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

Journal of Pharmacology and Experimental Therapeutics, Journal Year: 2023, Volume and Issue: 385(2), P. 117 - 134

Published: Feb. 24, 2023

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

SIGNIFICANCE STATEMENT

potent had producing than both sexes, whereas rats were sensitive heroin-induced Tolerance/cross-tolerance develops administration but minimized long interadministration intervals.

Language: Английский

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S-Nitrosylation of CRTC1 in Alzheimer’s disease impairs CREB-dependent gene expression induced by neuronal activity

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(9)

Published: Feb. 27, 2025

cAMP response element-binding protein (CREB)-regulated transcription coactivator 1 (CRTC1) plays an important role in synaptic plasticity, learning, and long-term memory formation through the regulation of neuronal activity-dependent gene expression, CRTC1 dysregulation is implicated Alzheimer’s disease (AD). Here, we show that increased S-nitrosylation (forming SNO-CRTC1), as seen cell-based, animal-based, human-induced pluripotent stem cell (hiPSC)-derived cerebrocortical neuron-based AD models, disrupts its binding with CREB diminishes expression mediated by CRTC1/CREB pathway. We identified Cys216 primary target nitric oxide (NO)-related species. Using CRISPR/Cas9 techniques, mutated to Ala hiPSC-derived neurons bearing one allele APP Swe mutation (AD-hiPSC neurons). Introduction this nonnitrosylatable mutant rescued defects AD-hiPSC neurons, including decreased neurite length death. Additionally, vivo hippocampus plasticity form potentiation 5XFAD mice. Taken together, these results demonstrate SNO-CRTC1 contributes pathogenesis attenuating transcriptional pathway, suggests a therapeutic for AD.

Language: Английский

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Endogenous opiates and behavior: 2022

Peptides, Journal Year: 2023, Volume and Issue: 169, P. 171095 - 171095

Published: Sept. 12, 2023

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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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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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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Comparison of fentanyl-induced brain oxygen responses following intravenous and intraperitoneal injections in rats

Neuropharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 110412 - 110412

Published: March 1, 2025

Language: Английский

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L-cysteine methyl ester overcomes the deleterious effects of morphine on ventilatory parameters and arterial blood-gas chemistry in unanesthetized rats

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

Published: Sept. 28, 2022

We are developing a series of thiolesters that produce an immediate and sustained reversal the deleterious effects opioids, such as morphine fentanyl, on ventilation without diminishing antinociceptive these opioids. report here systemic injections L-cysteine methyl ester (L-CYSme) morphine-induced changes in ventilatory parameters, arterial-blood gas (ABG) chemistry (pH, pCO2, pO2, sO2), Alveolar-arterial (A-a) gradient (i.e., index alveolar gas-exchange within lungs), antinociception unanesthetized Sprague Dawley rats. The administration (10 mg/kg, IV) produced including decreases tidal volume, minute ventilation, inspiratory drive peak flow were accompanied by increase end pause. A single injection L-CYSme (500 μmol/kg, rapid long-lasting second elicited pronounced increases to values well above pre-morphine levels. (250 or 500 also arterial blood pH, sO2 A-a gradient, whereas itself was inactive. did not appear modulate sedative measured righting reflex times, but diminish duration, however, magnitude actions (5 10 determined tail-flick latency hindpaw-withdrawal assays. These findings provide evidence can powerfully overcome breathing rats while affecting early stage opioid. mechanisms which interferes with OR-induced signaling pathways mediate performance, diminishes late action remain be determined.

Language: Английский

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L-NAC and L-NAC methyl ester prevent and overcome physical dependence to fentanyl in male rats

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: April 20, 2024

Abstract N-acetyl-L-cysteine (L-NAC) is a proposed therapeutic for opioid use disorder. This study determined whether co-injections of L-NAC (500 μmol/kg, IV) or its highly cell-penetrant analogue, methyl ester (L-NACme, 500 IV), prevent acquisition acute physical dependence induced by twice-daily injections fentanyl (125 μg/kg, and overcome acquired to these in freely-moving male Sprague Dawley rats. The injection the receptor antagonist, naloxone HCl (NLX; 1.5 mg/kg, elicited series withdrawal phenomena (i.e. behavioral cardiorespiratory responses, hypothermia body weight loss) rats that received 5 10 similar numbers vehicle co-injections. With respect development dependence, NLX-precipitated were reduced had L-NAC, more greatly L-NACme. In regard overcoming established L-NACme beginning with 6 fentanyl. provides compelling evidence higher efficacy likely due greater cell penetrability brain regions mediating interaction intracellular signaling cascades, including redox-dependent processes, responsible

Language: Английский

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