Inhibition by intrathecal prazosin but not yohimbine of fentanyl-induced muscular rigidity in the rat

Lui, Ping-Wing; Tsen, Le-Yin; Fu, Miin-Jiuan; Yeh, C C; Lee, Tak-Yu; Chan, Samuel H.H.

doi:10.1016/0304-3940(95)12162-5

Cited by 9 publications

(13 citation statements)

References 29 publications

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“…Similarly, cholinergic pathways in medullary nuclei were suggested by Hustveit (1994) in studies of underlying mechanisms of F/FA-induced muscle rigidity in centrally mediated anticholinergic syndrome (Hustveit, 1994). However, the most consistent experimental data set for the underlying mechanism of FIMR seems to involve the LC and noradrenergic pathways (Lui et al, 1989(Lui et al, , 1990(Lui et al, , 1993(Lui et al, , 1995.…”

Section: Preclinical Research: Central Role Of the Locus Coeruleus Anmentioning

confidence: 85%

“…The LC has a topographical fiber distribution, and FIMR was attenuated by bilateral electrolytic lesions of the middle and ventral portions of the LC at the level of the trigeminal motor nucleus. Shamoperated rats demonstrated FIMR (Lui et al, 1989(Lui et al, , 1990(Lui et al, , 1993(Lui et al, , 1995.…”

Section: Preclinical Research: Central Role Of the Locus Coeruleus Anmentioning

confidence: 99%

“…Rat models for FIMR, first developed in the 1980s, have suggested underlying mechanisms for the phenomenon. Systematic isolation of regions of the brainstem and spinal cord indicate that the LC and noradrenergic neurotransmission are part of the underlying mechanisms for FIMR (Weinger et al, 1988;Lui et al, 1989Lui et al, , 1990Lui et al, , 1993Lui et al, , 1995. Other mechanisms have been examined including cerulospinal glutamatergic pathways in the rat spinal cord, suggesting that N-methyl-D-aspartate and non-N-methyl-D-aspartate receptors may be involved in FIMR and that intrathecal glutamate-inhibiting drugs or receptor antagonists may be effective in treating FIMR (Fu et al, 1997).…”

Section: Preclinical Research: Central Role Of the Locus Coeruleus Anmentioning

confidence: 99%

“…The origin of LC coerulospinal efferent fibers is primarily from the ventral-posterior portion of the pontine nuclei (pons) and terminates in noradrenergic varicosities in the ventral horn of the rat spinal cord (Loughlin et al, 1986). Noradrenergic outflow originating from the LC travels via these cerulopsinal fibers to terminate in these ventral horn cells (Lui et al, 1989(Lui et al, , 1990(Lui et al, , 1993(Lui et al, , 1995. Ablation of the LC, ablation of the ventral portion of the pontine nucleus, or severing of these cerulospinal fibers eliminates FIMR (Lui et al, 1989).…”

Section: Preclinical Research: Central Role Of the Locus Coeruleus Anmentioning

confidence: 99%

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Noradrenergic Mechanisms in Fentanyl-Mediated Rapid Death Explain Failure of Naloxone in the Opioid Crisis

Torralva

Janowsky

2019

J Pharmacol Exp Ther

113

112

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In December 2018, the Centers for Disease Control declared fentanyl the deadliest drug in America. Opioid overdose is the single greatest cause of death in the United States adult population (ages 18-50), and fentanyl and its analogs [fentanyl/ fentanyl analogs (F/FAs)] are currently involved in .50% of these deaths. Anesthesiologists in the United States were introduced to fentanyl in the early 1970s when it revolutionized surgical anesthesia by combining profound analgesia with hemodynamic stability. However, they quickly had to master its unique side effect. F/FAs can produce profound rigidity in the diaphragm, chest wall and upper airway within an extremely narrow dosing range. This clinical effect was called wooden chest syndrome (WCS) by anesthesiologists and is not commonly known outside of anesthesiology or to clinicians or researchers in addiction research/medicine. WCS is almost routinely fatal without expert airway management. This review provides relevant clinical human pharmacology and animal data demonstrating that the significant increase in the number of F/FA-induced deaths may involve a-adrenergic and cholinergic receptor-mediated mechanical failure of the respiratory and cardiovascular systems with rapid development of rigidity and airway closure. Although morphine and its prodrug, heroin, can cause mild rigidity in abdominal muscles at high doses, neither presents with the distinct and rapid respiratory failure seen with F/FA-induced WCS, separating F/FA overdose from the slower onset of respiratory depression caused by morphine-derived alkaloids. This distinction has significant consequences for the design and implementation of new pharmacologic strategies to effectively prevent F/FA-induced death. SIGNIFICANCE STATEMENT Deaths from fentanyl and F/FAs are increasing in spite of availability and awareness of the opioid reversal drug naloxone. This article reviews literature suggesting that naloxone may be ineffective against centrally mediated noradrenergic and cholinergic effects of F/FAs, which clinically manifest as severe muscle rigidity and airway compromise (e.g., wooden chest syndrome) that is rapid and distinct from respiratory depression seen with morphine-derived alkaloids. A physiologic model is proposed and implications for new drug development and treatment are discussed.

