Pain And Opioid Systems, Implications In The Opioid Epidemic

Abstract

Pain has a useful protective role; through avoidance learning, it helps to decrease the probability of engaging in tissue-damaging, or otherwise dangerous experiences. In our modern society, the experience of acute post-surgical pain and the development of chronic pain states represent an unnecessary negative outcome. This has become an important health issue as more than 30% of the US population reports experiencing "unnecessary" pain at any given time. Opioid therapies are often efficacious treatments for severe and acute pain; however, in addition to their powerful analgesic properties, opioids produce potent reinforcing properties and their inappropriate use has led to the current opioid overdose epidemic in North America. Dissecting the allostatic changes occurring in nociceptors and neuronal pathways in response to pain are the first and most important steps in understanding the physiologic changes underlying the opioid epidemic. Full characterization of these adaptations will provide novel targets for the development of safer pharmacotherapies. In this review, we highlight the current efforts toward safer opioid treatments and describe our current knowledge of the interaction between pain and opioid systems.

The Downregulation of Opioid Receptors and Neuropathic Pain

“…As another important component of the opioid system, there are three main canonical opioid receptors, namely μ, δ, and κ opioid receptors (MOR, DOR, and KOR, respectively), which play important roles in various physiological and pathological functions of the body ( Table 1 ), as well as the nociceptin/orphanin FQ receptor (NOR), which was previously known as opioid receptor-like-1, and are widely distributed in systemic cells [ 12 , 13 ]. The endogenous opioid system has been studied for decades, as it plays an important role in analgesia, in addition to participating in learning and memory, immunological response, gastrointestinal function, and many other functions [ 23 , 24 ]. Opioid receptors are a class of classical G-protein-coupled receptors and are among the most widely expressed receptors in the nervous systems; the composition and distribution of different opioid receptor types vary depending on the region [ 25 ].…”

Cues conditioned to withdrawal and negative reinforcement: Neglected but key motivational elements driving opioid addiction

“…Despite compelling clinical evidence, few studies have directly investigated the intersection between pain relief and opioid-related cue processing in animal models. Data show that physical pain induces a rightward shift of the dose-response function for opioids, such that animals require more drug to achieve pain relief ( 53 , 54 ). Animals in an inflammatory pain state induced by complete Freund’s adjuvant exhibited an increase in heroin consumption at a high drug dose, but a decrease in intake and motivation at a lower dose, compared with control rats, which was linked to pain-induced decreased μ-opioid receptor activation of the mesolimbic dopamine system ( 52 ) (see below).…”

Endogenous opioid systems alterations in pain and opioid use disorder

“…Both pain and exogenous opioids can disrupt function of the endogenous opioid system ( Roeckel et al, 2016 ) and similarly, alterations in endogenous opioid activity can predict variations in pain thresholds, opioid-induced analgesia, and the proclivity for opioid misuse and abuse ( Corder et al, 2018 ; Jassar et al, 2019 ; Llorca-Torralba et al, 2019a ; Massaly and Morón, 2019 ; Bodnar, 2021 ). The endogenous opioid system plays an important role in analgesia, but it is also critically involved in autonomic regulation, immunological responses, gastrointestinal function, learning and memory, and many other functions ( Bodnar, 2021 ).…”