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The Mechanisms Involved in Morphine Addiction: An Overview

Department of Pharmacology and Pharmacodynamics, Medical University of Lublin, Chodzki 4a St., 20–093 Lublin, Poland
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(17), 4302;
Submission received: 10 July 2019 / Revised: 23 August 2019 / Accepted: 29 August 2019 / Published: 3 September 2019
(This article belongs to the Special Issue Mechanistic Effects of Human Variants Associated with Addiction)


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.

1. Introduction

Among opioid drugs, morphine, codeine, fentanyl or buprenorphine are considered the most effective analgesics for application in post-operative and cancer pain. Their chronic administration is associated with a high rate of abuse potential [1]. Moreover, other opioids, including heroin, are used as recreational drugs and have the ability to induce opioid dependence. Substance 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 [2,3]. Substance use disorder develops as a result of long-term administration of substances with abuse potential and include physical dependence and/or psychological addiction. Physical dependence is associated with the formation of neuroadaptive changes in the CNS, both at the molecular and cellular level [4,5,6,7,8,9,10,11]. These changes are responsible for the occurrence of characteristic withdrawal signs after cessation of drug-taking. The type and severity of withdrawal signs depend on various factors, such as the type of abused drug, drug doses, time period of drug use, patient’s age, age of the first use of drugs or genetic predispositions [12,13]. Psychological dependence is defined as compulsive drug use to improve the perception of well-being [14]. A typical syndrome of psychological addiction in humans includes intensified drug-seeking behaviour, compromised capacity of will, compulsive drug intake despite awareness of its harmful effects, as well as persistent and recurrent obsession, even after years of abstinence.
Scientific research shows that despite numerous social, psychological and medical projects aimed at reducing the phenomenon of substance abuse, the number of individuals with opioid use disorders is steadily increasing worldwide. Nowadays, opioid dependence is considered a global public health crisis. According to the World Health Organization, opioid overdose deaths increased from 69,000 people in 2014 [15] to 118,000 in 2015 [16]. Dramatic increases in maternal opioid use and neonatal abstinence syndrome also has been observed during the last decade. Therefore, in response to the opioid crisis, scientific and government efforts should be focused on several priorities: improving pain management with non-dependent drugs; promoting knowledge of opioid risks; or providing support for cutting-edge research on pain and addiction. The aim of this review is to present current knowledge on mechanisms involved in morphine activity which develop after its acute or chronic administration. The understanding of morphine mechanisms is important for further studies on the activity of the opioidergic system.

2. Morphine and Its Receptors

Morphine and other opioid drugs are able to induce a broad spectrum of pharmacological activity. Occurring in the CNS, they induce strong analgesia, euphoria, sedation, endocrine dysregulation, miosis, antitussive activity or respiratory depression. Additionally, they induce muscle spasms and histamine release in the peripheral nervous system. Observed in clinical practices, there are many opioid drugs that mainly are used as analgesics (Table 1).
The pharmacological action of acute doses of morphine is associated with stimulation of the opioid receptors. It interacts predominantly with the μ opioid receptors. Generally, opioid receptors can be divided into subtypes: μ (μ1, μ2, μ3); δ (δ1, δ2, δ3); and κ (κ1, κ2, κ3) [13,62]. The novel nociception/orphanin FQ receptor is considered to be a non-opioid branch of the opioid receptor family [13]. Opioid receptors are a group of G protein-coupled receptors [63]. They consist of seven transmembrane domains, three extracellular and three intracellular loops, extracellular amino acid N-terminus and intracellular carboxyl C-terminus. Opioid receptors are located both in the central and peripheral nervous system. The first data on localisation of opioid receptors in the nervous system appeared in 1973 [64]. Nowadays, it is known that opioid receptor subtypes are located in areas involved in: 1) pain transmission, such as the thalamus, rostroventral medulla (RVM), periaqueductal grey area (PAG), pons or in the spinal cord of the dorsal horn; 2) the rewarding system, such as the nucleus accumbens, ventral tegmental area or the cortex; 3) other brain areas, such as the hypothalamus, amygdala, ventral pallidum, globus pallidus, nucleus raphe, hippocampus and olfactory bulb [64,65,66,67]. They also occur in peripheral tissues, for example, in the gastrointestinal and in the respiratory tract [67,68].
The localization of opioid receptors in the gut [69] is responsible for regulation of gastrointestinal motility and secretion [70]. Consequently, μ-opioid receptor agonists inhibit gastric emptying, increase pyloric muscle tone, and delay transit through the small and large intestine. All these effects lead to constipation—one of the most impactful adverse effects of morphine and other opioid drugs.
The presence of opioid receptors in the respiratory tract is associated with important clinical indications of morphine [71]. Morphine is used as an antitussive drug, also after surgery within the respiratory system, and in the control of pain due to lung cancer. Conversely, the overdose of morphine induces a high risk of respiratory depression, which is an important limiting factor in morphine therapy [72].
Endogenously, opioid receptors are stimulated by endogenous peptides, such as endomorphins, dynorphins and enkephalins. Endomorphins consist of four aminoacids, including two endogenous ligands (endomorphin-1 and endomorphin-2) that have the highest affinity and selectivity for the µ-opioid receptor in the central and peripheral nervous systems. They are involved in analgesia and reward. Dynorphins (dynorphin A and dynorphin B) exert their effects primarily through the κ-opioid receptor and have less affinity for the μ-opioid receptor and δ-opioid receptor. Enkephalins (met-enkephalin and leu-enkephalin) produce the effect mainly on δ receptors, but they also have an affinity for μ receptors.

3. Molecular Effects of Acute and Chronic Dose of Morphine

A binding of an endogenous (endomorphin molecule) or exogenous (morphine molecule) ligand with an opioid receptor leads to activation of a Go or Gi protein and to subsequent phosphorylation by a family of kinases called the G protein-coupled receptor kinases (GRKs). This induces molecular changes inside the cell, including β-arrestin binding. G protein is composed of three subunits: α, ß and γ. Binding of the ligand to the receptor results in opioid receptor activation by GTP binding to the α subunit, while the α-GTP complex dissociates from the dimer ßγ-subunits. Both complexes, α-GTP and dimer ßγ, participate in intracellular signal transduction. This leads to an inhibition of adenylate cyclase activity and a reduction of cyclic adenosine monophosphate (cAMP) levels in the cell [73,74], as well as suppression of the activity of protein kinase A [75,76]. α-GTP also activates phospholipase-C (PLC) and mitogen-activated protein (MAP) kinases pathways [77]. PLC hydrolyses phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 increases calcium release from the endoplasmic reticulum that activates calcium-dependent signalling. The activation of potassium channels (G-protein gated inward rectifying potassium channel–GIRK-3) is also observed [78], leading to increased hyperpolarisation of the cell, and, indirectly, to reduced cell excitability [77]. The ßγ dimer directly blocks the calcium channel (P/Q-type, N-type, and L-type channel) and reduces calcium concentration [79] in the cell, leading to suppression of other neurotransmitters. The effect of stimulation of opioid receptors on the activity of potassium and calcium channels was repeatedly confirmed in various brain areas (hippocampus, nucleus locus coeruleus, the area abdominal caps, etc.), and this mechanism has been considered a key effect for the stimulation of the opioid receptors [80,81,82,83].
Chronic exposure to morphine induces the phosphorylation of opioid receptors by GRKs. This phosphorylation prepares opioid receptors for arrestin binding. Arrestin binding blocks further G protein-mediated signalling, thereby, inducing desensitization of opioid receptors [84].
Thus, clinically important pharmacological effects of morphine, induced by a single administration of this substance, are connected with multidirectional, molecular mechanisms which occur within the cell. The molecular effects of morphine are shown graphically in Figure 1.

4. Opioid Analgesia

Opioid analgesia is associated strongly with activation of the μ opioid receptors located in CNS. These receptors are localized in subcortical regions of the brain, as previously mentioned, from which the descending pain pathways originate, such as in the thalamus, the PAG and the RVM, as well as in the spinal cord’s dorsal horn [85]. Occurring at the supraspinal level, opioid analgesics stimulate the μ opioid receptors located on GABAergic interneurons in the RVM, hence, decrease GABA release. Physiologically, GABA, by acting on GABA-A receptors, suppresses the “OFF” cells in the RVM, which subsequently raises the action potential. When the GABA level is reduced, the tonic inhibition of “OFF” cells is relieved (i.e., disinhibition) and the “OFF” cells’ signal suppresses pain perception in the spinal cord (descending pain regulation). Additionally, opioid-induced activation of μ opioid receptors on GABAergic “ON” cells in the RVM inhibits the firing of these cells. Thus, the disinhibition of “OFF” cells and the direct inhibition of “ON” cells produce analgesia, an effect which can be measured using thermal nociception tests [86]. Additionally, the amygdala, a brain area responsible for emotional states, indirectly can modify pain transmission.
Regarding the spinal level, opioid-induced analgesic effects are mediated by the activation of presynaptic μ opioid receptors localized in the dorsal horn of the spinal cord. The triggering of these presynaptic receptors causes membrane hyperpolarization. Such changes in membrane polarization lead to the inhibition of mediators of the pain pathway, such as glutamate, substantia P and calcitonin gene-related peptide (CGRP) from nociceptive primary afferent neuron terminals. Consequently, the ascending pain pathway transmission is attenuated.
It should be noted that opioid induced analgesia is a complex process in which μ opioid receptors can be heteromerized with δ or κ opioid receptors. Heterodimeric associations between μ–δ opioid receptors, for example, can be used as a model for the development of novel combination therapies for the treatment of chronic pain and other pathologies [87]. The mechanisms of opioid analgesia are shown graphically in Figure 2.

