Blockade of phosphodiesterase 4 reverses morphine-induced ventilatory disturbance without loss of analgesia

Kimura, Satoko; Ohi, Yoshiaki; Haji, Akira

doi:10.1016/j.lfs.2015.02.006

Cited by 17 publications

(11 citation statements)

References 39 publications

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“…24; D1 dopamine receptors, Refs. 134-136), 2) Methylxanthines, caffeine, and theophylline given to counter apneas of prematurity (137)(138)(139), and 3) Phosphodiesterase 4 (PDE4) inhibitors (rolipram) (140)(141)(142). Each of these manipulations would be expected to counter cAMP decreases due canonical Ga i/o signaling downstream of activated MOR (143).…”

Section: Opioid Action On the Preb€ Otc-cellular Mechanismsmentioning

confidence: 99%

Neuronal mechanisms underlying opioid-induced respiratory depression: our current understanding

Ramirez

Burgraff²,

Wei³

et al. 2021

Journal of Neurophysiology

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Opioid induced respiratory depression (OIRD) represents the primary cause of death associated with therapeutic and recreational opioid use. Within the U.S., the rate of death from opioid abuse since the early 1990's has grown disproportionally, prompting the classification as a nationwide "epidemic". Since this time, we have begun to unravel many fundamental cellular and systems-level mechanisms associated with opioid-related death. However, factors such as individual vulnerability, neuromodulatory compensation, and redundancy of opioid effects across central and peripheral nervous systems have created a barrier to a concise, integrative view of OIRD. Within this review, we bring together multiple perspectives in the field of OIRD to create an overarching viewpoint of what we know, and where we view this essential topic of research going forward into the future.

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Section: Opioid Action On the Preb€ Otc-cellular Mechanismsmentioning

confidence: 99%

Neuronal mechanisms underlying opioid-induced respiratory depression: our current understanding

Ramirez

Burgraff²,

Wei³

et al. 2021

Journal of Neurophysiology

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“…65,66 Phosphodiesterase-4 Inhibitors Methylxanthine alkaloids such as caffeine, aminophylline, and theophylline stimulate respiratory rhythmogenesis and cause hyperexcitability of respiratory motor neurons by increasing cyclic adenosine monophosphate (cAMP) through inhibition of the enzyme phosphodiesterase 4 within the CNS. [67][68][69] Caffeine was used historically to treat opium and morphine poisoning and is still used to counter apnea of prematurity and stabilize breathing in preterm infants. 70,71 For example, a report from 1913 showed a brisk increase in respiratory rate after caffeine injection in rabbits pretreated with morphine.…”

Section: Serotonin (5-hydroxytryptamine) Receptor Agonistsmentioning

confidence: 99%

Averting Opioid-induced Respiratory Depression without Affecting Analgesia

et al. 2018

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The ventilatory control system is highly vulnerable to exogenous administered opioid analgesics. Particularly respiratory depression is a potentially lethal complication that may occur when opioids are overdosed or consumed in combination with other depressants such as sleep medication or alcohol. Fatalities occur in acute and chronic pain patients on opioid therapy and individuals that abuse prescription or illicit opioids for their hedonistic pleasure. One important strategy to mitigate opioid-induced respiratory depression is cotreatment with nonopioid respiratory stimulants. Effective stimulants prevent respiratory depression without affecting the analgesic opioid response. Several pharmaceutical classes of nonopioid respiratory stimulants are currently under investigation. The majority acts at sites within the brainstem respiratory network including drugs that act at α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (ampakines), 5-hydroxytryptamine receptor agonists, phospodiesterase-4 inhibitors, D1-dopamine receptor agonists, the endogenous peptide glycyl-glutamine, and thyrotropin-releasing hormone. Others act peripherally at potassium channels expressed on oxygen-sensing cells of the carotid bodies, such as doxapram and GAL021 (Galleon Pharmaceuticals Corp., USA). In this review we critically appraise the efficacy of these agents. We conclude that none of the experimental drugs are adequate for therapeutic use in opioid-induced respiratory depression and all need further study of efficacy and toxicity. All discussed drugs, however, do highlight potential mechanisms of action and possible templates for further study and development.

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“…A second approach involves the use of respiratory stimulants in combination with opioid medication as a compensatory strategy to protect against OIRD (Algera et al, 2019, Manzke et al, 2003, Imam et al, 2020. Such strategies have shown promise in animal models (Mosca et al, 2014, Kimura et al, 2015, Guenther et al, 2010, Sun et al, 2019, Haw et al, 2016, Dai et al, 2017 and in some human trials (Oertel et al, 2010, Persson et al, 1999 but not others (Lötsch et al, 2005, Oertel et al, 2007. Optimization of this approach will require a detailed mechanistic understanding of the physiological consequences of MOR activation in the respiratory network.…”

Section: Introductionmentioning

confidence: 99%

Dual mechanisms of opioid-induced respiratory depression in the inspiratory rhythm-generating network

Baertsch

Bush

Burgraff

et al. 2021

eLife

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The analgesic utility of opioid-based drugs is limited by the life-threatening risk of respiratory depression. Opioid-induced respiratory depression (OIRD), mediated by the μ-opioid receptor (MOR), is characterized by a pronounced decrease in the frequency and regularity of the inspiratory rhythm, which originates from the medullary preBӧtzinger Complex (preBӧtC). To unravel the cellular- and network-level consequences of MOR activation in the preBӧtC, MOR- expressing neurons were optogenetically identified and manipulated in transgenic mice in vitro and in vivo. Based on these results, a model of OIRD was developed in silico. We conclude that hyperpolarization of MOR-expressing preBӧtC neurons alone does not phenocopy OIRD. Instead, the effects of MOR activation are twofold: 1) pre-inspiratory spiking is reduced and 2) excitatory synaptic transmission is suppressed, thereby disrupting network-driven rhythmogenesis. These dual mechanisms of opioid action act synergistically to make the normally robust inspiratory rhythm generating network particularly prone to collapse when challenged with exogenous opioids.

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Blockade of phosphodiesterase 4 reverses morphine-induced ventilatory disturbance without loss of analgesia

Cited by 17 publications

References 39 publications

Neuronal mechanisms underlying opioid-induced respiratory depression: our current understanding

Neuronal mechanisms underlying opioid-induced respiratory depression: our current understanding

Averting Opioid-induced Respiratory Depression without Affecting Analgesia

Dual mechanisms of opioid-induced respiratory depression in the inspiratory rhythm-generating network

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