Elsevier eBooks, Journal Year: 2023, Volume and Issue: unknown, P. 601 - 609
Published: June 10, 2023
Language: Английский
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.
Language: Английский
Citations
31
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
Citations
4
Neuropharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 110479 - 110479
Published: April 1, 2025
Language: Английский
Citations
0
Basic & Clinical Pharmacology & Toxicology, Journal Year: 2024, Volume and Issue: 134(4), P. 460 - 471
Published: Jan. 29, 2024
Abstract Fentanyl exposure and overdose are growing concerns in public health occupational safety. This study aimed to establish parameters of fentanyl lethality SKH1 mice for future research. Lethality was determined using the up‐down procedure, with subjects monitored post‐administration pulse oximetry (5 min) then whole‐body plethysmography (40 min). Following determination subcutaneous dose–response, [18F]Fluorodeoxyglucose positron emission tomography ( 18 F‐FDG PET) performed after LD10 at 40 min, 6 h, 24 h or 7 days post‐dose. LD50 were observed be 110 135 mg/kg, respectively, consistent four‐parameter logistic fit values 111.2 134.6 mg/kg r 2 = 0.9996). Overdose (LD10 greater) yielded three distinct cardiovascular groups: survival, non‐survival blood oxygen saturation (SpO2) minimum ≥37% SpO2 <37%. Breaths per minute, minute volume inspiratory quotient significantly different between surviving non‐surviving animals up min post‐injection. PET revealed decreased glucose uptake heart, lungs brain h. These findings provide critical insights into mice, including non‐invasive respiratory effects organ‐specific impacts that invaluable translational studies investigating temporal overdose.
Language: Английский
Citations
3
Frontiers in Physiology, Journal Year: 2024, Volume and Issue: 14
Published: Feb. 6, 2024
Histone deacetylase 6 (HDAC6) is a class II histone that predominantly localized in the cytoplasm of cells. HDAC6 associates with microtubules and regulates acetylation tubulin other proteins. The possibility participates hypoxic signaling supported by evidence 1) gas challenges cause microtubule depolymerization, 2) expression hypoxia inducible factor alpha (HIF-1α) regulated alterations response to hypoxia, 3) inhibition prevents HIF-1α protects tissue from hypoxic/ischemic insults. aim this study was address whether absence alters ventilatory responses during and/or after challenge (10% O 2 , 90% N for 15 min) adult male wildtype (WT) C57BL/6 mice knock-out (KO) mice. Key findings were baseline values frequency breathing, tidal volume, inspiratory expiratory times, end pause different between mice, more robust KO than WT recorded parameters including, minute ventilation, durations, peak flows, drives, upon return room-air markedly compared (but not pause), drives. These data suggest may have fundamentally important role regulating
Language: Английский
Citations
3
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
Citations
3
Frontiers in Pharmacology, Journal Year: 2023, Volume and Issue: 14
Published: Sept. 19, 2023
Introduction: Despite their inclination to induce tolerance, addictive states, and respiratory depression, synthetic opioids are among the most effective clinically administered drugs treat severe acute/chronic pain surgical anesthesia. Current medical interventions for opioid-induced depression (OIRD), wooden chest syndrome, opioid use disorder (OUD) show limited efficacy marked by low success in face of highly potent such as fentanyl. D-Cysteine ethylester (D-CYSee) prevents OIRD post-treatment withdrawal male/female rats mice with minimal effect on analgesic status. However, potential aversive or rewarding effects D-CYSee have yet be fully characterized its could compromised interactions opioid-reward pathology. Methods: Using a model fentanyl-induced conditioned place preference (CPP), this study evaluated 1) dose sex dependent fentanyl 2) extent which alters affective state acquisition seeking behaviors. Results: Fentanyl reward-related were found dependent. Male exhibited range-bound response centered at 5 µg/kg. Female CPP only 50 This was 25% females remaining 75% showing no significant any dose. Pretreatment 100 mg/kg, but not 10 prevented males while both doses preventing females. Discussion: These findings suggest that is an co-treatment prescribed reduce development OUD.
Language: Английский
Citations
7
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
Citations
2
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
Citations
2
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
Citations
2