Buprenorphine and Methadone as Opioid Maintenance Treatments for Heroin-Addicted Patients Induce Oxidative Stress in Blood

Leventelis, Christonikos; Goutzourelas, Nikolaos; Kortsinidou, Aikaterini; Spanidis, Ypatios; Toulia, Georgia; Kampitsi, Antzouletta; Tsitsimpikou, Christina; Stagos, Dimitrios; Veskoukis, Aristidis S.; Kouretas, Demetrios

doi:10.1155/2019/9417048

Cited by 24 publications

(15 citation statements)

References 59 publications

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“…There is conflicting evidence as to whether opioids induce oxidative stress. For example, there is compelling evidence that morphine, buprenorphine and methadone can both increase or decrease oxidative stress depending on the circumstances and experimental conditions ( Lee et al, 2004 ; Almeida et al, 2014 ; Motaghinejad et al, 2015 ; Skrabalova et al, 2018 ; Leventelis et al, 2019 ). In contrast, the available evidence suggested that fentanyl and analogues either reduce ( Kim et al, 2017 ) or have no effect ( Krumholz et al, 1993 ; Jaeger et al, 1998 ) on oxidative stress although there is a report that a high-dose remifentanil increases myocardial oxidative stress and compromises remifentanil infarct-sparing effects in rats ( Mei et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

Systemic Administration of Tempol Attenuates the Cardiorespiratory Depressant Effects of Fentanyl

Baby¹,

Gruber²,

Discala³

et al. 2021

Front. Pharmacol.

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Fentanyl is a high-potency opioid receptor agonist that elicits profound analgesia and suppression of breathing in humans and animals. To date, there is limited evidence as to whether changes in oxidant stress are important factors in any of the actions of acutely administered fentanyl. This study determined whether the clinically approved superoxide dismutase mimetic, Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl), or a potent antioxidant, N-acetyl-L-cysteine methyl ester (L-NACme), modify the cardiorespiratory and analgesic actions of fentanyl. We examined whether the prior systemic injection of Tempol or L-NACme affects the cardiorespiratory and/or analgesic responses elicited by the subsequent injection of fentanyl in isoflurane-anesthetized and/or freely moving male Sprague-Dawley rats. Bolus injections of Tempol (25, 50 or 100 mg/kg, IV) elicited minor increases in frequency of breathing, tidal volume and minute ventilation. The ventilatory-depressant effects of fentanyl (5 μg/kg, IV) given 15 min later were dose-dependently inhibited by prior injections of Tempol. Tempol elicited dose-dependent and transient hypotension that had (except for the highest dose) resolved when fentanyl was injected. The hypotensive responses elicited by fentanyl were markedly blunted after Tempol pretreatment. The analgesic actions of fentanyl (25 μg/kg, IV) were not affected by Tempol (100 mg/kg, IV). L-NACme did not modify any of the effects of fentanyl. We conclude that prior administration of Tempol attenuates the cardiorespiratory actions of fentanyl without affecting the analgesic effects of this potent opioid. As such, Tempol may not directly affect opioid-receptors that elicit the effects of fentanyl. Whether, the effects of Tempol are solely due to alterations in oxidative stress is in doubt since the powerful antioxidant, L-NACme, did not affect fentanyl-induced suppression of breathing.

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Section: Introductionmentioning

confidence: 99%

Systemic Administration of Tempol Attenuates the Cardiorespiratory Depressant Effects of Fentanyl

Baby¹,

Gruber²,

Discala³

et al. 2021

Front. Pharmacol.

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show abstract

“…In support of this, there is no real consensus as to whether opioids induce oxidative stress. For example, morphine, buprenorphine and methadone can increase or decrease oxidative stress depending on the experimental conditions ( Lee et al, 2004 ; Almeida et al, 2014 ; Motaghinejad et al, 2015 ; Skrabalova et al, 2018 ; Leventelis et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Tempol Reverses the Negative Effects of Morphine on Arterial Blood-Gas Chemistry and Tissue Oxygen Saturation in Freely-Moving Rats

Baby¹,

Discala²,

Gruber³

et al. 2021

Front. Pharmacol.