5. Opioid Rewarding Effects

Generally, the rewarding effect of various addictive substances, including opioids, is associated with stimulation of structures within the mesolimbic system, such as the ventral tegmental area and the nucleus accumbens. This increases the dopamine release in the nucleus accumbens [88] which determines the feeling of pleasure. However, the impulses from other brain structures, such as the ventral striatum, hippocampus, prefrontal cortex or amygdala, also may stimulate the mesolimbic system [8], affecting dopamine levels in the nucleus accumbens. Thus, a dramatic escalation in drug intake, with extended access to drug self-administration, is characterized by a dysregulation of rewarding dopamine pathways in the brain [89,90,91]. Therefore, the rewarding effect of morphine and other opioids is associated with stimulation of μ opioid receptors localized at the GABAergic terminals of the ventral tegmental area. Such stimulation inhibits GABA release that, in turn, disinhibits dopaminergic neurons and leads to the release of dopamine in the nucleus accumbens that induces feelings of euphoria and promotes the development of drug dependence [13,92,93].
While dopamine plays a crucial role in the rewarding action of morphine, many neurotransmitters and neuromodulators in the CNS affect the dopaminergic system and indirectly modulate various aspects of morphine addiction. These neurotransmitters include glutamate [94,95], serotonin [96], γ-aminobutyric acid (GABA) [97,98], noradrenaline [96,99], adenosine [91], nitric oxide [100], orexin [101], and others. Pharmacological manipulation of these neurotransmitters found in the reward pathway potentially can modify craving for drugs of abuse. The mechanisms of a morphine-induced rewarding effect are shown graphically in Figure 3.

6. Morphine as a Dependent Drug

Chronic morphine abuse leads to physical and psychological dependence [8,12,14,102]. Physical dependence on morphine is manifested by characteristic withdrawal symptoms that can develop after abrupt cessation of drug administration [103,104]. Morphine withdrawal symptoms in people include sneezing, runny nose, cough, abdominal pain, diarrhoea, anorexia, anxiety and other effects [105,106]. Withdrawal effects observed in animals include jumping, paw tremors, teeth chattering, wet dog shakes and diarrhoea [103,105,107,108]. Morphine withdrawal symptoms are evoked in experimental studies either by discontinuation of chronic morphine administration or via the administration of opioid receptor antagonists. Naloxone, the most commonly used opioid receptor antagonist in experimental pharmacology, usually is applied in a dose range from 1 to 6 mg/kg [109,110,111]. The severity of morphine withdrawal symptoms is analyzed on the basis of the number of withdrawal episodes [103,111] (Table 2).
Some authors suggest that the decrease in dopamine concentrations in the mesocorticolimbic system plays a critical role in morphine withdrawal [112,113,114,115]. Still, neurotransmitters such as noradrenaline [116], glutamate [117], serotonin [118], orexin [119] and cortisol [120] also may be involved in morphine withdrawal. Furthermore, these changes in neurotransmitters are accompanied by changes in cell signalling pathways such as a significant increase in cAMP level [121] and the deregulation of the MAP kinase pathway (ERK 1/2) [122,123].
Morphine tolerance, the second parameter of physical dependence on this substance, is defined as a need to increase the morphine dose (a rightward shift in the dose–response curve) to achieve the same pharmacological effect [124]. The phenomenon of tolerance develops regarding analgesic, euphoric, sedative, respiratory depressant, and nauseating effects of opioids, but not to their effects on miosis and bowel motility (constipation) [125]. Generally, there are three types of tolerance: pharmacokinetic tolerance; learned tolerance; and pharmacodynamic tolerance. Pharmacokinetic tolerance refers to changes in the distribution or metabolism of the drug, while learned tolerance refers to a reduction in the effects of a drug due to compensatory mechanisms that are learned, such as behaving normally while still intoxicated. The most important form of tolerance relevant to opioids is pharmacodynamic tolerance. This type of tolerance has been related to neuroadaptive changes that take place after long-term exposure to the drug, including changes in receptor density and alteration in receptor coupling to G proteins and signal transduction pathways [126].
During experimental studies, morphine tolerance commonly is analyzed by means of nociception, measured in behavioural tests, like the tail immersion test [103,127] or the hot plate test [128,129] (Table 2). Morphine tolerance may be modified by various neurotransmitters including dopamine [130,131], but also serotonin [132], acetylcholine [133], orexin [134] or endocannabinoids [135] and others.
Behavioral sensitization is a phenomenon involving escalating behavioral responses to repeated exposure to a stimulus such as a drug of abuse like cocaine or opioids, after a drug-free period which can be long-lasting—even to the extent of many years. This effect is related closely to the environment in which the addictive substance is taken. Behavioural sensitization is an important parameter in evaluating the degree of psychological addiction. Animal studies reflect the drug-seeking behaviour in people which often leads to drug use relapse [14]. Experimentally, behavioural sensitization is commonly manifested and measured as an increase in locomotor activity of animals after administration of a challenging dose of the abused substance [136,137]. Furthermore, behavioural sensitization also may be expressed as the enhanced rewarding effect of the addictive substance. During animal studies, this can be observed in the conditioned place preference test [100,138,139]. Less commonly, sensitization may be observed through the intensification of withdrawal signs after repeated withdrawal periods [91,140] (Table 2).
The development of behavioural sensitization occurs through the neuroadaptive changes observed in glutamatergic and dopaminergic neurotransmission [102,141,142,143]. Sensitization is associated with an increased dopamine release in the mesolimbic structures [14,144,145]. The main pathways involved in behavioural sensitization are the dopaminergic pathway from the ventral tegmental area and the glutamatergic pathways from the prefrontal cortex, both terminating in the nucleus accumbens.
The expression of morphine sensitization is associated primarily with an increased dopamine release and with alterations in the sensitivity of dopaminergic D1 receptors in the mesolimbic structures, including the striatum, nucleus accumbens, ventral tegmental area, hippocampus and the prefrontal cortex [4,5,6,7,91,146,147]. Observed in rats, the pharmacological blockade of D1 receptors impairs the expression of sensitization [148]. Similarly, the administration of D1 and D2 receptor antagonists into the nucleus accumbens also inhibits the development of behavioural sensitization in rats [147]. Moreover, published data show that the increased expression of D1 receptors in the shell of the nucleus accumbens, observed during the morphine sensitization process, is associated with elevated MAP kinase activity (ERK 1/2) and this effect is reduced by the D1 receptor antagonist—SCH 23390 [149]. Alternatively, the development of behavioural sensitization is associated more with the glutamatergic system and with the ventral tegmental area because the antagonists of NMDA and AMPA receptors inhibit the acquisition, but not the expression, of behavioural sensitization [150,151]. Thus, various neuroadaptive changes, including alterations in the density of receptors, the neurotransmitter level or deregulation in cell signalling, can be responsible for the expression and acquisition of behavioural sensitization.

