The ventilatory depressant actions but not the antinociceptive effects of morphine are blunted in rats receiving intravenous infusion of L-cysteine ethyl ester

Lewis, Thomas A.; May, Walter J.; Young, Alex P.; Bates, James N.; Baby, Santhosh M.; Getsy, Paulina M.; Ryan, Richard M.; Hsieh, Yee‐Hsee; Seckler, James M.; Lewis, Stephen J.

doi:10.1016/j.biopha.2022.113939

Cited by 7 publications

(17 citation statements)

References 81 publications

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“…Of the eight calculated parameters, we measured, we chose the following to be presented here: minute ventilation, tidal volume, inspiratory time, peak inspiratory flow and apneic pause (calculated as: (expiratory time/relaxation time) -1). These parameters are those that give a fuller understanding of the effects of the opioids on ventilatory timing and mechanics (Getsy, Baby, Gruber, Gaston, et al, 2022;Getsy, Baby, May, Young, et al, 2022;Getsy, Young, Grossfield, Seckler, et al, 2022;Lewis et al, 2022;Seckler et al, 2022). Minute ventilation provides a general assessment of how opioids affect the total volume of air breathed per minute and is the multiplicative index of frequency of breathing and tidal volume.…”

Section: Plethysmography Apparatusmentioning

confidence: 99%

“…Minute ventilation provides a general assessment of how opioids affect the total volume of air breathed per minute and is the multiplicative index of frequency of breathing and tidal volume. To further the analyses, we also determined (1) inspiratory time to characterize the effects of the opioids on ventilatory timing patterns, (2) tidal volume to better understand the potential consequences to arterial blood-gas chemistry (pH, pCO 2 , pO 2 , sO 2 ) since tidal volume is a definitive index of the volume of air reaching alveoli, (3) peak inspiratory flow to provide direct information as to the ability of the opioids to compromise the efficacy of inspiration, and (4) apneic pause as it represents the central delay in transitioning from inspiration to expiration, a hall-mark of opioid-induced respiratory depression (Getsy, Baby, Gruber, Gaston, et al, 2022;Getsy, Young, Grossfield, Seckler, et al, 2022;Lewis et al, 2022;Seckler et al, 2022).…”

Section: Plethysmography Apparatusmentioning

confidence: 99%

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Heroin- and Fentanyl-Induced Respiratory Depression in a Rat Plethysmography Model: Potency, Tolerance, and Sex Differences

Marchette¹,

Carlson²,

Frye³

et al. 2023

J Pharmacol Exp Ther

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The opioid overdose death toll in the United States is an ongoing public health crisis. We characterized the magnitude and duration of respiratory depression, the leading cause of death in opioid overdose cases, induced by heroin or fentanyl and the development of tolerance in male and female rats. We used whole-body plethysmography to first establish dose-response curves by recording breathing for 60 min post-intravenous opioid injection. We then tested the development of respiratory tolerance to acute heroin or fentanyl over several weeks and to chronic fentanyl with acute fentanyl or heroin challenge. Heroin and fentanyl each provoked dose-dependent respiratory depression. Heroin caused prolonged (45-60 min) respiratory depression in female and male rats, characterized by decreased frequency, tidal volume, and minute ventilation, and increased inspiratory time and apneic pause. Fentanyl produced similar changes with a shorter duration (10-15 min). High-dose heroin or fentanyl produced robust respiratory depression that was slightly more severe in females and, when given intermittently (acute doses 2-3 weeks apart), did not lead to tolerance. In contrast, chronic fentanyl delivered with an osmotic minipump resulted in tolerance to acute fentanyl and heroin, characterized by a shorter duration of respiratory depression. This effect persisted during withdrawal in males only. Our model and experimental design will allow for investigation of the neurobiology of opioid-induced respiratory depression and for testing potential therapeutics to reverse respiratory depression or stimulate breathing.

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Section: Plethysmography Apparatusmentioning

confidence: 99%

Section: Plethysmography Apparatusmentioning

confidence: 99%

Heroin- and Fentanyl-Induced Respiratory Depression in a Rat Plethysmography Model: Potency, Tolerance, and Sex Differences

Marchette¹,

Carlson²,

Frye³

et al. 2023

J Pharmacol Exp Ther

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“…The changes in Freq and TV resulted in a prompt increase in MV of approximately 25–30 min in duration. Note that the minor degree of variability in baseline (pre-fentanyl) levels of Freq and TV that resulted in a consistent level of MV is to be expected when recording values from freely-moving rats ( Henderson et al, 2013 ; 2014 ; Gaston et al, 2020; Getsy et al, 2014 ; Gaston et al, 2021 ; Jenkins et al, 2021 ; Getsy et al, 2022a ; Getsy et al, 2022b ; Getsy et al, 2022c ; Getsy et al, 2022d ; Getsy et al, 2022e ; Lewis et al, 2022 ; Seckler et al, 2022 ).…”

