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Rationale <p>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 GABA<sub>A</sub> 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.</p> Objectives <p>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.</p> Methods <p>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&#xa0;mg/kg; i.v.; TPA023B, 1.0&#xa0;mg/kg; i.v; or vehicle) followed by a fentanyl injection (0.01, 0.03, 0.1&#xa0;mg/kg, i.v., or vehicle) and 60&#xa0;min of respiration assessment.</p> Results <p>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.</p> Conclusions <p>Benzodiazepines prolong fentanyl-induced respiratory depression, but this effect may be reduced by eliminating activity at α1GABA<sub>A</sub> receptor subtypes.</p>

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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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月1日

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  • Loc M. Pham,
  • Andria B. Nanney,
  • Jordan Hasting,
  • Daniela Rüedi-Bettschen,
  • Kevin B. Freeman,
  • James K. Rowlett

摘要

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.