The Mechanisms Involved in Morphine Addiction: An Overview

Abstract

Opioid use disorder is classified as a chronic recurrent disease of the central nervous system (CNS) which leads to personality disorders, co-morbidities and premature death. It develops as a result of long-term administration of various abused substances, along with morphine. The pharmacological action of morphine is associated with its stimulation of opioid receptors. Opioid receptors are a group of G protein-coupled receptors and activation of these receptors by ligands induces significant molecular changes inside the cell, such as an inhibition of adenylate cyclase activity, activation of potassium channels and reductions of calcium conductance. Recent data indicate that other signalling pathways also may be involved in morphine activity. Among these are phospholipase C, mitogen-activated kinases (MAP kinases) or β-arrestin. The present review focuses on major mechanisms which currently are considered as essential in morphine activity and dependence and may be important for further studies.

Keywords: adenylate cyclase activity; mesolimbic system; mitogen-activated kinases (MAP kinases); morphine tolerance and withdrawal signs; opioid receptors; β-arrestin.

Figure 1

Molecular mechanisms of morphine action. A binding of ligand with an opioid receptor activates Go or Gi protein. G protein is composed of three subunits: α, β and γ. The ligand binding results in opioid receptor activation by GTP binding to the α subunit. The α-GTP complex dissociates from the dimer βγ-subunits. Both complexes: α-GTP and dimer βγ, participate in intracellular signal transduction. This leads to an inhibition of adenylate cyclase activity and reduction of cAMP level and protein kinase A inside the cell. The activation of potassium channel and cellular hyperpolarisation is observed. The βγ dimer blocks the calcium channel and reduces calcium concentration inside the cells. The chronic stimulation of opioid receptors by morphine induces the phosphorylation of opioid receptors. sAC–soluble adenylyl cyclase; PKA–protein kinase A; CREB–cAMP response element binding protein; PIP2–phosphatidylinositol biphosphate; PLC–phospholipase C; DAG–diacylglycerol; IP3–inositol triphosphate; MAPK–mitogen-activated protein kinases.

Figure 2

Mechanisms of morphine analgesia. Regarding the supraspinal level, opioid analgesics stimulate the μ receptors located on GABAergic interneurons in the RVM decreasing GABA release. GABA suppresses the “OFF” cells in the RVM, which subsequently raises the action potential. Additionally, opioid-induced activation of μ opioid receptors on GABAergic “ON” cells in the RVM inhibits the firing of these cells. Observed at the spinal level, opioid-induced analgesia is mediated by the activation of presynaptic μ opioid receptors localized in the dorsal horn of the spinal cord. PAG–periaqueductal gray in midbrain; RVM–rostral ventromedial medulla; GABA–gamma-aminobutyric acid; SP–substance P; CGRP–calcitonin gene-related peptide; NMDA-R–N-methyl-D-aspartate receptor; NK1-R–neurokinin-1 receptor; AMPA-R–α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor.

Figure 3

Mechanisms of morphine-induced rewarding effect. The rewarding effect of morphine is associated with stimulation of μ opioid receptors localized at the GABAergic terminals in VTA. It inhibits GABA release and disinhibits dopaminergic neurons in NAc. PFC (prefrontal cortex); NAc (nucleus accumbens); HP (hypothalamus); Amy (amygdala); VTA (ventral tegmental area); GABA (gamma–aminobutyric acid); DA (dopamine).