Untangling the complexity of opioid receptor function

Abstract

Mu opioid receptor agonists are among the most powerful analgesic medications but also among the most addictive. The current opioid crisis has energized a quest to develop opioid analgesics that are devoid of untoward effects. Since their discovery in the 1970’s, there have been major advances in our understanding of the endogenous opioid systems that these drugs target. Yet many questions remain and the development of non-addictive opioid analgesics has not been achieved. However, access to new molecular, genetic and computational tools have begun to elucidate the structural dynamics of opioid receptors, the scaffolding that links them to intracellular signaling cascades, their cellular trafficking and the distinct ways that various opioid drugs modify them. This mini-review highlights some of the chemical and pharmacological findings and new perspectives that have arisen from studies using these tools. They reveal multiple layers of complexity of opioid receptor function, including a spatiotemporal specificity in opioid receptor-induced cellular signaling, ligand-directed biased signaling, allosteric modulation of ligand interactions, heterodimerization of different opioid receptors, and the existence of slice variants with different ligand specificity. By untangling these layers, basic research into the chemistry and pharmacology of opioid receptors is guiding the way towards deciphering the mysteries of tolerance and physical dependence that have plagued the field and is providing a platform for the development of more effective and safer opioids.

New viral‐genetic mapping uncovers an enrichment of corticotropin‐releasing hormone‐expressing neuronal inputs to the nucleus accumbens from stress‐related brain regions

“…The mPFC is a well‐established regulator of NAc (Russo & Nestler, ), and altered mPFC‐NAc signaling has been implicated in pathological conditions involving the reward/pleasure circuitry such as addiction, alcoholism, anhedonia, and PTSD (Garavan et al, ; Goldstein & Volkow, ; Kalivas, Volkow, & Seamans, ; Sailer et al, ). Putative roles of CRH + mPFC‐origin NAc afferents may thus contribute to stress‐related pathologies such as relapse in alcoholism or drug use disorders (Koob & Le Moal, ; Valentino & Volkow, ).…”

“…Putative roles of CRH + mPFC-origin NAc afferents may thus contribute to stress-related pathologies such as relapse in alcoholism or drug use disorders (Koob & Le Moal, 2001;Valentino & Volkow, 2018).…”

Epidemiology of the U.S. opioid crisis: the importance of the vector

“…They interact with endogenous opioid systems that regulate several functions via three types of G protein–coupled receptors: mu, delta, and kappa. Principally, they are potent agonists at the mu receptor . Mu‐opioid receptors are particularly concentrated in areas of the brain involved in processing pain and reward.…”

Novel Opioids: Systematic Web Crawling Within the e-Psychonauts’ Scenario

“…Owing to a range of reasons, the non-medical use of opioids such as fentanyl analogs and a range of remaining prescription/nonprescription substances is spreading worldwide (Prekupec et al, 2017;Lovrecic et al, 2019) and is affecting the entire life span, from youngsters to the elderly (Huhn et al, 2018;Kelley-Quon et al, 2019). Opioids are among the most powerful analgesic drugs, but they are burdened by unwanted adverse effects, in particular the abuse liability and the respiratory depression, with the last being the primary cause of death from overdose (Valentino and Volkow, 2018;Algera et al, 2019;Varga et al, 2020). Further, the evidence suggests that opioids' consumption impacts the in utero neuronal development and induces in humans long-lasting transgenerational changes in subsequent generations owing to epigenetic alterations (Gilardi et al, 2018).…”