L-NAC reverses of the adverse effects of fentanyl infusion on ventilation and blood-gas chemistry

Getsy, Paulina M.; Baby, Santhosh M.; May, Walter J.; Lewis, Thomas A.; Bates, James N.; Hsieh, Yee‐Hsee; Gaston, Benjamin; Lewis, Stephen J.

doi:10.1016/j.biopha.2022.113277

Cited by 13 publications

(25 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…With an average time of death of 44.9 ± 7.4 min post‐exposure to fentanyl, these trends indicate vital determinants for survival. Our plethysmography data generally agree with previous reports in rodents, showing decreases in tidal volume, bpm, minute volume and inspiratory quotient within 10 min of fentanyl administrations 34,53,61,62 . However, while previous rodent studies have shown dose–response relationships via plethysmography at low doses, 34,63 we did not observe dose–response effects across the overdose range used in this study.…”

Section: Discussionsupporting

confidence: 92%

“…Our plethysmography data generally agree with previous reports in rodents, showing decreases in tidal volume, bpm, minute volume and inspiratory quotient within 10 min of fentanyl administrations. 34,53,61,62 However, while previous rodent studies have shown dose-response relationships via plethysmography at low doses, 34,63 we did not observe dose-response effects across the overdose range used in this study. This unique plateau effect of fentanyl overdose on breathing implies saturation of underlying μ receptormediated central respiratory depression and secondary effects determining survival.…”

Section: Discussioncontrasting

confidence: 76%

See 1 more Smart Citation

Fentanyl overdose: Temporal effects and prognostic factors in SKH1 mice

Newman,

Lynch,

Connery

et al. 2024

Basic Clin Pharma Tox

View full text Add to dashboard Cite

Fentanyl exposure and overdose are growing concerns in public health and occupational safety. This study aimed to establish parameters of fentanyl lethality in SKH1 mice for future overdose research. Lethality was determined using the up‐down procedure, with subjects monitored post‐administration using pulse oximetry (5 min) and then whole‐body plethysmography (40 min). Following the determination of subcutaneous dose–response, [18F]Fluorodeoxyglucose positron emission tomography (18F‐FDG PET) was performed after LD10 fentanyl at 40 min, 6 h, 24 h or 7 days post‐dose. LD10 and LD50 were observed to be 110 and 135 mg/kg, respectively, and consistent with four‐parameter logistic fit values of 111.2 and 134.6 mg/kg (r2 = 0.9996). Overdose (LD10 or greater) yielded three distinct cardiovascular groups: survival, non‐survival with blood oxygen saturation (SpO2) minimum ≥37% and non‐survival with SpO2 <37%. Breaths per minute, minute volume and inspiratory quotient were significantly different between surviving and non‐surviving animals for up to 40 min post‐injection. 18F‐FDG PET revealed decreased glucose uptake in the heart, lungs and brain for up to 24 h. These findings provide critical insights into fentanyl lethality in SKH1 mice, including non‐invasive respiratory effects and organ‐specific impacts that are invaluable for future translational studies investigating the temporal effects of fentanyl overdose.

show abstract

Section: Discussionsupporting

confidence: 92%

Section: Discussioncontrasting

confidence: 76%

Fentanyl overdose: Temporal effects and prognostic factors in SKH1 mice

Newman,

Lynch,

Connery

et al. 2024

Basic Clin Pharma Tox

View full text Add to dashboard Cite

show abstract

“…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%

“…Ventilatory parameters were recorded continuously in the unrestrained, freely-moving rats using a whole-body plethysmography system (PLY3223; Data Sciences International , St. Paul, MN), as detailed previously ( Jenkins et al, 2021 ; Getsy et al, 2022a ; Getsy et al, 2022b ; Seckler et al, 2022 ; Seckler et al, 2023 ). The directly recorded and derived parameters are defined in Supplemental Table S1 .…”

Section: Methodsmentioning

confidence: 99%

“…The high-potency μ-opioid receptor agonist, fentanyl, is an important clinical analgesic that has adverse side effects, including ventilatory depression and the development of hyperalgesia (enhanced pain perception) upon repeated administration ( Scholz et al, 1996 ; Suzuki and El-Haddad, 2017 ; Armenian et al, 2018 ; Tyler and Guarnieri, 2023 ). In addition, although the systemic injection of fentanyl causes profound analgesia in rats, it also exerts adverse effects on ventilatory parameters, the alveolar–arterial (A-a) gradient (index of alveolar gas exchange), and arterial blood–gas chemistry ( Henderson et al, 2014 ; Baby et al, 2021 ; Jenkins et al, 2021 ; Getsy et al, 2022a ; Getsy et al, 2022b ; Seckler et al, 2022 ; Marchette et al, 2023 ). The roles of μ-, δ-, and κ-opioid receptors ( Trescott et al, 2008 ; Valentino and Volkow, 2018 ), cell-signaling/molecular mechanisms ( Al-Hasani and Bruchas, 2011 ; Shang and Filizola, 2015 ), and multiple sites of action of opioids ( May et al, 1989 ; Lalley, 2003 ; Vadivelu et al, 2011 ; Henderson et al, 2013 ; 2014 ; Baby et al, 2018 ; Birdsong and Williams, 2020 ; Rossi and Bodnar, 2021 ) have been extensively studied.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Baby,

May,

Getsy

et al. 2024

Front. Pharmacol.

Self Cite

View full text Add to dashboard Cite

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.

show abstract