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Section: Preclinical Research: Central Role Of the Locus Coeruleus Anmentioning

confidence: 85%

Section: Preclinical Research: Central Role Of the Locus Coeruleus Anmentioning

confidence: 99%

Section: Preclinical Research: Central Role Of the Locus Coeruleus Anmentioning

confidence: 99%

Section: Preclinical Research: Central Role Of the Locus Coeruleus Anmentioning

confidence: 99%

See 2 more Smart Citations

Noradrenergic Mechanisms in Fentanyl-Mediated Rapid Death Explain Failure of Naloxone in the Opioid Crisis

Torralva

Janowsky

2019

J Pharmacol Exp Ther

113

112

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“…For this purpose, we prepared animals for drug administration via the intrathecal route using our modification of the procedures (Lui et al, 1995) described by Wang et al (1991). Briefly, a limited laminectomy was carried out at the level of the first lumbar vertebrae under pentobarbital sodium anesthesia (50 mg/kg, i.p.).…”

Section: Subarachnoid Catheterizationmentioning

confidence: 99%

Differential participation of hippocampal formation in cocaine-induced cortical electroencephalographic desynchronization and penile erection in the rat

Chang

Chan

Tsen³

et al. 1998

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We evaluated the role of the hippocampal formation in cocaine-induced cortical electroencephalographic (EEG) desynchronization and penile erection. Adult, male Sprague-Dawley rats anesthetized and maintained by chloral hydrate were used. Intravenous (1.5 or 3.0 mg/kg) administration of cocaine dose-dependently increased intracavernous pressure (ICP), our experimental index for penile erection. This was accompanied by desynchronization of EEG activity recorded from the somatosensory cortex (cEEG), as represented by a decrease in root mean square (RMS) and an increase in mean power frequency (MPF) values. There was a simultaneous increase in the RMS values, without significant changes in the MPF values of EEG signals recorded from the hippocampal formation (hEEG). In animals that received prior application of 10% xylocaine either intrathecally (i.t.) at the L6-S1 spinal levels or directly into the bilateral hippocampal formation, the RMS values of both cEEG and hEEG signals induced by cocaine (1.5 or 3.0 mg/kg, i.v.) were appreciably reduced, along with a further increase in ICP. Unilateral microinjection of cocaine (15 or 30 microg) into the hippocampal formation elicited discernible excitation of both cEEG and hEEG signals. Intriguingly, the ICP underwent a significant and dose-dependent reduction, which was discernibly antagonized by i.t. application of xylocaine. We conclude that cocaine may effect cortical EEG desynchronization but cause a reduction in ICP via an action on the hippocampal formation.

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Treatment of opioid overdose: current approaches and recent advances

Britch

Walsh

2022

Psychopharmacology

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Background The USA has recently entered the third decade of the opioid epidemic. Opioid overdose deaths reached a new record of over 74,000 in a 12-month period ending April 2021. Naloxone is the primary opioid overdose reversal agent, but concern has been raised that naloxone is not efficacious against the pervasive illicit high potency opioids (i.e., fentanyl and fentanyl analogs). Methods This narrative review provides a brief overview of naloxone, including its history and pharmacology, and the evidence regarding naloxone efficacy against fentanyl and fentanyl analogs. We also highlight current advances in overdose treatments and technologies that have been tested in humans. Results and conclusions The argument that naloxone is not efficacious against fentanyl and fentanyl analogs rests on case studies, retrospective analyses of community outbreaks, pharmacokinetics, and pharmacodynamics. No well-controlled studies have been conducted to test this argument, and the current literature provides limited evidence to suggest that naloxone is ineffective against fentanyl or fentanyl analog overdose. Rather a central concern for treating fentanyl/fentanyl analog overdose is the rapidity of overdose onset and the narrow window for treatment. It is also difficult to determine if other non-opioid substances are contributing to a drug overdose, for which naloxone is not an effective treatment. Alternative pharmacological approaches that are currently being studied in humans include other opioid receptor antagonists (e.g., nalmefene), respiratory stimulants, and buprenorphine. None of these approaches target polysubstance overdose and only one novel approach (a wearable naloxone delivery device) would address the narrow treatment window.

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Inhibition by intrathecal prazosin but not yohimbine of fentanyl-induced muscular rigidity in the rat

Cited by 9 publications

References 29 publications

Noradrenergic Mechanisms in Fentanyl-Mediated Rapid Death Explain Failure of Naloxone in the Opioid Crisis

Noradrenergic Mechanisms in Fentanyl-Mediated Rapid Death Explain Failure of Naloxone in the Opioid Crisis

Differential participation of hippocampal formation in cocaine-induced cortical electroencephalographic desynchronization and penile erection in the rat

Treatment of opioid overdose: current approaches and recent advances

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