethysmography.

Methods: Male Sprague-Dawley rats were implanted with chronic indwelling intravenous (i.v.) catheters for drug infusions. Respiration (frequency, tidal volume, and minute volume) was measured using whole-body plethysmography. The tests consisted of a pretreatment (midazolam, 30 mg/kg; i.v.; TPA023B, 1.0 mg/kg; i.v; or vehicle) followed by a fentanyl injection (0.01, 0.03, 0.1 mg/kg, i.v., or vehicle) and 60 min of respiration assessment.

Results: Overall, fentanyl alone, but not TPA023B or midazolam alone, produced dose-dependent reductions in tidal volume and minute volume. When administered as pre-treatments, neither midazolam nor TPA023B increased the magnitude of fentanyl-induced respiratory depression, instead producing prolonged reductions in tidal volume and minute volume. Midazolam produced a more sustained reduction in these parameters than TPA023B.

Conclusions: Benzodiazepines prolong fentanyl-induced respiratory depression, but this effect may be reduced by eliminating activity at α1GABAA receptor subtypes.

Keywords: Fentanyl; Midazolam; Respiratory depression; TPA023B; Whole-body plethysmography.

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Conflict of interest statement

Declarations. Competing interests: Dr. Rowlett is the director of Impatia Therapeutics, LLC, and is holder of US Patent Application No. 12,233,070 B2 (Feb 25, 2025) for certain uses of TPA023B. The other authors have no conflicts of interest to disclose. Ethical approval: All procedures followed the National Research Council’s Guide for Care and Use of Laboratory Animals (2011), and all procedures were approved by the University of Mississippi Medical Center’s Institutional Animal Care and Use Committee. All animal facilities were fully accredited by AAALAC International. Consent to participate: Not applicable. Consent to publish: Not applicable.

References

    1. Afzal A, Kiyatkin EA (2019) Interactions of benzodiazepines with heroin: respiratory depression, temperature effects, and behavior. Neuropharmacology 158:107677 - DOI - PubMed - PMC
    1. Atack JR, Hallett DJ, Tye S, Wafford KA, Ryan C, Sanabria-Bohórquez SM, Eng WS, Gibson RE, Burns HD, Dawson GR, Carling RW, Street LJ, Pike A, De Lepeleire I, Van Laere K, Bormans G, de Hoon JN, Van Hecken A, McKernan RM, Murphy MG, Hargreaves RJ (2010) Preclinical and clinical pharmacology of TPA023B, a GABAA receptor α2/α3 subtype-selective partial agonist. J Psychopharmacol 25:329–344 - DOI - PubMed
    1. Bailey PL, Pace NL, Ashburn MA, Moll JW, East KA, Stanley TH (1990) Frequent hypoxemia and apnea after sedation with Midazolam and Fentanyl. Anesthesiology 73:826–830 - DOI - PubMed
    1. Berro LF, Zamarripa CA, Rowlett JK (2022) Self-administration of fentanyl-alprazolam combinations by rhesus monkeys responding under a progressive-ratio schedule. J Pharmacol Exp Ther 383:199–207 - DOI - PubMed - PMC
    1. Bird HE, Huhn AS, Dunn KE (2023) Fentanyl absorption, distribution, metabolism, and excretion: narrative review and clinical significance related to illicitly manufactured fentanyl. J Addict Med 17:503–508 - DOI - PubMed - PMC

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