7. Molecular Mechanisms of Morphine Tolerance and Dependence

Considering the cellular level, the major effect of an acute dose of morphine is the decrease in cAMP level and hyperpolarization that is induced by changes in the activity of potassium and calcium channels. However, chronic stimulation of opioid receptors by morphine and other opioid ligands induces adaptive changes within opioid receptors. This leads to a decrease in the acute receptor response. Such changes are essential in controlling the receptor activity as they protect receptors against hyperstimulation, promote signal termination and regulate their expression [86]. Consequently, desensitization, internalization, resensitization or downregulation of opioid receptors is developed. These mechanisms lead to the attenuation of the pharmacological activity of morphine and other opioid drugs, which often is observed after chronic exposure to them.
Regarding chronic morphine exposure, it was previously suggested that the down-regulation of µ receptors was responsible mainly for the reduced morphine activity which was manifested as tolerance. This hypothesis, however, was not confirmed in experiments because chronic exposure to morphine did not produce down-regulation of μ receptors [152,153]. Similarly, internalization of μ receptors was previously considered as a neural mechanism underlying morphine tolerance. However, in vitro studies do not confirm the hypothesis because morphine is able to induce a strong tolerance but its effect on μ receptor internalization is poor [154]. Nowadays, an increasing number of evidences link mechanisms of tolerance with desensitization of μ opioid receptors. It should be underlined that the definitions of cellular tolerance and desensitization are similar and, for many years, these terms have been confused. Both are defined as the reduced capacity to respond to the same drug dose. However, desensitization (expressed as “rapid tolerance” in earlier studies) means a progressive agonist-induced reduction of signal transduction in opioid receptors seen during in vitro models, while tolerance is observed during in vivo models. Desensitization develops directly after opioid exposure and is reversed rapidly in agonist-free circumstances [84]. Rapid desensitization depends on potassium and calcium ion activity, while sustained desensitization is related to enzyme activity (adenylyl cyclase or MAP kinases). Nowadays, the enhanced desensitization of opioid receptors is considered as being an important mechanism of morphine tolerance, which results from numerous neuroadaptive changes. The desensitization may be caused by increased adenylate cyclase activity and an elevated cAMP level, for example, which, in turn, affects the activity of the cAMP response element-binding protein (CREB) [155]. Additionally, the desensitization involves G protein uncoupling because, in morphine treated animals, the binding of the GTPα complex is reduced in comparison with control animals. Moreover, morphine induced desensitization of µ receptors is associated closely with deregulation of β-arrestin-1 and β-arrestin-2 levels in the cell [156,157,158]. β-arrestin, a cytosolic protein, is bound to the opioid receptor surface after opioid receptor phosphorylation by a class of serine/threonine kinases (GRKs). Activation of β-arrestin inhibits further cell signalling, which directly produces the receptor desensitization [86,159]. The process of desensitization also is produced by an increase in phosphorylation of MAP kinases. MAP kinases have a large range of potential substrates, including transcription factors controlling gene expression. The role of extracellular signal-regulated kinase 1/2 (ERK1/2) in the effect of chronic morphine administration also was confirmed, although these results are contradictory. Narita et al. [160] and Macey et al. [161] observed that chronic exposure to morphine induced the increase in ERK1/2 phosphorylation, while other authors showed the lack of effect [162,163,164]. There also are some data showing the role of phospholipase C in morphine-induced desensitization [165]. Phospholipase C increases the level of other secondary neurotransmitters, such as inositol– (1,4,5) –triphosphate (IP3) and 1,2-diacylglycerol (DAG). These lead to the elevation of calcium levels in the cell. The phospholipase C also catalyzes the release of arachidonic acid from cell membranes participating in the formation of inflammation [166]. Phospholipase C plays a significant role in morphine activity. The inhibitors of phospholipase C potentiate the antinociceptive effect of a single dose of morphine and reduce morphine tolerance [167,168].
The molecular effects of morphine tolerance and dependence is demonstrated graphically in Figure 1.

8. Epigenetic Mechanisms of Morphine Tolerance and Dependence

Novel data shows that chronic exposure to abused drugs may induce complex epigenetic interactions within a genome thereby regulating patterns of gene expression [169,170,171]. These epigenetic modifications include changes in DNA methylation [172], histone acetylation and demethylation, alterations in DNA accessibility, and chromatin structure modification. They are inherited despite a lack of effect on DNA structure. First evidence on the role of DNA methylation and histone deacetylation in µ opioid receptor expression was published in 2007 [173]. Observed in P19 mouse embryonal carcinoma cells, hypermethylation of DNA silences µ opioid genes at the transcriptional level and DNA demethylation induces higher µ opioid gene expression. Moreover, µ opioid receptor expression also was increased after pharmacological manipulation, such as administration of a demethylating agent (5′-aza-2′-deoxycytidine) and histone deacetylase inhibitors. It was demonstrated in another study that chromatin modification also participates in µ opioid gene expression [174]. Mashayekhi et al. [175] documented that the alternations in mRNA levels of brain-derivative neurotrophic factor, BDNF, in the ventral tegmental area and the locus coeruleus of rats on the seventh day of morphine abstinence were associated with histone modifications. Another study also confirmed the role of histone methylation in the effects of chronic morphine exposure [176]. Ciccarelli et al. [177] found the augmentation of histone acetylation during naloxone-precipitated morphine withdrawal in the shell of the nucleus accumbens and in the lateral septum. There also are experiments showing that pharmacological inhibition of DNA methylation by 5′-aza-2′-deoxycytidine have an influence on morphine place preference in rats [178,179]. Recent study confirmed the existence of epigenetic changes in numerous brain structures (among others: cerebral cortex, cerebellum, hippocampus, hypothalamus, medulla oblongata, etc.) after acute and chronic exposure to opiates [180].
Although much progress has been made in understanding the mechanisms of opioid activity, little is known about the mechanisms of transcriptional regulation. It seems they are essential regulators of gene expression. Further studies are necessary to define the precise links between the epigenetic alterations and behavioral effects of morphine and other opioids.

9. Biased Opioid Ligands as a New Class of Opioid Analgesics

Since traditional morphine-like drugs hold many adverse effects (itching, constipation, nausea/vomiting, respiratory depression or abuse lability), recently, the ligand biased at the G protein-coupled receptor has been synthesized. These compounds were perceived to preferentially stimulate certain intracellular pathways over others and produce less side-effects. Thus, such drugs could be safer, more effective and well-tolerated then morphine [181]. Thus far, several G protein-biased μ opioid receptor (GPB–MOR) agonists have been developed [182]. They preferentially activate Gαi protein signalling connected with analgesia over β-arrestin signalling that mediate some undesirable effects. TRV130 (oliceridine), was the first such agonist progressed to clinical trial [183]. Another GPB–MOR ligand is a compound referred to as PZM21, which represents the first example of the structure-based discovery of a biased G protein-coupled receptor ligand. PZM21 showed initial promise in animal studies as a potent analgesic without respiratory depression and morphine-like reinforcing effects [184]. However, although GPB–MOR may produce less respiratory depression and gastrointestinal dysfunction at analgesic doses than currently available opioid analgesics, they retain their abuse liability [185]. Other promising therapeutic candidates for pain and itch relief are G protein-biased agonists for the κ opioid receptor [186]. The example of such a compound is Triazole. It did not alter locomotor activity and did not cause sedation in animal models. These effects appeared to arise from its inability to decrease the dopamine release in mouse striatum, thus not adversely affecting the dopaminergic transmission. Furthermore, this compound did not influence the reward circuit in the brain, thus did not trigger signs of dysphoria and aversion, unlike a typical κ opioid agonist. Generally, the discoveries of new pathways and new ligands at the μ/ κ opioid receptor highlight the opportunities for biased ligands as a new class of analgesics providing more efficacious and safer relief from moderate-to-severe pain.
Summing up, morphine, acting on opioid receptors, induces a broad spectrum of pharmacological activity. However, long-term morphine administration generates dysregulation at cellular and molecular levels in the brain, leading to addiction. Despite extensive studies, the effective management of opioid disorders is limited. Therefore, the recognition of mechanisms underlying morphine/opioid dependence seems to be extremely important in searching for new strategies of therapy for morphine/opioid abusers. The present review summarizes the current knowledge on morphine activity and provides a major overview of the mechanisms involved in its acute and chronic exposure.

Author Contributions

Conceptualization, J.L.; Making the table, M.Ł.; Drawing the figures, S.T. and A.M.; Writing—Review and Editing, J.L., M.Ł., S.T., A.M., J.O.-G., J.K.; Supervision J.L.; Edition of Reference M.Ł.


The review was supported by Statutory Activity of Medical University of Lublin (DS 20/2019).

Conflicts of Interest

The authors declare no conflict of interest.


