Engaging endogenous opioid circuits in pain affective processes.

The pervasive use of opioid compounds for pain relief is rooted in their utility as one of the most effective therapeutic strategies for providing analgesia. While the detrimental side effects of these compounds have significantly contributed to the current opioid epidemic, opioids still provide millions of patients with reprieve from the relentless and agonizing experience of pain. The human experience of pain has long recognized the perceived unpleasantness entangled with a unique sensation that is immediate and identifiable from the first-person subjective vantage point as "painful." From this phenomenological perspective, how is it that opioids interfere with pain perception? Evidence from human lesion, neuroimaging, and preclinical functional neuroanatomy approaches is sculpting the view that opioids predominately alleviate the affective or inferential appraisal of nociceptive neural information. Thus, opioids weaken pain-associated unpleasantness rather than modulate perceived sensory qualities. Here, we discuss the historical theories of pain to demonstrate how modern neuroscience is revisiting these ideas to deconstruct the brain mechanisms driving the emergence of aversive pain perceptions. We further detail how targeting opioidergic signaling within affective or emotional brain circuits remains a strong avenue for developing targeted pharmacological and gene-therapy analgesic treatments that might reduce the dependence on current clinical opioid options.