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

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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

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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

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The ventilatory depressant actions but not the antinociceptive effects of morphine are blunted in rats receiving intravenous infusion of L-cysteine ethyl ester

Biomedicine & Pharmacotherapy, Journal Year: 2022, Volume and Issue: 156, P. 113939 - 113939

Published: Oct. 28, 2022

This study demonstrates that intravenous infusion of the cell-penetrant thiol ester, L-cysteine ethyl ester (L-CYSee), to adult male Sprague-Dawley rats elicited (a) minor alterations in frequency breathing, expiratory time, tidal volume, minute ventilation, or drive but pronounced changes inspiratory end-inspiratory and pauses, peak flows, EF50, relaxation apneic pause, non-eupneic breathing index, (b) minimal arterial blood-gas (ABG) chemistry (pH, pCO2, pO2, SO2) Alveolar-arterial (A-a) gradient (index alveolar gas exchange), (c) antinociception (tail-flick latency). Subsequent injection morphine (10 mg/kg, IV) markedly smaller effects on above parameters, ABG chemistry, A-a receiving L-CYSee, whereas was not impaired. Infusions L-serine (oxygen rather than sulfur moiety), did affect actions gradient. L-CYSee (250 μmol/kg, dramatic ventilatory parameters given 15 min after L-CYSee. Our findings suggest acts neurons reversal adverse may be via modulation intracellular signaling pathways activated by direct antagonism opioid receptors since diminished moiety is vital efficacy, (d) conversion an S-nitrosylated form part its mechanism action.

Language: Английский

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L-cysteine ethylester reverses the adverse effects of morphine on breathing and arterial blood-gas chemistry while minimally affecting antinociception in unanesthetized rats

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 171, P. 116081 - 116081

Published: Jan. 19, 2024

L-cysteine ethylester (L-CYSee) is a membrane-permeable analogue of with variety pharmacological effects. The purpose this study was to determine the effects L-CYSee on morphine-induced changes in ventilation, arterial-blood gas (ABG) chemistry, Alveolar-arterial (A-a) gradient (i.e., measure index alveolar gas-exchange), antinociception and sedation male Sprague Dawley rats. An injection morphine (10 mg/kg, IV) produced adverse breathing, including sustained decreases minute ventilation. (500 μmol/kg, given 15 min later immediately reversed actions morphine. Another after elicited more pronounced excitatory ventilatory responses. (250 or 500 rapid prolonged reversal ABG chemistry (pH, pCO

Language: Английский

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Functional evidence that S-nitroso-L-cysteine may be a candidate carotid body neurotransmitter

Neuropharmacology, Journal Year: 2024, Volume and Issue: unknown, P. 110229 - 110229

Published: Nov. 1, 2024

Language: Английский

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The ability of Ibutropin to blunt fentanyl-induced respiratory depression is independent of its activation of carotid body chemoafferents

Journal of Pharmacology and Experimental Therapeutics, Journal Year: 2024, Volume and Issue: 392(2), P. 100060 - 100060

Published: Dec. 10, 2024

This study examined the effects of intravenous injection isobutyric tropine ester (Ibutropin) on ventilation in freely-moving sham-operated (SHAM) male Sprague Dawley rats and those with bilateral carotid sinus nerve transection (CSNX). also a subsequent fentanyl ventilatory parameters both groups rats. Ibutropin (200 μmol/kg, i.v.) elicited rapid pronounced increases breathing frequency, tidal volume, minute ventilation, peak inspiratory expiratory flows, drives SHAM rats, but substantially smaller responses CSNX The (75 μg/kg, similar Ibutropin-treated markedly different changes end-inspiratory end-expiratory pauses, delay, apneic pause. Moreover, fentanyl-induced were than that pre-injected vehicle (saline) rather Ibutropin. These novel findings suggest acts at body-chemoafferent complex to drive by mechanisms may involve entry this cell-permeant into chemoafferent terminals and/or primary glomus cells. A key finding was ability blunt adverse does not require functional body chemoreceptor afferent input brainstem structures controlling breathing. As such, greatly diminish actions within central respiratory control centers peripheral other bodies. SIGNIFICANCE STATEMENT: revealed depressant present

Language: Английский

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L-cysteine ethyl ester prevents and reverses acquired physical dependence on morphine in male Sprague Dawley rats

Frontiers in Pharmacology, Journal Year: 2023, Volume and Issue: 14

Published: Dec. 4, 2023

The molecular mechanisms underlying the acquisition of addiction/dependence on morphine may result from ability opioid to diminish transport L-cysteine into neurons via inhibition excitatory amino acid transporter 3 (EAA3). objective this study was determine whether co-administration cell-penetrant L-thiol ester, ethyl ester (L-CYSee), would reduce physical dependence in male Sprague Dawley rats. Injection opioid-receptor antagonist, naloxone HCl (NLX; 1.5 mg/kg, IP), elicited pronounced withdrawal phenomena rats which received a subcutaneous depot (150 mg/kg) for 36 h and were receiving continuous infusion saline (20 μL/h, IV) osmotic minipumps same period. included wet-dog shakes, jumping, rearing, fore-paw licking, 360° circling, writhing, apneas, cardiovascular (pressor tachycardia) responses, hypothermia, body weight loss. NLX substantially reduced syndrome that an L-CYSee (20.8 μmol/kg/h, h. precipitated marked had depots 48 h) co-infusion vehicle. However, NLX-precipitated signs markedly mg/kg h)-treated began at In similar studies those described previously, neither nor L-serine (both 20.8 mimicked effects L-CYSee. This demonstrates 1) attenuates development 2) prior administration reverses dependence, most likely by intracellular actions within brain. lack effect (oxygen atom instead sulfur atom) strongly implicates thiol biochemistry efficacy Accordingly, analogs be novel class therapeutics ameliorate opioids humans.

Language: Английский

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The cell-permeant antioxidant D-thiol ester D-cysteine ethyl ester overcomes physical dependence to morphine in male Sprague Dawley rats

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

Published: Aug. 26, 2024

The ability of morphine to decrease cysteine transport into neurons by inhibition excitatory amino acid transporter 3 (EAA3) may be a key molecular mechanism underlying the acquisition physical and psychological dependence morphine. This study examined whether co-administration cell-penetrant antioxidant D-thiol ester, D-cysteine ethyl ester (D-CYSee), with morphine, would diminish development in male Sprague Dawley rats. Systemic administration opioid receptor antagonist, naloxone (NLX), elicited pronounced withdrawal signs (e.g., wet-dog shakes, jumps, rears, circling) rats that received subcutaneous depot (150 mg/kg, SC) for 36 h continuous intravenous infusion vehicle (20 μL/h, IV). NLX-precipitated were reduced an D-CYSee, but not D-cysteine, (both at 20.8 μmol/kg/h, IV) full h. NLX treated 48 SC), plus began timepoint treatment. 12 These findings suggest D-CYSee attenuate reverse established Alternatively, simply suppress processes responsible withdrawal. Nonetheless, analogues novel therapeutics treatment use disorders.

Language: Английский

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