  1. Nutt, D.J.; King, L.A.; Phillips, L.D. Drug harms in the UK: A multicriteria decision analysis. Lancet 2010, 376, 1558–1565. [Google Scholar] [CrossRef]
  2. Korsgaard, H.O.; Torgersen, S.; Wentzel-Larsen, T.; Ulberg, R. Substance abuse and personality disorder comorbidity in adolescent outpatients: Are girls more severely ill than boys? Child Adolesc. Psychiatry Ment. Health 2016, 10, 8. [Google Scholar] [CrossRef] [PubMed]
  3. Fridell, M.; Bäckström, M.; Hesse, M.; Krantz, P.; Perrin, S.; Nyhlén, A. Prediction of psychiatric comorbidity on premature death in a cohort of patients with substance use disorders: A 42-year follow-up. BMC Psychiatry 2019, 19, 150. [Google Scholar] [CrossRef] [PubMed]
  4. Spanagel, R.; Almeida, O.F.X.; Shippenberg, T.S. Long lasting changes in morphine-induced mesolimbic dopamine release after chronic morphine exposure. Synapse 1993, 14, 243–245. [Google Scholar] [CrossRef] [PubMed]
  5. Spanagel, R.; Shippenberg, T.S. Modulation of morphine induced sensitization by endogenous kappa opioid systems in the rat. Neurosci. Lett. 1993, 153, 232–236. [Google Scholar] [CrossRef]
  6. Tjon, G.H.K.; De Vries, T.J.; Ronken, E.; Hogenboom, F.; Wardeh, G.; Mulder, A.H.; Schoffelmeer, A.N. Repeated and chronic morphine administration causes differential long-lasting changes in dopaminergic neurotransmission in rat striatum without changing its δ- and κ-opioid receptor regulation. Eur. J. Pharmacol. 1994, 252, 205–212. [Google Scholar] [CrossRef]
  7. Tjon, G.H.K.; Voorn, P.; Vanderschuren, L.J.M.J.; De Vries, T.J.; Michiels, N.H.L.M.; Jonker, A.J.; Klop, H.; Nestby, P.; Mulder, A.H.; Schoffelmeer, A.N. Delayed occurrence of enhanced striatal preprodynorphin gene expression in behaviorally sensitized rats: Differential long-term effects of intermittent and chronic morphine administration. Neuroscience 1997, 76, 167–176. [Google Scholar] [CrossRef]
  8. Koob, G.F.; Ahmed, S.H.; Boutrel, B.; Chen, S.A.; Kenny, P.J.; Markou, A.; O’Dell, L.E.; Parsons, L.H.; Sanna, P.P. Neurobiological mechanisms in the transition from drug use to drug dependence. Neurosci. Biobehav. Rev. 2004, 27, 739–749. [Google Scholar] [CrossRef] [PubMed]
  9. Nestler, E.J. Molecular mechanisms of drug addiction. Neuropharmacology 2004, 47, 24–32. [Google Scholar] [CrossRef]
  10. Robinson, T.E.; Kolb, B. Structural plasticity associated with exposure to drugs of abuse. Neuropharmacology 2004, 47, 33–46. [Google Scholar] [CrossRef]
  11. Motahari, A.A.; Sahraei, H.; Meftahi, G.H. Role of nitric oxide on dopamine release and morphine-dependency. Basic Clin. Neurosci. 2016, 7, 283–290. [Google Scholar] [PubMed]
  12. Goodman, A. Neurobiology of addiction. An integrative review. Biochem. Pharmacol. 2008, 75, 266–322. [Google Scholar] [CrossRef] [PubMed]
  13. Bodnar, R.J. Endogenous opiates and behavior: 2014. Peptides 2016, 75, 18–70. [Google Scholar] [CrossRef] [PubMed]
  14. Robinson, T.E.; Berridge, K.C. The psychology and neurobiology of addiction: An incentive-sensitization view. Addiction 2000, 95, 91–117. [Google Scholar]
  15. WHO. Guidelines on Community Management of Opioid Overdose. 2014. Available online: 15.06.2019 (accessed on 15 June 2019).
  16. WHO. Information Sheet on Opioid Overdose. Available online: 22.08.2019 (accessed on 22 August 2019).
  17. Orfei, P.; Bigetti, E.; Patrizio, A.; Pinto, G. The use of alfentanil for short duration surgery in pediatric anesthesia. Minerva Anestesiol. 2000, 66, 123–129. [Google Scholar] [PubMed]
  18. White, L.D.; Hodge, A.; Vlok, R.; Hurtado, G.; Eastern, K.; Melhuish, T.M. Efficacy and adverse effects of buprenorphine in acute pain management: Systematic review and meta-analysis of randomised controlled trials. Br. J. Anaesth. 2018, 120, 668–678. [Google Scholar] [CrossRef] [PubMed]
  19. Kumar, R.; Saadabadi, A. Buprenorphine; StatPearls Publishing: Treasure Island, FL, USA, 2018. [Google Scholar]
  20. Harricharan, S.; Farah, K. Buprenorphine Formulations for the Treatment of Opioid Use Disorders: A Review of Comparative Clinical Effectiveness. Cost-Effectiveness and Guidelines; CADTH Rapid Response Reports; Canadian Agency for Drugs and Technologies in Health: Ottawa, ON, Canada, 2017. [Google Scholar]
  21. Szabova, A.; Sadhasivam, S.; Wang, Y.; Nick, T.G.; Goldschneider, K. Comparison of postoperative analgesia with epidural butorphanol/bupivacaine versus fentanyl/bupivacaine following pediatric urological procedures. J. Opioid Manag. 2010, 6, 401–407. [Google Scholar] [CrossRef]
  22. Yokoyama, Y.; Yokoyama, T.; Nagao, Y.; Nakagawa, T.; Magaribuchi, T. Treatment of epidural morphine induced pruritus with butorphanol. Masui 2009, 58, 178–182. [Google Scholar]
  23. Chung, K.F.; Pavord, I.D. Prevalence, pathogenesis, and causes of chronic cough. Lancet 2008, 371, 1364–1374. [Google Scholar] [CrossRef]
  24. Peechakara, B.V.; Gupta, M. Codeine; StatPearls Publishing: Treasure Island, FL, USA, 2018. [Google Scholar]
  25. Palmer, K.R.; Corbett, C.L.; Holdsworth, C.D. Double-blind cross-over study comparing loperamide; codeine and diphenoxylate in the treatment of chronic diarrhea. Gastroenterology 1980, 79, 1272–1275. [Google Scholar] [CrossRef]
  26. Koskela, H.; Naaranlahti, T. Drug therapy for cough. Duodecim 2016, 132, 455–460. [Google Scholar] [PubMed]
  27. Leung, F.W.; Rao, S.S. Approach to fecal incontinence and constipation in older hospitalized patients. Hosp. Pract. (1995) 2011, 39, 97–104. [Google Scholar] [CrossRef] [PubMed]
  28. Schiller, L.R. Treatment of Fecal Incontinence. Curr. Treat. Options Gastroenterol. 2003, 6, 319–327. [Google Scholar] [CrossRef] [PubMed]
  29. Leppert, W. Dihydrocodeine as an opioid analgesic for the treatment of moderate to severe chronic pain. Curr. Drug Metab. 2010, 11, 494–506. [Google Scholar] [CrossRef] [PubMed]
  30. Schug, S.A.; Ting, S. Fentanyl Formulations in the Management of Pain: An Update. Drugs 2017, 77, 747–763. [Google Scholar] [CrossRef] [PubMed]
  31. Dhillon, S. Hydrocodone Bitartrate ER (Hysingla® ER): A Review in Chronic Pain. Clin. Drug Investig. 2016, 36, 969–980. [Google Scholar] [CrossRef]
  32. Davis, M.P.; McPherson, M.L.; Mehta, Z.; Behm, B.; Fernandez, C. What Parenteral Opioids to Use in Face of Shortages of Morphine, Hydromorphone, and Fentanyl. Am. J. Hosp. Palliat. Med. 2018, 35, 1118–1122. [Google Scholar] [CrossRef]
  33. Schildmann, E.K.; Rémi, C.; Bausewein, C. Levodropropizine in the management of cough associated with cancer or nonmalignant chronic disease—A systematic review. J. Pain Palliat. Care Pharmacother. 2011, 25, 209–218. [Google Scholar] [CrossRef]
  34. Gudin, J.; Fudin, J.; Nalamachu, S. Levorphanol use: Past, present and future. Postgrad. Med. 2015, 128, 46–53. [Google Scholar] [CrossRef]
  35. Lasoff, D.R.; Koh, C.H.; Corbett, B.; Minns, A.B.; Cantrell, F.L. Loperamide Trends in Abuse and Misuse Over 13 Years: 2002–2015. Pharmacotherapy 2017, 37, 249–253. [Google Scholar] [CrossRef]
  36. Singer, J.; Jank, A.; Amara, S.; Stepan, P.D.; Kaisers, U.; Hoehne, C. Efficacy and Effects of Parenteral Pethidine or Meptazinol and Regional Analgesia for Pain Relief during Delivery. A Comparative Observational Study. Geburtshilfe Frauenheilkd. 2016, 76, 964–971. [Google Scholar] [CrossRef] [Green Version]
