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

When it comes to treating severe pain, a doctor's arsenal is somewhat limited: synthetic or natural opioids such as morphine, fentanyl or oxycodone are often one of the only options available to relieve patients. Yet these compounds can make breathing slower and shallower, quickly depriving the body of oxygen and causing death. This lethal side-effect is particularly devastating as opioids misuse has reached dangerously high levels in the United States, creating an 'opioid epidemic' which has claimed the lives of over 80,000 Americans in 2020. It is therefore crucial to find safer drugs that do not have this effect on breathing, but this research has been slowed down by the lack of animal models in which to study the effect of new compounds. Zebrafish are small freshwater fish that reproduce and develop fast, yet they are also remarkably genetically similar to mammals and feature a complex nervous system. However, it is not known whether the effect of opioids on zebrafish is comparable to mammals, and therefore whether these animals can be used to test new drugs for pain relief. To investigate this question, Zaig et al. exposed zebrafish larvae to fentanyl, showing that the fish then exhibited slower lower jaw movements ­ a sign of decreased breathing. The fish also could also tolerate a painful stimulus for longer, suggesting that this opioid does reduce pain in the animals. Together, these results point towards zebrafish and mammals sharing similar opioid responses, demonstrating that the fish could be used to test potential pain medications. The methods Zaig et al. have developed to establish these results could be harnessed to quickly assess large numbers of drug compounds, as well as decipher how pain emerges and can be stopped.