Morphine has latent deleterious effects on the ventilatory responses to a hypoxic challenge*

May, Walter J.; Gruber, Ryan B.; Discala, Joseph F.; Puskovic, Veljko; Henderson, Fraser; Palmer, Lisa A.; Lewis, Stephen J.

doi:10.4236/ojmip.2013.34022

Cited by 27 publications

(9 citation statements)

References 70 publications

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“…As was expected (Henderson et al, 2013, 2014; May et al, 2013a), the increases in fR (and concomitant decreases in TI and Te) and Vt, Ve and Vt/Ti (respiratory drive) elicited by the HC and HX challenges were substantially smaller in morphine-treated SHAM rats than in their saline-treated counterparts. However, it was evident that the ventilatory depressant effects of morphine were substantially greater against HC than HX.…”

Section: Discussionsupporting

confidence: 80%

“…Ventilatory parameters were continuously recorded in unrestrained freely-moving rats via a whole-body 12-chamber plethysmography system (PLY 3223; BUXCO Inc., Wilmington, NC, USA), as detailed previously (Henderson et al, 2013, 2014; May et al, 2013a,b) and as diagrammed in Fig. 1.…”

Section: Methodsmentioning

confidence: 99%

“…All values are expressed as mean ± SEM. The data was analyzed by one-way or two-way repeated measures analyses of variance followed by Bonferroni corrections for multiple comparisons between means (May et al, 2013a,b). …”

Section: Methodsmentioning

confidence: 99%

“…Systemic morphine blunts hypoxic (HVR), hypercapnic (HCVR) and hypoxic-hypercapnic ventilatory responses in conscious rats (Emry et al, 2016; May et al, 2013a,b; Murphy et al, 1995) probably by actions in the brain since μ-ORs are expressed in numerous nuclei involved in respiratory control such as the nucleus tractus solitarius (NTS) (see Zhang et al, 2007). Moreover, microinjections of the μ-OR agonist, DAMGO, into medullary raphe regions of anesthetized rats blunt HVR whereas microinjections of DAMGO into the commissural NTS suppress HVR and HCVR (Zhang et al, 2007, 2009, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Bilateral carotid sinus nerve transection exacerbates morphine-induced respiratory depression

Baby¹,

Gruber²,

Young

et al. 2018

European Journal of Pharmacology

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Opioid-induced respiratory depression (OIRD) involves decreased sensitivity of ventilatory control systems to decreased blood levels of oxygen (hypoxia) and elevated levels of carbon dioxide (hypercapnia). Understanding the sites and mechanisms by which opioids elicit respiratory depression is pivotal for finding novel therapeutics to prevent and/or reverse OIRD. To examine the contribution of carotid body chemoreceptors OIRD, we used whole-body plethysmography to evaluate hypoxic (HVR) and hypercapnic (HCVR) ventilatory responses including changes in frequency of breathing, tidal volume, minute ventilation and inspiratory drive, after intravenous injection of morphine (10 mg/kg) in sham-operated (SHAM) and in bilateral carotid sinus nerve transected (CSNX) Sprague-Dawley rats. In SHAM rats, morphine produced sustained respiratory depression (e.g., decreases in tidal volume, minute ventilation and inspiratory drive) and reduced the HVR and HCVR responses. Unexpectedly, morphine-induced suppression of HVR and HCVR were substantially greater in CSNX rats than in SHAM rats. This suggests that morphine did not compromise the function of the carotid body-chemoafferent complex and indeed, that the carotid body acts to defend against morphine-induced respiratory depression. These data are the first in vivo evidence that carotid body chemoreceptor afferents defend against rather than participate in OIRD in conscious rats. As such, drugs that stimulate ventilation by targeting primary glomus cells and/or chemoafferent terminals in the carotid bodies may help to alleviate OIRD.

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Section: Discussionsupporting

confidence: 80%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Bilateral carotid sinus nerve transection exacerbates morphine-induced respiratory depression

Baby¹,

Gruber²,

Young

et al. 2018

European Journal of Pharmacology

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“…Opioid analgesics (e.g., fentanyl, morphine, etorphine, buprenorphine, methadone, butorphanol, oxymorphone) have been demonstrated to increase A-a gradient in a variety of species including humans 136 – 138 , goats 139 , rabbits 140 , dogs 141 , impala 142 , and rats 15 , 94 , 95 . As discussed by Meyer et al 139 , and Henderson et al 15 , opioids increase A-a gradients by impairing ventilation-perfusion ratios in the lungs (ventilation-perfusion mismatch).…”

Section: Resultsmentioning

confidence: 99%

Glutathione ethyl ester reverses the deleterious effects of fentanyl on ventilation and arterial blood-gas chemistry while prolonging fentanyl-induced analgesia

Jenkins

Khalid

Baby

et al. 2021

Sci Rep

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There is an urgent need to develop novel compounds that prevent the deleterious effects of opioids such as fentanyl on minute ventilation while, if possible, preserving the analgesic actions of the opioids. We report that L-glutathione ethyl ester (GSHee) may be such a novel compound. In this study, we measured tail flick latency (TFL), arterial blood gas (ABG) chemistry, Alveolar-arterial gradient, and ventilatory parameters by whole body plethysmography to determine the responses elicited by bolus injections of fentanyl (75 μg/kg, IV) in male adult Sprague–Dawley rats that had received a bolus injection of GSHee (100 μmol/kg, IV) 15 min previously. GSHee given alone had minimal effects on TFL, ABG chemistry and A-a gradient whereas it elicited changes in some ventilatory parameters such as an increase in breathing frequency. In vehicle-treated rats, fentanyl elicited (1) an increase in TFL, (2) decreases in pH, pO2 and sO2 and increases in pCO2 (all indicative of ventilatory depression), (3) an increase in Alveolar-arterial gradient (indicative of a mismatch in ventilation-perfusion in the lungs), and (4) changes in ventilatory parameters such as a reduction in tidal volume, that were indicative of pronounced ventilatory depression. In GSHee-pretreated rats, fentanyl elicited a more prolonged analgesia, relatively minor changes in ABG chemistry and Alveolar-arterial gradient, and a substantially milder depression of ventilation. GSHee may represent an effective member of a novel class of thiolester drugs that are able to prevent the ventilatory depressant effects elicited by powerful opioids such as fentanyl and their deleterious effects on gas-exchange in the lungs without compromising opioid analgesia.

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S-nitroso-L-cysteine stereoselectively blunts the adverse effects of morphine on breathing and arterial blood gas chemistry while promoting analgesia

Getsy

Young

Bates

et al. 2022

Biomedicine & Pharmacotherapy

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Morphine has latent deleterious effects on the ventilatory responses to a hypoxic challenge*

Cited by 27 publications

References 70 publications

Bilateral carotid sinus nerve transection exacerbates morphine-induced respiratory depression

Bilateral carotid sinus nerve transection exacerbates morphine-induced respiratory depression

Glutathione ethyl ester reverses the deleterious effects of fentanyl on ventilation and arterial blood-gas chemistry while prolonging fentanyl-induced analgesia

S-nitroso-L-cysteine stereoselectively blunts the adverse effects of morphine on breathing and arterial blood gas chemistry while promoting analgesia

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