Opioids, stress and addiction: From stress-induced analgesia to opioid heterodimers with extraordinary analgesic efficacy and without the side effects of traditional opioids

The Special Issue on Stress and Addiction is concerned with interrelationships between environmental stimuli such as stress and endogenous opioid systems that lead to addiction and other behaviors. Stress can have a profound effect on pain that is mediated in part through endogenous opioids. Here we briefly summarize investigation pertaining to the involvement of endogenous opioids in stress-induced analgesia, and their mediation by hypothalamo-pituitary-adrenal systems. Subsequent studies of the contribution of opioid receptor subtypes mediating supraspinal pain-inhibitory systems are examined using selective agonists and antagonists largely developed by Dr. Philip Portoghese. Because of the ongoing opioid epidemic yet the need to discover effective analgesics, we conclude with a discussion of several approaches to manage pain effectively without such serious side effects as tolerance and addiction, associated with traditional opioid use. These include opioid analgesic synergy, biased opioid agonism, and targeting of opioid receptor heteromers with bivalent ligands.