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Review
. 2022 Jun 22;3(3):e148.
doi: 10.1002/mco2.148. eCollection 2022 Sep.

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

Jia-Jia Zhang  1 , Chang-Geng Song  2 , Ji-Min Dai  3 , Ling Li  1 , Xiang-Min Yang  1 , Zhi-Nan Chen  1
Affiliations
Review

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

Jia-Jia Zhang et al. MedComm (2020). .

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.

Keywords: dependence; mu‐opioid receptor; opioid addiction; reward circuitry; withdrawal syndrome.

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Conflict of interest statement

The authors declare that there is no conflict of interest.

Figures

FIGURE 1
FIGURE 1
Biased signaling of Mu opioid receptors (MORs). The analgesic effects and adverse effects of MORs ligands are mediated by the G‐protein pathway and β‐arrestin pathway, respectively. The analgesic effects are mediated by G proteins, which inhibit AC, activate IRP channels, inhibit T‐type Ca2+ channels, and finally decrease the excitability of neurons. The adverse effects such as tolerance or respiratory depression are mediated by β‐arrestin 2, which leads to the internalization of the receptors. AC, adenylyl cyclase; cAMP, cyclic adenosine monophosphate; Ca2+, calcium ion; Na+, sodion; IRP, inwardly rectifying potassium channels; GRKs, G‐protein receptor kinases; PKC, protein kinase C
FIGURE 2
FIGURE 2
Brain regions within the reward circuitry and the role of MORs. Brain regions and nuclei that participate in reward circuitry and MORs‐mediated rewarding effects are widely distributed in the central nervous system. Ach, acetylcholine; BLA, basolateral amygdala; BNST, bed nuclei of the stria terminalis; DA, dopamine; GABA, γ‐aminobutyric acid; Glu, glutamate; LDT, laterodorsal tegmental nucleus; LH, lateral hypothalamus; NAc, nucleus accumbens; PPT, pedunculopontine tegmental nucleus; PFC, prefrontal cortex; PVT, paraventricular nucleus; RMTg, rostromedial tegmental nucleus; SuM, supramammillary nucleus; VTA, ventral tegmental area
FIGURE 3
FIGURE 3
Schematic coronary view of the dorsal thalamus. The dorsal striatum is located dorsally to the nucleus accumbens and can be subdivided into four territories according to the spatial distribution. The four territories of the dorsal striatum include the DL striatum, the DM striatum, the VL striatum, and the VM striatum. MORs are highly expressed on MSNs and Ci in the dorsal striatum. The DL striatum and DM striatum were reported to be involved in the drug addiction process (denoted as red star), while little attention has been given to the role of the VL and VM striatum (denoted as blue star) in drug addiction. Ci, cholinergic interneuron; DL, dorsolateral; DM, dorsomedial; MSN, medium spiny neuron;; VL, ventrolateral; VM, ventromedial
FIGURE 4
FIGURE 4
Schematic horizontal view of the extended amygdala (EA) continuum showing the composition of brain regions. The central EA extends from the central nucleus of the amygdala through IPAC to the lateral bed nuclei of the stria terminalis (BNST). Central EA surrounds the VP. The medial EA is located medially to the central EA and contains the medial nucleus of the amygdala and the lateral BNST. Glu and dopaminergic neurotransmission in the BNST is involved in the rewarding aspects of drug addiction, while PV interneurons are involved in withdrawal behaviors of dependent subjects. Chronic morphine exposure could significantly alter the gene expression profiles of EA. Glu, Glutamatergic; IPAC, interstitial nucleus of the posterior limb of the anterior commissure; PV, parvalbumin; VP, ventral pallidum
FIGURE 5
FIGURE 5
The role of MORs in the development of opioid withdrawal syndrome. MORs are highly expressed in adrenergic neurons in the locus coeruleus (LC). During acute morphine exposure, the activation of MORs by morphine inhibits the activity of adenylyl cyclase (AC), which leads to a decrease in cAMP and subsequent norepinephrine (NA) release. When morphine is chronically administered, adaptation of the LC adrenergic neurons results in the normalization of intracellular cAMP levels. When the supply of morphine stops, the inhibitory effects of morphine on AC diminish, leading to the excess production of cAMP and release of NA, which triggers the occurrence of morphine withdrawal syndrome, including symptoms of aches, muscle spasms, anxiety, and so forth
FIGURE 6
FIGURE 6
Strategies to treat opioid addiction and dependence. Current strategies to treat opioid addiction mainly involve detoxification therapy followed by maintenance of opioid substitution therapy. Detoxification therapies harness MOR antagonists such as naloxone and naltrexone to reverse the acute intoxication effects. Substitution therapies include dose‐monitored opioid agonists, methadone and buprenorphine (with formulations of Suboxone and RBP‐6000), with lasting and less euphoric effects to reduce withdrawal syndrome. α2‐Adrenergic receptor agonists, including clonidine and lofexidine, are non‐opioid therapies targeting the withdrawal symptoms caused by norepinephrine hyperactivity during opioid abstinence
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References

    1. Brownstein MJ. A brief history of opiates, opioid peptides, and opioid receptors. Proc Natl Acad Sci USA. 1993;90(12):5391‐5393. - PMC - PubMed
    1. Corder G, Castro DC, Bruchas MR, Scherrer G. Endogenous and exogenous opioids in pain. Annu Rev Neurosci. 2018;41:453‐473. - PMC - PubMed
    1. McQuay H. Opioids in pain management. Lancet. 1999;353(9171):2229‐2232. - PubMed
    1. Carr DB, Goudas LC. Acute pain. Lancet. 1999;353(9169):2051‐2058. - PubMed
    1. Krauss BS, Calligaris L, Green SM, Barbi E. Current concepts in management of pain in children in the emergency department. Lancet. 2016;387(10013):83‐92. - PubMed