Fentanyl causes naloxone-resistant vocal cord closure: A platform for testing opioid overdose treatments

Drug and Alcohol Dependence, Journal Year: 2021, Volume and Issue: 227, P. 108974 - 108974

Published: Aug. 28, 2021

Language: Английский

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

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15

Published: April 18, 2024

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

Language: Английский

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S-Nitroso-L-Cysteine Stereoselectively Blunts the Deleterious Effects of Fentanyl on Breathing While Augmenting Antinociception in Freely-Moving Rats

Frontiers in Pharmacology, Journal Year: 2022, Volume and Issue: 13

Published: May 26, 2022

Endogenous and exogenously administered S-nitrosothiols modulate the activities of central peripheral systems that control breathing. We have unpublished data showing deleterious effects morphine on arterial blood-gas chemistry (i.e., pH, pCO2, pO2, sO2) Alveolar-arterial gradient index gas exchange) were markedly diminished in anesthetized Sprague Dawley rats received a continuous intravenous infusion endogenous S-nitrosothiol, S-nitroso-L-cysteine. The present study extends these findings by unanesthetized adult male receiving an S-nitroso-L-cysteine (100 or 200 nmol/kg/min) ability injections potent synthetic opioid, fentanyl (10, 25, 50 μg/kg), to depress frequency breathing, tidal volume, minute ventilation. Our also found intravenously injected μg/kg) disturb eupneic which was measured as marked increase non-eupneic breathing index, substantially reduced infusions nmol/kg/min). In contrast, ventilation fully expressed (200 parent amino acid, L-cysteine, D-isomer, namely, S-nitroso-D-cysteine. addition, antinociceptive actions above doses monitored tail-flick latency assay, enhanced S-nitroso-L-cysteine, but not L-cysteine Taken together, add existing knowledge stereoselectively modulates detrimental opioids opens door for mechanistic studies designed establish whether pharmacological involve signaling processes include 1) activation plasma membrane ion channels receptors, 2) selective intracellular entry and/or 3) S-nitrosylation events. Whether alterations bioavailability bioactivity is key factor determining potency/efficacy intriguing question.

Language: Английский

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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

Biomedicine & Pharmacotherapy, Journal Year: 2022, Volume and Issue: 153, P. 113436 - 113436

Published: July 26, 2022

S-nitrosothiols exert multiple effects on neural processes in the central and peripheral nervous system. This study shows that intravenous infusion of S-nitroso-L-cysteine (SNO-L-CYS, 1 μmol/kg/min) anesthetized male Sprague Dawley rats elicits (a) sustained increases minute ventilation, via frequency breathing tidal volume, (b) a decrease Alveolar-arterial (A-a) gradient, thus improving alveolar gas-exchange, (c) concomitant changes arterial blood-gas chemistry, such as an increase pO2 pCO2, (d) mean blood pressure (MAP), (e) tail-flick (TF) latency (antinociception). Infusion S-nitroso-D-cysteine (SNO-D-CYS, μmol/kg/min, IV), did not elicit similar responses, except for MAP equivalent to elicited by SNO-L-CYS. A bolus injection morphine (2 mg/kg, IV) receiving vehicle decreases therefore MAP, pH, maximal sO2 with pCO2 A-a TF latency. In SNO-L-CYS infusion, markedly smaller gas gradient MAP. contrast, antinociceptive were enhanced The morphine-induced responses SNO-D-CYS vehicle-infused rats. These data are first demonstrate S-nitrosothiol, SNO-L-CYS, can stereoselectively ameliorate adverse exchange while promoting antinociception.

Language: Английский

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D-cysteine ethyl ester and D-cystine dimethyl ester reverse the deleterious effects of morphine on arterial blood-gas chemistry and Alveolar-arterial gradient in anesthetized rats

Respiratory Physiology & Neurobiology, Journal Year: 2022, Volume and Issue: 302, P. 103912 - 103912

Published: April 18, 2022

We determined whether intravenous injections of the membrane-permeable ventilatory stimulants, D-cysteine ethyl ester (ethyl (2 S)− 2-amino-3-sulfanylpropanoate) (D-CYSee) and D-cystine dimethyl (methyl 2-amino-3-[[(2 2-amino-3-methoxy-3-oxopropyl]disulfanyl] propanoate) (D-CYSdime), could overcome deleterious actions morphine on arterial blood pH, pCO2, pO2 sO2, Alveolar-arterial (A-a) gradient (i.e., measure exchange gases in lungs) Sprague Dawley rats anesthetized with isoflurane. Injection mg/kg, IV) caused pronounced reductions sO2 accompanied by elevations all which are suggestive diminished ventilation, A-a gradient, suggests a mismatch ventilation-perfusion. Subsequent boluses ×100 μmol/kg, or ×50 rapidly reversed negative gradient. Similar were without effect, whereas produced modest reversal. Our data show that readily effects gas (ABG) chemistry mechanisms may depend upon their ability to enter cells. As result known brain, lungs, muscles chest wall, most likely major peripheral chemoreceptors carotid bodies), thiolesters changes ABG elicited involve central mechanisms. employing target prediction methods identify an array vitro vivo test potential functional proteins D-CYSee D-CYSdime modulate breathing.

