Mu opioid receptors (MOR) agonists exert strong anti-nociceptive activity but their ability to cause tolerance and physical dependence are serious issues of concern and limit their use. The activation of another branch of opioid receptors discovered lately, the opioid-related nociceptin receptor 1 (OPRL1) has recently shown the ability to enhance MOR agonist-induced analgesia while limiting tolerance and side effects.