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We have reported that pretreatment with the clinically approved superoxide dismutase mimetic, Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl), blunts the cardiorespiratory depressant responses elicited by a subsequent injection of fentanyl, in halothane-anesthetized rats. The objective of the present study was to determine whether Tempol is able to reverse the effects of morphine on arterial blood-gas (ABG) chemistry in freely-moving Sprague Dawley rats. The intravenous injection of morphine (10 mg/kg) elicited substantial decreases in pH, pO2 and sO2 that were accompanied by substantial increases in pCO2 and Alveolar-arterial gradient, which results in diminished gas-exchange within the lungs. Intravenous injection of a 60 mg/kg dose of Tempol 15 min after the injection of morphine caused minor improvements in pO2 and pCO2 but not in other ABG parameters. In contrast, the 100 mg/kg dose of Tempol caused an immediate and sustained reversal of the negative effects of morphine on arterial blood pH, pCO2, pO2, sO2 and Alveolar-arterial gradient. In other rats, we used pulse oximetry to determine that the 100 mg/kg dose of Tempol, but not the 60 mg/kg dose elicited a rapid and sustained reversal of the negative effects of morphine (10 mg/kg, IV) on tissue O2 saturation (SpO2). The injection of morphine caused a relatively minor fall in mean arterial blood pressure that was somewhat exacerbated by Tempol. These findings demonstrate that Tempol can reverse the negative effects of morphine on ABG chemistry in freely-moving rats paving the way of structure-activity and mechanisms of action studies with the host of Tempol analogues that are commercially available.

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“…This effect has been demonstrated in morphine-addicted rodents [ 3 , 4 , 5 , 6 ], in morphine-addicted human beings (reviewed in [ 5 , 6 , 7 ]), and the mechanism elucidated in rodent [ 8 ] and human [ 9 , 10 ] hepatocytes at clinically-relevant concentrations of opioids. The loss of glutathione activity extends to blood serum [ 10 , 11 ] and is also found in patients being treated with methadone and buprenorphine [ 12 ]. Loss of neurons associated with glutathione depletion has also been reported in rodents treated with morphine or heroin [ 13 , 14 , 15 , 16 ] but the evidence for equivalent depletion in human brains from opioid abusers is mixed, with one group reporting significant depletion [ 17 , 18 ] and another reporting none [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Glutathione and Glutathione-Like Sequences of Opioid and Aminergic Receptors Bind Ascorbic Acid, Adrenergic and Opioid Drugs Mediating Antioxidant Function: Relevance for Anesthesia and Abuse

Root‐Bernstein

Churchill

Turke

2020

IJMS

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Opioids and their antagonists alter vitamin C metabolism. Morphine binds to glutathione (l-γ-glutamyl-l-cysteinyl-glycine), an intracellular ascorbic acid recycling molecule with a wide range of additional activities. The morphine metabolite morphinone reacts with glutathione to form a covalent adduct that is then excreted in urine. Morphine also binds to adrenergic and histaminergic receptors in their extracellular loop regions, enhancing aminergic agonist activity. The first and second extracellular loops of adrenergic and histaminergic receptors are, like glutathione, characterized by the presence of cysteines and/or methionines, and recycle ascorbic acid with similar efficiency. Conversely, adrenergic drugs bind to extracellular loops of opioid receptors, enhancing their activity. These observations suggest functional interactions among opioids and amines, their receptors, and glutathione. We therefore explored the relative binding affinities of ascorbic acid, dehydroascorbic acid, opioid and adrenergic compounds, as well as various control compounds, to glutathione and glutathione-like peptides derived from the extracellular loop regions of the human beta 2-adrenergic, dopamine D1, histamine H1, and mu opioid receptors, as well as controls. Some cysteine-containing peptides derived from these receptors do bind ascorbic acid and/or dehydroascorbic acid and the same peptides generally bind opioid compounds. Glutathione binds not only morphine but also naloxone, methadone, and methionine enkephalin. Some adrenergic drugs also bind to glutathione and glutathione-like receptor regions. These sets of interactions provide a novel basis for understanding some ways that adrenergic, opioid and antioxidant systems interact during anesthesia and drug abuse and may have utility for understanding drug interactions.

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Buprenorphine and Methadone as Opioid Maintenance Treatments for Heroin-Addicted Patients Induce Oxidative Stress in Blood

Cited by 24 publications

References 59 publications

Systemic Administration of Tempol Attenuates the Cardiorespiratory Depressant Effects of Fentanyl

Systemic Administration of Tempol Attenuates the Cardiorespiratory Depressant Effects of Fentanyl

Tempol Reverses the Negative Effects of Morphine on Arterial Blood-Gas Chemistry and Tissue Oxygen Saturation in Freely-Moving Rats

Glutathione and Glutathione-Like Sequences of Opioid and Aminergic Receptors Bind Ascorbic Acid, Adrenergic and Opioid Drugs Mediating Antioxidant Function: Relevance for Anesthesia and Abuse

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