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

Abstract

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.

A novel small molecule, AS1, reverses the negative hedonic valence of noxious stimuli

“…Given the wealth of literature upon opioid analgesics—which have anti-nociceptive properties and engage reward/valence circuitry—we explored the possibility of whether AS1 might be acting in a similar fashion. Both in vitro and in vivo studies suggest that zebrafish mu opioid receptor (MOR) has a pharmacological profile similar to that of mammalian MORs and that its activation elicits analogous physiological and behavioral effects [ 49 , 50 ]. In line with our previous findings, where we demonstrated that buprenorphine acts as an analgesic in larval zebrafish in both sensitized and acute thermal preference assays, in our current study buprenorphine likewise reduced the amount of time larval zebrafish spent at 28.5 °C, but did not elicit an actual preference for noxious heat (Fig.…”

Embryonic exposure to fentanyl induces behavioral changes and neurotoxicity in zebrafish larvae

“…Oprm1 (Opioid receptor mu1) expression is detectable in numerous nerve centers at 24 h post fertilization in zebrafish embryos ( Sarmah et al, 2020 ). The motor impairment caused by fentanyl in zebrafish may be a result of the analgesic and sedative effects provided by the binding of opioid receptors ( Gampfer et al, 2020 ; Zaig, daSilveira Scarpellini & Montandon, 2021 ). In fact, after the recovery period, we observed no significant difference in the behavioral capacity of zebrafish larvae exposed to all concentrations of fentanyl under bright conditions compared to the control group, indicating that behavioral capacity under light conditions was recovered.…”

“…Despite differences in the mode of ingestion of anesthetics, the teratogenicity of fentanyl has been demonstrated in studies with zebrafish embryos tested. For example, zebrafish embryos have revealed that developmental fentanyl exposure produced cardiotoxicity and respiratory depression, along with reduced swimming ability in larvae ( Kirla et al, 2021 ; Zaig, daSilveira Scarpellini & Montandon, 2021 ; Cooman et al, 2022 ). However, these studies have been limited to tests on larvae that have developed to day 5, and only superior behavioral testing on more neurodevelopmental zebrafish larvae can provide a comprehensive evaluation of the neurobehavioral toxicity induced by fentanyl exposure.…”

Risk Factors Associated with Simultaneous Use of Alcohol and Prescription Opioids Among Young Adults in Michigan

“…Alcohol is a GABA A agonist that produces anxiolytic effects, disinhibition, and ataxia (Wallner & Olsen, 2009). Opioids induce sedation, analgesia, and respiratory depression (Gupta et al, 2018;Zaig, Scarpellini, & Montandon, 2021). Together, these substances can increase the risk of overdose through additive respiratory depressant effects.…”