Mechanism of opioid addiction and its intervention therapy: Focusing on the reward circuitry and mu‐opioid receptor

Abstract

Opioid abuse and addiction have become a global pandemic, posing tremendous health and social burdens. The rewarding effects and the occurrence of withdrawal symptoms are the two mainstays of opioid addiction. Mu‐opioid receptors (MORs), a member of opioid receptors, play important roles in opioid addiction, mediating both the rewarding effects of opioids and opioid withdrawal syndrome (OWS). The underlying mechanism of MOR‐mediated opioid rewarding effects and withdrawal syndrome is of vital importance to understand the nature of opioid addiction and also provides theoretical basis for targeting MORs to treat drug addiction. In this review, we first briefly introduce the basic concepts of MORs, including their structure, distribution in the nervous system, endogenous ligands, and functional characteristics. We focused on the brain circuitry and molecular mechanism of MORs‐mediated opioid reward and withdrawal. The neuroanatomical and functional elements of the neural circuitry of the reward system underlying opioid addiction were thoroughly discussed, and the roles of MOR within the reward circuitry were also elaborated. Furthermore, we interrogated the roles of MORs in OWS, along with the structural basis and molecular adaptions of MORs‐mediated withdrawal syndrome. Finally, current treatment strategies for opioid addiction targeting MORs were also presented.

The (–)-Borneol Effect on Addiction/Abstinence by Morphine in Mice

“…Opioid withdrawal is a complex phenomenon formed by many signs and symptoms [68]. The opioid withdrawal can be simulated in animal models with the administration of opioid antagonists such as naloxone [69].…”

Teneurin C-terminal associated peptide (TCAP)-1 attenuates the development and expression of naloxone-precipitated morphine withdrawal in male Swiss Webster mice

“…These studies establish that TCAP-1 inhibits both CRF stress and addiction-related behaviors, but these attenuating effects on behavior associated with cocaine -a psychostimulant -may not necessarily generalize to other classes of psychoactive drugs, such as opioids. However, because the opioid-associated neurological circuit encompasses both stress-and addiction-related behaviors (Crowley and Kash 2015; Haun et al 2022;Leconte et al 2022;Rysztak and Jutkiewicz 2022;Simmons et al 2020;Tkaczynski et al 2022;Zhang et al 2022), and because opioid cessation results in withdrawal which is itself as stressor, it is possible that TCAP-1 could have utility in facilitating opioid abstinence.…”

Fentanyl-induced reward seeking is sex and dose dependent and is prevented by D-cysteine ethylester

“…In 2021, opioid use disorder (OUD) and subsequent overdose resulted in an estimated 80,411 deaths in the US, incurring a medical cost of more than 1–1.5 trillion dollars ( Serdarevic et al, 2017 ; Torralva and Janowsky, 2019 ; CDC, 2020 ; National Center on Health Statistics, 2021 ; NIDA, 2023 ). OUD is a chronically relapsing disorder that is characterized by compulsive drug-seeking behavior that can be enhanced by drug abstinence and is maintained by encounters with drug-associated cues which elicit strong cravings and promote drug-seeking behaviors ( Mueller et al, 2002 ; Zanda et al, 2021 ; Zhang et al, 2022 ). A large body of literature shows that sex differences impose clinically relevant changes in the vulnerability to OUD with women being prescribed and escalating to higher doses of opioid faster with greater craving and withdrawal symptoms compared to their male counterparts ( Lee and Ho, 2013 ; Manubay et al, 2015 ; Serdarevic et al, 2017 ; Huhn et al, 2019a ; Huhn et al, 2019b ; Pisanu et al, 2019 ; Torralva and Janowsky, 2019 ; CDC, 2020 ; National Center on Health Statistics, 2021 ; Wightman et al, 2021 ).…”