Section: Resultsmentioning

confidence: 91%

“…The question arises as to whether this arousal is directly linked to the observed ventilatory responses that will be addressed below. The two processes may not be linked since the injection of the 2.5 mg/kg dose of NLXmi caused pronounced ventilatory responses in fentanyl-treated rats, whereas these ventilatory responses were not associated with increases in either NEBI or NEBI/Freq, which are hallmarks of ventilatory instability ( Getsy et al, 2014 ; Gaston et al, 2021 ; Getsy et al, 2022c ; Getsy et al, 2022d ; Getsy et al, 2022e ; Lewis et al, 2022 ). More specifically, it appeared that the 2.5 mg/kg dose of NLXmi merely restored the behavioral status of the fentanyl-treated rats but caused unexpectedly dramatic changes in ventilation, which suggests the existence of an inhibitory opioid receptor system in ventilatory control pathways.…”

Section: Discussionmentioning

confidence: 99%

“…The administration of fentanyl caused the rats to assume numerous types of postures, including being motionless, sprawled out on their stomach on the chamber floor, lying motionless on their side, and splayed out on their stomach with the head up against the chamber wall. The duration of the fentanyl sedation was taken as the time to full recovery of the righting reflex (i.e., when rats attained and maintained a normal posture on all four legs) following the injections of vehicle or NLXmi ( Gaston et al, 2021 ; Getsy et al, 2022c ; Getsy et al, 2022d ; Getsy et al, 2022e ; Lewis et al, 2022 ). Male rats: one group (304 ± 2 g in body weight, n = 9) received an injection of fentanyl (75 μg/kg, IV), followed by an injection of vehicle (saline) after 15 min.…”

Section: Methodsmentioning

confidence: 99%

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Fentanyl activates opposing opioid and non-opioid receptor systems that control breathing

Baby,

May,

Getsy

et al. 2024

Front. Pharmacol.

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Fentanyl elicits profound disturbances in ventilatory control processes in humans and experimental animals. The traditional viewpoint with respect to fentanyl-induced respiratory depression is that once the effects on the frequency of breathing (Freq), tidal volume (TV), and minute ventilation (MV = Freq × TV) are resolved, then depression of breathing is no longer a concern. The results of the present study challenge this concept with findings, as they reveal that while the apparent inhibitory effects of fentanyl (75 μg/kg, IV) on Freq, TV, and MV in adult male rats were fully resolved within 15 min, many other fentanyl-induced responses were in full effect, including opposing effects on respiratory timing parameters. For example, although the effects on Freq were resolved at 15 min, inspiratory duration (Ti) and end inspiratory pause (EIP) were elevated, whereas expiratory duration (Te) and end expiratory pause (EEP) were diminished. Since the effects of fentanyl on TV had subsided fully at 15 min, it would be expected that the administration of an opioid receptor (OR) antagonist would have minimal effects if the effects of fentanyl on this and other parameters had resolved. We now report that the intravenous injection of a 1.0 mg/kg dose of the peripherally restricted OR antagonist, methyl-naloxone (naloxone methiodide, NLXmi), did not elicit arousal but elicited some relatively minor changes in Freq, TV, MV, Te, and EEP but pronounced changes in Ti and EIP. In contrast, the injection of a 2.5 mg/kg dose of NLXmi elicited pronounced arousal and dramatic changes in many variables, including Freq, TV, and MV, which were not associated with increases in non-apneic breathing events such as apneas. The two compelling conclusions from this study are as follows: 1) the blockade of central ORs produced by the 2.5 mg/kg dose of NLXmi elicits pronounced increases in Freq, TV, and MV in rats in which the effects of fentanyl had apparently resolved, and 2) it is apparent that fentanyl had induced the activation of two systems with counter-balancing effects on Freq and TV: one being an opioid receptor inhibitory system and the other being a non-OR excitatory system.

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L-cysteine ethylester reverses the adverse effects of morphine on breathing and arterial blood-gas chemistry while minimally affecting antinociception in unanesthetized rats

Baby,

May,

Young

et al. 2024

Biomedicine & Pharmacotherapy

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The ventilatory depressant actions but not the antinociceptive effects of morphine are blunted in rats receiving intravenous infusion of L-cysteine ethyl ester

Cited by 7 publications

References 81 publications

Heroin- and Fentanyl-Induced Respiratory Depression in a Rat Plethysmography Model: Potency, Tolerance, and Sex Differences

Heroin- and Fentanyl-Induced Respiratory Depression in a Rat Plethysmography Model: Potency, Tolerance, and Sex Differences

Fentanyl activates opposing opioid and non-opioid receptor systems that control breathing

L-cysteine ethylester reverses the adverse effects of morphine on breathing and arterial blood-gas chemistry while minimally affecting antinociception in unanesthetized rats

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