  37. Johnson, K.; Gerada, C.; Greenough, A. Treatment of neonatal abstinence syndrome. Arch. Dis. Child. Fetal Neonatal Ed. 2003, 88, F2–F5. [Google Scholar] [CrossRef] [PubMed]
  38. Anderson, I.B.; Kearney, T.E. Medicine Cabinet Use of methadone. West. J. Med. 2000, 172, 43–46. [Google Scholar] [CrossRef] [PubMed]
  39. Siu, A.; Robinson, C.A. Neonatal Abstinence Syndrome: Essentials for the Practitioner. J. Pediatr. Pharmacol. Ther. 2014, 19, 147–155. [Google Scholar]
  40. Murphy, P.B.; Barrett, M.J. Morphine; StatPearls Publishing: Treasure Island, FL, USA, 2018. [Google Scholar]
  41. Bolser, D.C. Pharmacologic Management of Cough. Otolaryngol. Clin. N. Am. 2010, 43, 147–155. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Logash, M.; Pokotylo, P.; Zboina, B.; Stępień, R.B. Nalbuphine: Some aspects of the research and applications. Med. Stud. 2017, 33, 146–154. [Google Scholar] [CrossRef]
  43. Zeng, Z.; Lu, J.; Shu, C.; Chen, Y.; Guo, T.; Wu, Q.; Yao, S.; Yina, P. A Comparision of Nalbuphine with Morphine for Analgesic Effects and Safety: Meta-Analysis of Randomized Controlled Trials. Sci. Rep. 2015, 5, 10927. [Google Scholar] [CrossRef] [PubMed]
  44. Kubica-Cielińska, A.; Zielińska, M. The use of nalbuphine in paediatric anaesthesia. Anaesthesiol. Intensive Ther. 2015, 47, 252–256. [Google Scholar] [CrossRef] [PubMed]
  45. Laux, G. Update Psychopharmacotherapy. Med. Monatsschr. Pharm. 2017, 40, 4–14. [Google Scholar]
  46. Behar, E.; Bagnulo, R.; Coffin, P.O. Acceptability and Feasibility of Naloxone Prescribing in Primary Care Settings: A Systematic Review. Prev. Med. 2018, 114, 79–87. [Google Scholar] [CrossRef]
  47. Jordan, M.R.; Morrisonponce, D. Naloxone; StatPearls Publishing: Treasure Island, FL, USA, 2018. [Google Scholar]
  48. Liu, M.; Wittbrodt, E. Low-dose oral naloxone reverses opioid-induced constipation and analgesia. J. Pain Symptom. Manag. 2002, 23, 48–53. [Google Scholar] [CrossRef]
  49. Sokol, R.; LaVertu, A.E.; Morrill, D.; Albanese, C.; Schuman-Olivier, Z. Group-based treatment of opioid use disorder with buprenorphine: A systematic review. J. Subst. Abuse Treat. 2018, 84, 78–87. [Google Scholar] [CrossRef] [PubMed]
  50. Gastfriend, D.R. A pharmaceutical industry perspective on the economics of treatments for alcohol and opioid use disorders. Ann. N. Y. Acad. Sci. 2014, 1327, 112–130. [Google Scholar] [CrossRef] [PubMed]
  51. Gkegkes, I.D.; Minis, E.E.; Iavazzo, C. Oxycodone/naloxone in postoperative pain management of surgical patients. J. Opioid Manag. 2018, 14, 52–60. [Google Scholar] [CrossRef] [PubMed]
  52. Wang, N.; Wang, L.; Gao, Y.; Zhou, H.; Wang, J. Analgesic Effect of Preoperative Pentazocine for Laparoscopic Cholecystectomy. Cureus 2016, 8, e948. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Yasaei, R.; Saadabadi, A. Meperidine; StatPearls Publishing: Treasure Island, FL, USA, 2018. [Google Scholar]
  54. Leong, W.L.; Sng, B.L.; Sia, A.T. A comparison between remifentanil and meperidine for labor analgesia: A systematic review. Anesth. Analg. 2011, 113, 818–825. [Google Scholar] [CrossRef] [PubMed]
  55. Bushuven, S.; Kreuer, S.; Kranke, P. Remifentanil Up2date—Part 1. Anasthesiol. Intensivmed. Notfallmed. Schmerzther. 2017, 52, 543–553. [Google Scholar]
  56. Mandel, J.E. Considerations for the use of short-acting opioids in general anesthesia. J. Clin. Anesth. 2014, 26, S1–S7. [Google Scholar] [CrossRef]
  57. Zajączkowska, R.; Przewłocka, B.; Kocot-Kępska, M.; Mika, J.; Leppert, W.; Wordliczek, J. Tapentadol—A representative of a new class of MOR-NRI analgesics. Pharmacol. Rep. 2018, 70, 812–820. [Google Scholar] [CrossRef]
  58. Wolfert, C.; Merbach, M.; Stammler, G.; Emrich, O.; Meid, A.D.; Burhenne, J.; Blank, A.; Mikus, G. Management of chronic pain using extended release tilidine: Quality of life and implication of comedication on tilidine metabolism. Schmerz 2017, 31, 516–523. [Google Scholar] [CrossRef]
  59. Bravo, L.; Mico, J.A.; Berrocoso, E. Discovery and development of tramadol for the treatment of pain. Expert Opin. Drug Discov. 2017, 12, 1281–1291. [Google Scholar] [CrossRef] [PubMed]
  60. Gray, K.; Adhikary, S.D.; Janicki, P. Pharmacogenomics of analgesics in anesthesia practice: A current update of literature. J. Anaesthesiol. Clin. Pharmacol. 2018, 34, 155–160. [Google Scholar] [PubMed]
  61. Khan, A.H.; Rasaily, D. Tramadol Use in Premature Ejaculation: Daily versus Sporadic Treatment. Indian J. Psychol. Med. 2013, 35, 256–259. [Google Scholar] [CrossRef] [PubMed]
  62. Waldhoer, M.; Bartlett, S.E.; Whistler, J.L. Opioid receptors. Annu. Rev. Biochem. 2004, 73, 953–990. [Google Scholar] [CrossRef]
  63. Dhawan, B.N.; Cesselin, F.; Raghubir, R.; Reisine, T.; Bradley, P.B.; Portoghese, P.S.; Hamon, M. International Union of Pharmacology. XII. Classification of opioid receptors. Pharmacol. Rev. 1996, 48, 567–592. [Google Scholar]
  64. Pert, C.B.; Snyder, S.H. Opiate receptor: Demonstration in nervous tissue. Science 1973, 179, 1011–1014. [Google Scholar] [CrossRef] [PubMed]
  65. Gray, A.C.; Coupar, I.M.; White, P.J. Comparison of opioid receptor distributions in the rat central nervous system. Life Sci. 2006, 79, 674–685. [Google Scholar] [CrossRef] [PubMed]
  66. Moskowitz, A.S.; Goodman, R.R. Autoradiographic distribution of mu1 and mu2 opioid binding in the mouse central nervous system. Brain Res. 1985, 360, 117–129. [Google Scholar] [CrossRef]
  67. Wittert, G.; Hope, P.; Pyle, D. Tissue distribution of opioid receptors gene expression in the rat. Biochem. Biophys. Res. Commun. 1996, 218, 877–881. [Google Scholar] [CrossRef]
  68. Gray, A.C.; Coupar, I.M.; White, P.J. Comparison of opioid receptor distributions in the rat ileum. Life Sci. 2006, 78, 1610–1616. [Google Scholar] [CrossRef]
  69. Hughes, J.; Kosterlitz, H.W.; Smith, T.W. The distribution of methionine-enkephalin and leucine-enkephalin in the brain and peripheral tissues. Br. J. Pharmacol. 1977, 61, 639–647. [Google Scholar] [CrossRef] [PubMed]
  70. Wood, J.D.; Galligan, J.J. Function of opioids in the enteric nervous system. Neurogastroenterol. Motil. 2004, 16, 17–28. [Google Scholar] [CrossRef] [PubMed]
  71. Zebraski, S.E.; Kochenash, S.M.; Raffa, R.B. Lung opioid receptors: Pharmacology and possible target for nebulized morphine in dyspnea. Life Sci. 2000, 66, 2221–2231. [Google Scholar] [CrossRef]
  72. Pattinson, K.T.S. Opioids and the control of respiration. Br. J. Anaesth. 2008, 100, 747–758. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Sharma, S.K.; Klee, W.A.; Nirenberg, M. Opiate-dependent modulation of adenylate cyclase. Proc. Natl. Acad. Sci. USA 1977, 74, 3365–3369. [Google Scholar] [CrossRef] [PubMed]
  74. Chakrabarti, S.; Chang, A.; Liu, N.J.; Gintzler, A.R. Chronic opioid treatment augments caveolin-1 scaffolding: Relevance to stimulatory μ-opioid receptor adenylyl cyclase signaling. J. Neurochem. 2016, 139, 737–747. [Google Scholar] [CrossRef] [PubMed]
  75. Fleming, L.M.; Ponjee, G.; Childers, S.R. Inhibition of protein phosphorylation by opioid-inhibited adenylyl cyclase in rat brain membranes. J. Pharmacol. Exp. Ther. 1992, 260, 1416–1424. [Google Scholar] [PubMed]
