Opioid-induced respiratory depression: reversal by non-opioid drugs

AbstractAn opioid epidemic is spreading in North America with millions of opioid overdoses annually. Opioid drugs, like fentanyl, target the mu opioid receptor system and induce potentially lethal respiratory depression. The challenge in opioid research is to find a safe pain therapy with analgesic properties but no respiratory depression. Current discoveries are limited by lack of amenable animal models to screen candidate drugs. Zebrafish (Danio rerio) is an emerging animal model with high reproduction and fast development, which shares remarkable similarity in their physiology and genome to mammals. However, it is unknown whether zebrafish possesses similar opioid system, respiratory and analgesic responses to opioids than mammals. In freely-behaving larval zebrafish, fentanyl depresses the rate of respiratory mandible movements and induces analgesia, effects reversed by mu-opioid receptor antagonists. Zebrafish presents evolutionary conserved mechanisms of action of opioid drugs, also found in mammals, and constitute amenable models for phenotype-based drug discovery.

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Respiratory depression and analgesia by opioid drugs in freely-behaving larval zebrafish

eLife ◽

10.7554/elife.63407 ◽

2021 ◽

Vol 10 ◽

Author(s):

Shenhab Zaig ◽

Carolina da Silveira Scarpellini ◽

Gaspard Montandon

Keyword(s):

Respiratory Depression ◽

Opioid Receptor ◽

Mu Opioid Receptor ◽

Receptor System ◽

Mu Opioid ◽

Larval Zebrafish ◽

Opioid Receptor Antagonists ◽

Opioid Drugs ◽

Fast Development ◽

Freely Behaving

An opioid epidemic is spreading in North America with millions of opioid overdoses annually. Opioid drugs, like fentanyl, target the mu opioid receptor system and induce potentially lethal respiratory depression. The challenge in opioid research is to find a safe pain therapy with analgesic properties but no respiratory depression. Current discoveries are limited by lack of amenable animal models to screen candidate drugs. Zebrafish (Danio rerio) is an emerging animal model with high reproduction and fast development, which shares remarkable similarity in their physiology and genome to mammals. However, it is unknown whether zebrafish possesses similar opioid system, respiratory and analgesic responses to opioids than mammals. In freely-behaving larval zebrafish, fentanyl depresses the rate of respiratory mandible movements and induces analgesia, effects reversed by mu-opioid receptor antagonists. Zebrafish presents evolutionary conserved mechanisms of action of opioid drugs, also found in mammals, and constitute amenable models for phenotype-based drug discovery.

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Electrocortical changes associating sedation and respiratory depression by the opioid analgesic fentanyl

Scientific Reports ◽

10.1038/s41598-019-50613-2 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 7

Author(s):

Gaspard Montandon ◽

Richard L. Horner

Keyword(s):

Respiratory Rate ◽

Respiratory Depression ◽

Respiratory Activity ◽

Opioid Analgesic ◽

Respiratory Network ◽

Opioid Drugs ◽

Freely Behaving ◽

New Evidence ◽

Frequency Power ◽

Brain Arousal

Abstract Opioid drugs are the mainstay of pain management but present the side-effect of respiratory depression that can be lethal with overdose. In addition to their respiratory effect, opioids also induce a profound sedative state and produce electrocortical features characteristic of a state of reduced brain arousal, similar to anaesthesia or sleep. In such states, respiratory activity depends more on the integrity of the brainstem respiratory network than it does during wakefulness. Accordingly, we propose that sedation by fentanyl induces specific electrocortical changes consistent with reduced brain arousal, and that the magnitude of respiratory depression is associated with distinct electrocortical changes. To these aims, we determined the effects of systemic injections of fentanyl (dosage 100 µg ·kg) versus control on electrocortical and respiratory activities of freely-behaving rats. We found that fentanyl induced electrocortical changes that differed from those observed in sleep or wakefulness. Fentanyl increased δ (1–3 Hz) frequency power (P < 0.001), but reduced α (7.5–13.5 Hz) and β2 (20–30 Hz) powers (P = 0.012 and P < 0.001, respectively), when compared to wakefulness. Interestingly, respiratory rate depression by fentanyl was significantly correlated with increased θ power (R = 0.61, P < 0.001), therefore showing a clear association between electrocortical activity and the magnitude of respiratory rate depression. Overall, we provide new evidence linking specific electrocortical changes to the severity of respiratory depression by opioids, which highlights the importance of considering the cortical and subcortical effects of opioids in addition to their impacts on breathing when evaluating opioid-induced respiratory depression.

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Pharmacological and genetic manipulations at the µ-opioid receptor reveal arrestin-3 engagement limits analgesic tolerance and does not exacerbate respiratory depression in mice

Neuropsychopharmacology ◽

10.1038/s41386-021-01054-x ◽

2021 ◽

Author(s):

Li He ◽

Sarah W. Gooding ◽

Elinor Lewis ◽

Lindsey C. Felth ◽

Anirudh Gaur ◽

...

Keyword(s):

G Protein ◽

Respiratory Depression ◽

Opioid Receptor ◽

Analgesic Tolerance ◽

Genetic Manipulations ◽

Opioid Ligands ◽

Analgesic Effects ◽

Opioid Drugs ◽

Opioid Receptor Agonists ◽

G Protein Coupled

AbstractOpioid drugs are widely used analgesics that activate the G protein-coupled µ-opioid receptor, whose endogenous neuropeptide agonists, endorphins and enkephalins, are potent pain relievers. The therapeutic utility of opioid drugs is hindered by development of tolerance to the analgesic effects, requiring dose escalation for persistent pain control and leading to overdose and fatal respiratory distress. The prevailing hypothesis is that the intended analgesic effects of opioid drugs are mediated by µ-opioid receptor signaling to G protein, while the side-effects of respiratory depression and analgesic tolerance are caused by engagement of the receptor with the arrestin-3 protein. Consequently, opioid drug development has focused exclusively on identifying agonists devoid of arrestin-3 engagement. Here, we challenge the prevailing hypothesis with a panel of six clinically relevant opioid drugs and mice of three distinct genotypes with varying abilities to promote morphine-mediated arrestin-3 engagement. With this genetic and pharmacological approach, we demonstrate that arrestin-3 recruitment does not impact respiratory depression, and effective arrestin-3 engagement reduces, rather than exacerbates, the development of analgesic tolerance. These studies suggest that future development of safer opioids should focus on identifying opioid ligands that recruit both G protein and arrestin-3, thereby mimicking the signaling profile of most endogenous µ-opioid receptor agonists.

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