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

---

Endogenous opiates and behavior: 2022

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

Published: Sept. 12, 2023

Language: Английский

---

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

---

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

---

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

---

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

Biomedicine & Pharmacotherapy, Journal Year: 2022, Volume and Issue: 153, P. 113277 - 113277

Published: June 17, 2022

There is an urgent need for development of drugs that are able to reverse the adverse effects opioids on breathing and arterial blood-gas (ABG) chemistry while preserving opioid analgesia. The present study describes bolus injections N-acetyl-L-cysteine (L-NAC, 500 μmol/kg, IV) ventilatory parameters, ABG chemistry, Alveolar-arterial (A-a) gradient, sedation (righting reflex) analgesia status (tail-flick latency assay) in unanesthetized adult male Sprague Dawley rats receiving a continuous infusion fentanyl (1 μg/kg/min, IV). Fentanyl elicited pronounced disturbances (1) parameters (e.g., decreases frequency breathing, tidal volume minute ventilation), (2) (decreases pH, pO

Language: Английский

---

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

---

Lipophilic analogues of D-cysteine prevent and reverse physical dependence to fentanyl in male rats

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 14

Published: April 5, 2024

We examined whether co-injections of the cell-permeant D-cysteine analogues, ethyl ester (D-CYSee) and amide (D-CYSea), prevent acquisition physical dependence induced by twice-daily injections fentanyl, reverse acquired to these in freely-moving male Sprague Dawley rats. Injection opioid receptor antagonist, naloxone HCl (NLX, 1.5 mg/kg, IV), elicited a series withdrawal phenomena that included cardiorespiratory behavioral responses, falls body weight temperature, rats received 5 or 10 fentanyl (125 μg/kg, same number vehicle co-injections. Regarding development dependence, NLX-precipitated were markedly reduced fentanyl-injected had D-CYSee (250 μmol/kg, IV) D-CYSea (100 but not IV). reversal established was starting with injection 6 fentanyl. This study provides evidence The lack effect suggests enhanced cell-penetrability into cells, particularly within brain, is key their ability interact intracellular signaling events involved

Language: Английский

---

Tropine exacerbates the ventilatory depressant actions of fentanyl in freely-moving rats

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

Published: June 24, 2024

Our lab is investigating the efficacy profiles of tropine analogs against opioid-induced respiratory depression. The companion manuscript reports that cell-permeant tropeine, ester (Ibutropin), produces a rapid and sustained reversal deleterious actions fentanyl on breathing, alveolar-arterial (A-a) gradient (i.e., index alveolar gas exchange), arterial blood-gas (ABG) chemistry in freely-moving male Sprague Dawley rats, while not compromising analgesia. We report here contrast to Ibutropin, injection parent molecule, (200 μmol/kg, IV), worsens adverse (75 μg/kg, IV) ventilatory parameters (e.g., frequency tidal volume, minute ventilation, peak inspiratory expiratory flows, drives), A-a gradient, ABG pH, pCO 2 , pO sO ), sedation righting reflex), affecting antinociception tail-flick latency) rats. These data suggest augments opioid receptor-induced signaling events mediate breathing exchange. opposite effects Ibutropin may result from ability readily enter peripheral central cells. Of direct relevance tropine, resulting hydrolysis would combat Ibutropin-induced fentanyl. Because numerous drug classes, such as cocaine, atropine, neuromuscular blocking drugs contain moiety, it possible their has unexpected/unintended consequences. Indeed, others have found exerts same behavioral profile cocaine upon administration. Together, these add valuable information about pharmacological properties tropine.

Language: Английский

---

The epigenetic signatures of opioid addiction and physical dependence are prevented by D-cysteine ethyl ester and betaine

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

Published: Aug. 30, 2024

We have reported that D,L-thiol esters, including D-cysteine ethyl ester (D-CYSee), are effective at overcoming opioid-induced respiratory depression (OIRD) in rats. Our on-going studies reveal co-injections of D-CYSee with multi-day morphine injections markedly diminish spontaneous withdrawal usually occurs after cessation multiple Chronically administered opioids known (1) to alter cellular redox status, thus inducing an oxidative state, and (2) for overall decrease DNA methylation, therefore resulting the transcriptional activation previously silenced long interspersed elements (LINE-1) retrotransposon genes. The first objective present study was determine whether one carbon metabolism methyl donor, betaine, would maintain control normal methylation levels human neuroblastoma cell cultures (SH-SY5Y) under overnight challenge (100 nM). second and/or betaine could degree physical dependence male Sprague Dawley data showed treatment reduced GSH levels, induced mitochondrial damage, decreased global increased LINE-1 mRNA expression. These adverse effects by morphine, which diminished reducing capacity compromised maintenance membrane potential SH-SY5Y cells, prevented concurrent application µM) or (300 µM). Furthermore, our demonstrated (250 μmol/kg, IV) a lesser extent, IV), development (escalating daily doses 10-30 mg/kg, as assessed number phenomena elicited injection opioid receptor antagonist, naloxone (1.5 IV). findings provide evidence prevent appearance alterations epigenetic signatures commonly seen neural cells involved dependence/addiction, lessen morphine.

Language: Английский

---