  76. Zhang, Z.; Pan, Z.Z. Synaptic mechanism for functional synergism between delta- and mu-opioid receptors. J. Neurosci. 2010, 30, 4735–4745. [Google Scholar] [CrossRef] [PubMed]
  77. Law, P.Y.; Wong, Y.H.; Loh, H.H. Molecular mechanisms and regulation of opioid receptor signaling. Annu. Rev. Pharmacol. Toxicol. 2000, 40, 389–430. [Google Scholar] [CrossRef]
  78. North, R.A.; Williams, J.T.; Surprenant, A.; Christie, M.J. Mu and delta receptors belong to a family of receptors that are coupled to potassium channels. Proc. Natl. Acad. Sci. USA 1987, 84, 5487–5491. [Google Scholar] [CrossRef]
  79. Moises, H.C.; Rusin, K.I.; Macdonald, R.L. Mu- and kappa-opioid receptors selectively reduce the same transient components of high-threshold calcium current in rat dorsal root ganglion sensory neurons. J. Neurosci. 1994, 14, 5903–5916. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  80. Zamponi, G.W.; Snutch, T.P. Modulation of voltage-dependent calcium channels by G proteins. Curr. Opin. Neurobiol. 1998, 8, 351–356. [Google Scholar] [CrossRef]
  81. Zamponi, G.W.; Snutch, T.P. Modulating modulation: Crosstalk between regulatory pathways of presynaptic calcium channels. Mol. Interv. 2002, 2, 476–478. [Google Scholar] [CrossRef] [PubMed]
  82. Torrecilla, M.; Marker, C.L.; Cintora, S.C.; Stoffel, M.; Williams, J.T.; Wickman, K. G-protein-gated potassium channels containing Kir3.2 and Kir3.3 subunits mediate the acute inhibitory effects of opioids on locus ceruleus neurons. J. Neurosci. 2002, 22, 4328–4334. [Google Scholar] [CrossRef] [PubMed]
  83. Torrecilla, M.; Quillinan, N.; Williams, J.T.; Wickman, K. Pre- and postsynaptic regulation of locus coeruleus neurons after chronic morphine treatment: A study of GIRK-knockout mice. Eur. J. Neurosci. 2008, 28, 618–624. [Google Scholar] [CrossRef]
  84. Allouche, S.; Noble, F.; Marie, N. Opioid receptor desensitization: Mechanisms and its link to tolerance. Front. Pharmacol. 2014, 5, 280. [Google Scholar] [CrossRef] [PubMed]
  85. Fields, H. State-dependent opioid control of pain. Nat. Rev. Neurosci. 2004, 5, 565–575. [Google Scholar] [CrossRef]
  86. Raehal, K.M.; Bohn, L.M. β-arrestins: Regulatory role and therapeutic potential in opioid and cannabinoid receptor-mediated analgesia. Handb. Exp. Pharmacol. 2014, 219, 427–443. [Google Scholar]
  87. Gomes, I.; Gupta, A.; Filipovska, J.; Szeto, H.H.; Pintar, J.E.; Devi, L.A. A role for heterodimerization of μ and δ opiate receptors in enhancing morphine analgesia. Proc. Natl. Acad. Sci. USA 2004, 101, 5135–5139. [Google Scholar] [CrossRef]
  88. Di Chiara, G. Role of dopamine in the behavioural actions of nicotine related to addiction. Eur. J. Pharmacol. 2000, 393, 295–314. [Google Scholar] [CrossRef]
  89. Anderson, S.M.; Pierce, R.C. Cocaine-induced alterations in dopamine receptor signaling: Implications for reinforcement and reinstatement. Pharmacol. Ther. 2005, 106, 389–403. [Google Scholar] [CrossRef] [PubMed]
  90. Briand, L.A.; Flagel, S.B.; Garcia-Fuster, M.J.; Watson, S.J.; Akil, H.; Sarter, M.; Robinson, T.E. Persistent alterations in cognitive function and prefrontal dopamine D2 receptors following extended, but not limited, access to self-administered cocaine. Neuropsychopharmacology 2008, 33, 2969–2980. [Google Scholar] [CrossRef] [PubMed]
  91. Listos, J.; Baranowska-Bosiacka, I.; Wąsik, A.; Talarek, S.; Tarnowski, M.; Listos, P.; Łupina, M.; Antkiewicz-Michaluk, L.; Gutowska, I.; Tkacz, M.; et al. The adenosinergic system is involved in sensitization to morphine withdrawal signs in rats-neurochemical and molecular basis in dopaminergic system. Psychopharmacology 2016, 233, 2383–2397. [Google Scholar] [CrossRef] [PubMed]
  92. Wise, R.A.; Rompre, P.P. Brain dopamine and reward. Annu. Rev. Psychol. 1989, 40, 191–225. [Google Scholar] [CrossRef] [PubMed]
  93. Johnson, S.W.; North, R.A. Opioids excite dopamine neurons by hyperpolarization of local interneurons. J. Neurosci. 1992, 12, 4. [Google Scholar] [CrossRef]
  94. Sepehrizadeh, Z.; Bahrololoumi Shapourabadi, M.; Ahmadi, S.; Hashemi Bozchlou, S.; Zarrindast, M.R.; Sahebgharani, M. Decreased AMPA GluR2, but not GluR3, mRNA expression in rat amygdala and dorsal hippocampus following morphine-induced behavioural sensitization. Clin. Exp. Pharmacol. Physiol. 2008, 35, 1321–1330. [Google Scholar] [CrossRef] [PubMed]
  95. Farahmandfar, M.; Karimian, S.M.; Zarrindast, M.R.; Kadivar, M.; Afrouzi, H.; Naghdi, N. Morphine sensitization increases the extracellular level of glutamate in CA1 of rat hippocampus via μ-opioid receptor. Neurosci. Lett. 2011, 494, 130–134. [Google Scholar] [CrossRef]
  96. Reith, M.E.; Li, M.Y.; Yan, Q.S. Extracellular dopamine, norepinephrine, and serotonin in the ventral tegmental area and nucleus accumbens of freely moving rats during intracerebral dialysis following systemic administration. Psychopharmacology 1997, 134, 309–317. [Google Scholar] [CrossRef]
  97. Carr, D.B.; Sesack, S.R. GABA-containing neurons in the rat ventral tegmental area project to the prefrontal cortex. Synapse 2000, 38, 114–123. [Google Scholar] [CrossRef]
  98. Frankowska, M.; Wydra, K.; Faron-Górecka, A.; Zaniewska, M.; Kuśmider, M.; Dziedzicka-Wasylewska, M.; Filip, M. Alterations in gamma-aminobutyric acid(B) receptor binding in the rat brain after reinstatement of cocaine-seeking behavior. Pharmacol. Rep. 2008, 60, 834–843. [Google Scholar]
  99. Zaniewska, M.; Filip, M.; Przegalinski, E. The Involvement of Norepinephrine in Behaviors Related to Psychostimulant Addiction. Curr. Neuropharmacol. 2015, 13, 407–418. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  100. Sahraei, H.; Zarei, F.; Eidi, A.; Oryan, S.; Shams, J.; Khoshbaten, A.; Zarrindast, M.R. The role of nitric oxide within the nucleus accumbens on the acquisition and expression of morphine-induced place preference in morphine sensitized rats. Eur. J. Pharmacol. 2007, 556, 99–106. [Google Scholar] [CrossRef]
  101. Alijanpour, S.; Tirgar, F.; Zarrindast, M.R. Role of dorsal hippocampal orexin-1 receptors in memory restoration induced by morphine sensitization phenomenon. Neuroscience 2016, 312, 215–226. [Google Scholar] [CrossRef] [PubMed]
  102. Robinson, T.E.; Berridge, K.C. The incentive sensitization theory of addiction: Some current issues. Philos. Trans. R. Soc. B 2008, 363, 3137–3146. [Google Scholar] [CrossRef]
  103. Listos, J.; Baranowska-Bosiacka, I.; Talarek, S.; Listos, P.; Orzelska, J.; Fidecka, S.; Gutowska, I.; Kolasa, A.; Rybicka, M.; Chlubek, D. The effect of perinatal lead exposure on dopamine receptor D2 expression in morphine dependent rats. Toxicology 2013, 310, 73–83. [Google Scholar] [CrossRef] [PubMed]
  104. Taylor, A.M.; Castonguay, A.; Ghogha, A.; Vayssiere, P.; Pradhan, A.A.; Xue, L.; Mehrabani, S.; Wu, J.; Levitt, P.; Olmstead, M.C.; et al. Neuroimmune regulation of GABAergic neurons within the ventral tegmental area during withdrawal from chronic morphine. Neuropsychopharmacology 2016, 41, 949–959. [Google Scholar] [CrossRef]
  105. Harris, A.C.; Gewirtz, J.C. Acute opioid dependence: Characterizing the early adaptations underlying drug withdrawal. Psychopharmacology 2005, 178, 353–366. [Google Scholar] [CrossRef] [PubMed]