Language: Английский

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D-Cysteine Ethyl Ester Reverses the Deleterious Effects of Morphine on Breathing and Arterial Blood–Gas Chemistry in Freely-Moving Rats

Frontiers in Pharmacology, Journal Year: 2022, Volume and Issue: 13

Published: June 23, 2022

Cell-penetrant thiol esters including the disulfides, D-cystine diethyl ester and dimethyl ester, monosulfide, L-glutathione ethyl prevent and/or reverse deleterious effects of opioids, such as morphine fentanyl, on breathing gas exchange within lungs unanesthetized/unrestrained rats without diminishing antinociceptive or sedative opioids. We describe here monosulfide D-cysteine (D-CYSee), intravenous morphine-induced changes in ventilatory parameters, arterial blood-gas chemistry, alveolar-arterial (A-a) gradient (i.e., index lungs), sedation antinociception freely-moving rats. The bolus injection (10 mg/kg, IV) elicited breathing, depression tidal volume, minute ventilation, peak inspiratory flow, drive. Subsequent injections D-CYSee (2 × 500 μmol/kg, IV, given 15 min apart) an immediate sustained reversal these morphine. Morphine also A-a gradient, which caused a mismatch ventilation perfusion lungs, pronounced decreases blood pH, pO

Language: Английский

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Nitrosyl factors play a vital role in the ventilatory depressant effects of fentanyl in freely moving guinea pigs

Biomedicine & Pharmacotherapy, Journal Year: 2025, Volume and Issue: 183, P. 117847 - 117847

Published: Jan. 24, 2025

Language: Английский

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Isobutyric tropine ester (Ibutropin) overcomes fentanyl-induced respiratory depression in unanesthetized rats without compromising analgesia

Neuropharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 110479 - 110479

Published: April 1, 2025

Language: Английский

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Nitrosyl factors play a vital role in the ventilatory depressant effects of fentanyl in unanesthetized rats

Biomedicine & Pharmacotherapy, Journal Year: 2021, Volume and Issue: 146, P. 112571 - 112571

Published: Dec. 22, 2021

There is an urgent need to understand the intracellular mechanisms by which synthetic opioids, such as fentanyl, depress breathing. We used L-NAME (NG-nitro-L-arginine methyl ester), a nitric oxide synthase (NOS) inhibitor, provide evidence for role of (NO) and nitrosyl factors, including S-nitrosothiols, in fentanyl-induced suppression breathing rats. measured parameters using unrestrained plethysmography record changes produced bolus administration fentanyl (25 μg/kg, IV) male Sprague Dawley rats that were pretreated with vehicle (saline), (50 μmol/kg, or inactive D-isomer, D-NAME IV), 15 min previously. series ventilatory included (i) sustained elevations frequency, due reductions durations inspiration expiration, (ii) minute ventilation, accompanied minimal tidal volume, (iii) increases inspiratory drive expiratory drive, peak flow flow. Subsequent negative effects on breathing, decreases volume therefore ventilation. Fentanyl elicited markedly different responses L-NAME, conclusively, augmented NOS inhibitor. did not alter modulate Our study fully characterized ventilation first suggest potential factors fentanyl. data shows reduce expression

Language: Английский

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Tempol Reverses the Negative Effects of Morphine on Arterial Blood-Gas Chemistry and Tissue Oxygen Saturation in Freely-Moving Rats

Frontiers in Pharmacology, Journal Year: 2021, Volume and Issue: 12

Published: Sept. 22, 2021

We have reported that pretreatment with the clinically approved superoxide dismutase mimetic, Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl), blunts cardiorespiratory depressant responses elicited by a subsequent injection of fentanyl, in halothane-anesthetized rats. The objective present study was to determine whether is able reverse effects morphine on arterial blood-gas (ABG) chemistry freely-moving Sprague Dawley intravenous (10 mg/kg) substantial decreases pH, pO 2 and sO were accompanied increases pCO Alveolar-arterial gradient, which results diminished gas-exchange within lungs. Intravenous 60 mg/kg dose 15 min after caused minor improvements but not other ABG parameters. In contrast, 100 an immediate sustained reversal negative blood , gradient. rats, we used pulse oximetry Tempol, rapid mg/kg, IV) tissue O saturation (SpO ). relatively fall mean pressure somewhat exacerbated Tempol. These findings demonstrate can rats paving way structure-activity mechanisms action studies host analogues are commercially available.

Language: Английский

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