 A new study in rhesus monkeys clarifies one aspect of how the new drug, seborinopadol, relieves pain and finds that this effective analgesic has milder side effects than fentanyl and morphine. Pure mu-opioid receptor agonists like fentanyl and morphine are the most widely used analgesic drugs in medical settings. However, their severe side effects and high abuse potential have prompted the need for alternatives. Treatment with drugs that simultaneously target nociceptin receptors and mu receptors has been shown to limit mu receptor-related side effects. Seborinopadol, an effective pain reliever in rodents and humans, targets nociceptin receptors in various opioid receptors. But whether the mu-opioid receptor subtype is the most important for seborinopadol analgesia is unknown and the associated side effects haven't been investigated in non-human primate models. To better evaluate seborinopadol as an analgesic alternative to pure mu agonists, researchers compared it with fentanyl and morphine. Specifically, they compared the potency, abuse potential, and respiratory depressant and itching-inducing side effects of the drugs in rhesus monkeys. The results are published in the journal Anesthesiology. Pain response tests suggested that seborinopadol is a more potent analgesic than fentanyl. Compared with fentanyl, seborinopadol blooded the tail withdrawal reflex of the monkeys in response to warm water at a lower dose. In addition, seborinopadol didn't cause itching, while fentanyl did. Pre-treating monkeys with specific opioid receptor inhibitors revealed that the mu receptor subtype was the most important for the pain-relieving effects of seborinopadol. Reinforcement experiments reflected some capacity for abuse as monkeys tended to self-administer both seborinopadol and fentanyl over saline. However, the reinforcing strength of seborinopadol was weaker, indicating a lower abuse potential for seborinopadol than for fentanyl. At higher doses, systemic seborinopadol did not cause the respiratory depression observed with fentanyl treatment. Intrathically administered seborinopadol was also very effective in delaying tail withdrawal in response to warm water. Moreover, it did not cause the characteristic scratching behavior evoked by intrathical morphine. These findings suggest the potential of seborinopadol as an alternative spinal analgesic. Notably, the study did not test whether intrathical seborinopadol induced respiratory depression. The lack of this side effect should be confirmed in future studies. More importantly, as seborinopadol did exhibit potential for abuse, its further development and clinical use will require caution. Despite these limitations, the results of this study clarify the molecular targets of seborinopadol and suggest that this effective analgesic may have a better side effect profile than commonly used opioids.