  106. Evans, C.J.; Cahill, C.M. Neurobiology of opioid dependence in creating addiction vulnerability. F1000Research 2016, 5. [Google Scholar] [CrossRef]
  107. Schulteis, G.; Markou, A.; Gold, L.H.; Stinus, L.; Koob, G.F. Relative sensitivity to naloxone of multiple indices of opiate withdrawal: A quantitative dose-response analysis. J. Pharmacol. Exp. Ther. 1994, 271, 1391–1398. [Google Scholar] [PubMed]
  108. Zhang, Z.; Schulteis, G. Withdrawal from acute morphine dependence is accompanied by increased anxiety-like behavior in the elevated plus maze. Pharmacol. Biochem. Behav. 2008, 89, 392–403. [Google Scholar] [CrossRef] [Green Version]
  109. Done, C.; Silverstone, P.; Sharp, T. Effect of naloxone-precipitated morphine withdrawal on noradrenaline release in rat hippocampus in vivo. Eur. J. Pharmacol. 1992, 215, 333–336. [Google Scholar] [CrossRef]
  110. Diaz, S.L.; Kemmling, A.; Balerio, G.N. Baclofen reestablishes striatal and cortical dopamine concentrations during naloxone-precipitated withdrawal. Neurochem. Int. 2003, 42, 293–298. [Google Scholar] [CrossRef]
  111. Hooshmandi, M.; Hosseinmardi, N.; Janahmadi, M.; Khakpai, F.; Rohampour, K.; Doostmohammadi, J. Antagonism of orexin type-1 receptors (OX1Rs) attenuates naloxone-precipitated morphine withdrawal syndrome in rat dorsal hippocampus. Pharmacol. Biochem. Behav. 2017, 158, 39–48. [Google Scholar] [CrossRef] [PubMed]
  112. Koob, G.F.; Stinus, L.; Le Moal, M.; Bloom, F.E. Opponent process theory of motivation: Neurobiological evidence from studies of opiate dependence. Neurosci. Biobehav. Rev. 1989, 13, 135–140. [Google Scholar] [CrossRef]
  113. Acquas, E.; Di Chiara, G. Depression of mesolimbic dopamine transmission and sensitization to morphine during opiate abstinence. J. Neurochem. 1992, 58, 1620–1625. [Google Scholar] [CrossRef] [PubMed]
  114. Diana, M.; Pistis, M.; Muntoni, A.; Gessa, G. Profound decrease of mesolimbic dopaminergic neuronal activity in morphine withdrawn rats. J. Pharmacol. Exp. Ther. 1995, 272, 781–785. [Google Scholar] [PubMed]
  115. Elman, I.; Borsook, D.; Volkow, N.D. Pain and suicidality: Insights from reward and addiction neuroscience. Prog. Neurobiol. 2013, 109, 1–27. [Google Scholar] [CrossRef] [Green Version]
  116. Fox, M.E.; Rodeberg, N.T.; Wightman, R.M. Reciprocal catecholamine changes during opiate exposure and withdrawal. Neuropsychopharmacology 2017, 42, 671–681. [Google Scholar] [CrossRef]
  117. Sepulveda, M.J.; Hernandez, L.; Rada, P.; Tucci, S.; Contreras, E. Effect of precipitated withdrawal on extracellular glutamate and aspartate in the nucleus accumbens of chronically morphine-treated rats: An in vivo microdialysis study. Pharmacol. Biochem. Behav. 1998, 60, 255–262. [Google Scholar] [CrossRef]
  118. Zhang, G.; Wu, X.; Zhang, Y.M.; Liu, H.; Jiang, Q.; Pang, G.; Tao, X.; Dong, L.; Stackman, R.W., Jr. Activation of serotonin 5-HT(2C) receptor suppresses behavioral sensitization and naloxone-precipitated withdrawal symptoms in morphine-dependent mice. Neuropharmacology 2016, 101, 246–254. [Google Scholar] [CrossRef]
  119. Zhou, Y.; Bendor, J.; Hofmann, L.; Randesi, M.; Ho, A.; Kreek, M.J. Mu opioid receptor and orexin/hypocretin mRNA levels in the lateral hypothalamus and striatum are enhanced by morphine withdrawal. J. Endocrinol. 2006, 191, 137–145. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  120. Matinfar, M.; Esfahani, M.M.; Aslany, N.; Davoodi, S.H.; Parsaei, P.; Zarei, G.; Reisi, P. Effect of repeated morphine withdrawal on spatial learning, memory and serum cortisol level in mice. Adv. Biomed. Res. 2013, 2, 80. [Google Scholar] [PubMed]
  121. Meye, F.J.; van Zessen, R.; Smidt, M.P.; Adan, R.A.; Ramakers, G.M. Morphine withdrawal enhances constitutive μ-opioid receptor activity in the ventral tegmental area. J. Neurosci. 2012, 32, 16120–16128. [Google Scholar] [CrossRef] [PubMed]
  122. Bilecki, W.; Zapart, G.; Ligeza, A.; Wawrzczak-Bargiela, A.; Urbański, M.J.; Przewłocki, R. Regulation of the extracellular signal-regulated kinases following acute and chronic opioid treatment. Cell. Mol. Life Sci. 2005, 62, 2369–2375. [Google Scholar] [CrossRef] [PubMed]
  123. Cao, J.L.; He, J.H.; Ding, H.L.; Zeng, Y.M. Activation of the spinal ERK signaling pathway contributes naloxone-precipitated withdrawal in morphine-dependent rats. Pain 2005, 118, 336–349. [Google Scholar] [CrossRef] [PubMed]
  124. Nakamoto, K.; Kawasaki, S.; Kobori, T.; Fujita-Hamabe, W.; Mizoguchi, H.; Yamada, K.; Nabeshima, T.; Tokuyama, S. Involvement of matrix metalloproteinase-9 in the development of morphine tolerance. Eur. J. Pharmacol. 2012, 683, 86–92. [Google Scholar] [CrossRef] [PubMed]
  125. Gustin, H.B.; Akil, H. Opioid analgesics. In Goodman and Gilman’s The Pharmacological Basis of Therapeutics; Hardman, J.G., Limbird, L.E., Eds.; McGraw-Hill: New York, NY, USA, 2001; pp. 569–619. [Google Scholar]
  126. Mitra, S.; Sinatra, R.S. Perioperative management of acute pain in the opioid-dependent patient. Anesthesiology 2004, 101, 212–227. [Google Scholar] [CrossRef]
  127. Cecchi, M.; Capriles, N.; Watson, S.J.; Akil, H. Differential responses to morphine-induced analgesia in the tail-flick test. Behav. Brain Res. 2008, 194, 146–151. [Google Scholar] [CrossRef] [Green Version]
  128. Célérier, E.; Yazdi, M.T.; Castañé, A.; Ghozland, S.; Nyberg, F.; Maldonado, R. Effects of nandrolone on acute morphine responses, tolerance and dependence in mice. Eur. J. Pharmacol. 2003, 465, 69–81. [Google Scholar] [CrossRef]
  129. Joharchi, K.; Jorjani, M. The role of nitric oxide in diabetes-induced changes of morphine tolerance in rats. Eur. J. Pharmacol. 2007, 570, 66–71. [Google Scholar] [CrossRef]
  130. Zarrindast, M.R.; Dinkoub, Z.; Homayoun, H.; Bakhtiarian, A.; Khavandgar, S. Dopamine receptor mechanism(s) and morphine tolerance in mice. J. Psychopharmacol. 2002, 16, 261–266. [Google Scholar] [CrossRef] [PubMed]
  131. Ozdemir, E.; Bagcivan, I.; Gursoy, S. Role of D1/D2 dopamine receptors antagonist perphenazine in morphine analgesia and tolerance in rats. Bosn. J. Basic Med. Sci. 2013, 13, 119–125. [Google Scholar] [CrossRef] [PubMed]
  132. Singh, V.P.; Jain, N.K.; Kulkarni, S.K. Fluoxetine suppresses morphine tolerance and dependence: Modulation of NO-cGMP/DA/serotoninergic pathways. Methods Find. Exp. Clin. Pharmacol. 2003, 25, 273–280. [Google Scholar] [CrossRef] [PubMed]
  133. Gawel, K.; Gibula-Bruzda, E.; Dziedzic, M.; Jenda-Wojtanowska, M.; Marszalek-Grabska, M.; Silberring, J.; Kotlinska, J.H. Cholinergic activation affects the acute and chronic antinociceptive effects of morphine. Physiol. Behav. 2017, 169, 22–32. [Google Scholar] [CrossRef] [PubMed]
  134. Abdollahi, H.; Ghaemi-Jandabi, M.; Azizi, H.; Semnanian, S. The role of orexin type-1 receptors in the development of morphine tolerance in locus coeruleus neurons: An electrophysiological perspective. Brain Res. 2016, 1646, 91–97. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  135. Wilson-Poe, A.R.; Lau, B.K.; Vaughan, C.W. Repeated morphine treatment alters cannabinoid modulation of GABAergic synaptic transmission within the rat periaqueductal grey. Br. J. Pharmacol. 2015, 172, 681–690. [Google Scholar] [CrossRef] [PubMed]
  136. Liu, X.S.; Hou, Y.; Yan, T.L.; Guo, Y.Y.; Han, W.; Guan, F.L.; Chen, T.; Li, T. Dopamine D3 receptor-regulated NR2B subunits of N-methyl-d-aspartate receptors in the nucleus accumbens involves in morphine-induced locomotor activity. CNS Neurosci. Ther. 2014, 20, 823–829. [Google Scholar] [CrossRef] [PubMed]
  137. Guegan, T.; Cebrià, J.P.; Maldonado, R.; Martin, M. Morphine-induced locomotor sensitization produces structural plasticity in the mesocorticolimbic system dependent on CB1-R activity. Addict. Biol. 2016, 21, 1113–1126. [Google Scholar] [CrossRef] [PubMed]
  138. Shippenberg, T.S.; Heidbreder, C. Sensitization to the conditioned rewarding effects of cocaine: Pharmacological and temporal characteristics. J. Pharmacol. Exp. Ther. 1995, 273, 808–815. [Google Scholar]
  139. Manzanedo, C.; Aguilar, M.A.; Rodríguez-Arias, M.; Miñarro, J. Sensitization to the rewarding effects of morphine depends on dopamine. J. Neuroreport. 2005, 16, 201–205. [Google Scholar] [CrossRef]
  140. Rothwell, P.E.; Gewirtz, J.C.; Thomas, M.J. Episodic withdrawal promotes psychomotor sensitization to morphine. Neuropsychopharmacology 2010, 35, 2579–2589. [Google Scholar] [CrossRef] [PubMed]
  141. Vanderschuren, L.J.; Kalivas, P.W. Alterations in dopaminergic and glutamatergic transmission in the induction and expression of behavioral sensitization: A critical review of preclinical studies. Psychopharmacology 2000, 151, 99–120. [Google Scholar] [CrossRef] [PubMed]
  142. Wolf, M.E. LTP may trigger addiction. Mol. Interv. 2003, 3, 248–252. [Google Scholar] [CrossRef] [PubMed]
  143. Vanderschuren, L.J.; Pierce, R.C. Sensitization processes in drug addiction. In Behavioral Neuroscience of Drug Addiction 2010; Springer: Berlin/Heidelberg, Germany, 2010; pp. 179–195. [Google Scholar]
  144. Le Moal, M.; Simon, H. Mesocorticolimbic dopaminergic network: Functional and regulatory roles. Physiol. Rev. 1991, 71, 155–234. [Google Scholar] [CrossRef] [PubMed]
  145. Robinson, T.E.; Berridge, K.C. The neural basis of drug craving: An incentive-sensitization theory of addiction. Brain Res. Rev. 1993, 18, 247–291. [Google Scholar] [CrossRef]
  146. Kalivas, P.W.; Duffy, P. Sensitization to repeated morphine injection in the rat: Possible involvement of A10 dopamine neurons. J. Pharmacol. Exp. Ther. 1987, 241, 204–212. [Google Scholar]
  147. Reisi, Z.; Bani-Ardalan, M.; Zarepour, L.; Haghparast, A. Involvement of D1/D2 dopamine receptors within the nucleus accumbens and ventral tegmental area in the development of sensitization to antinociceptive effect of morphine. Pharmacol. Biochem. Behav. 2014, 118, 16–21. [Google Scholar] [CrossRef]
  148. Jeziorski, M.; White, F.J. Dopamine receptor antagonists prevent expression, but not development, of morphine sensitization. Eur. J. Pharmacol. 1995, 275, 235–244. [Google Scholar] [CrossRef]
  149. Borgkvist, A.; Valjent, E.; Santini, E.; Hervé, D.; Girault, J.A.; Fisone, G. Delayed, context- and dopamine D1receptor-dependent activation of ERK in morphine-sensitized mice. Neuropharmacology 2008, 55, 230–237. [Google Scholar] [CrossRef]
  150. Jeziorski, M.; White, F.J.; Wolf, M.E. MK-801 prevents the development of behavioral sensitization during repeated morphine administration. Synapse 1994, 16, 137–147. [Google Scholar] [CrossRef]
  151. Carlezon, W.A., Jr.; Rasmussen, K.; Nestler, E.J. AMPA antagonist LY293558 blocks the development, without blocking the expression, of behavioral sensitization to morphine. Synapse 1999, 31, 256–262. [Google Scholar] [CrossRef]
  152. Stafford, K.; Gomes, A.B.; Shen, J.; Yoburn, B.C. Mu-Opioid receptor downregulation contributes to opioid tolerance in vivo. Biochem. Behav. 2001, 69, 233–237. [Google Scholar] [CrossRef]
  153. Dang, V.C.; Christie, M.J. Mechanisms of rapid opioid receptor desensitization, resensitization and tolerance in brain neurons. Br. J. Pharmacol. 2012, 165, 1704–1716. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  154. Anselmi, L.; Jaramillo, I.; Palacios, M.; Huynh, J.; Sternini, C. Ligand-induced μ opioid receptor internalization in enteric neurons following chronic treatment with the opiate fentanyl. J. Neurosci. Res. 2013, 9, 854–860. [Google Scholar] [CrossRef] [PubMed]
  155. Nestler, E.J. Reflections on: “A general role for adaptations in G-Proteins and the cyclic AMP system in mediating the chronic actions of morphine and cocaine on neuronal function”. Brain Res. 2016, 1645, 71–74. [Google Scholar] [CrossRef] [PubMed]
  156. Bohn, L.M.; Gainetdinov, R.R.; Lin, F.T.; Lefkowitz, R.J.; Caron, M.G. Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence. Nature 2000, 408, 720–723. [Google Scholar] [CrossRef] [PubMed]
  157. Bohn, L.M.; Lefkowitz, R.J.; Gainetdinov, R.R.; Peppel, K.; Caron, M.G.; Lin, F.T. Enhanced morphine analgesia in mice lacking beta-arrestin 2. Science 1999, 286, 2495–2498. [Google Scholar] [CrossRef] [PubMed]
  158. Fan, X.L.; Zhang, J.S.; Zhang, X.Q.; Yue, W.; Ma, L. Differential regulation of beta-arrestin 1 and beta-arrestin 2 gene expression in rat brain by morphine. Neuroscience 2003, 117, 383–389. [Google Scholar] [CrossRef]
  159. Al-Hasani, R.; Bruchas, M.R. Molecular mechanisms of opioid receptor-dependent signaling and behavior. Anesthesiology 2011, 115, 1363–1381. [Google Scholar] [CrossRef]
  160. Narita, M.; Ioka, M.; Suzuki, M.; Narita, M.; Suzuki, T. Effect of repeated administration of morphine on the activity of extracellular signal regulated kinase in the mouse brain. Neurosci. Lett. 2002, 324, 97–100. [Google Scholar] [CrossRef]
  161. Macey, T.A.; Bobeck, E.N.; Hegarty, D.M.; Aicher, S.A.; Ingram, S.L.; Morgan, M.M. Extracellular signal-regulated kinase 1/2 activation counteracts morphine tolerance in the periaqueductal gray of the rat. J. Pharmacol. Exp. Ther. 2009, 331, 412–418. [Google Scholar] [CrossRef] [PubMed]
  162. Ferrer-Alcón, M.; García-Fuster, M.J.; La Harpe, R.; García-Sevilla, J.A. Long-term regulation of signaling components of adenylyl cyclase and mitogen-activated protein kinase in the pre-frontal cortex of human opiate addicts. J. Neurochem. 2004, 90, 220–230. [Google Scholar] [CrossRef] [PubMed]
  163. Muller, D.L.; Unterwald, E.M. In vivo regulation of extracellular signal-regulated protein kinase (ERK) and protein kinase B (Akt) phosphorylation by acute and chronic morphine. J. Pharmacol. Exp. Ther. 2004, 310, 774–782. [Google Scholar] [CrossRef] [PubMed]
  164. Asensio, V.J.; Miralles, A.; García-Sevilla, J.A. Stimulation of mitogen-activated protein kinase kinases (MEK1/2) by mu-, delta- and kappa-opioid receptor agonists in the rat brain: Regulation by chronic morphine and opioid withdrawal. Eur. J. Pharmacol. 2006, 539, 49–56. [Google Scholar] [CrossRef] [PubMed]
  165. Bianchi, E.; Lehmann, D.; Vivoli, E.; Norcini, M.; Ghelardini, C. Involvement of PLC-beta3 in the effect of morphine on memory retrieval in passive avoidance task. J. Psychopharmacol. 2010, 24, 891–896. [Google Scholar] [CrossRef] [PubMed]
  166. Nabemoto, M.; Mashimo, M.; Someya, A.; Nakamura, H.; Hirabayashi, T.; Fujino, H.; Kaneko, M.; Okuma, Y.; Saito, T.; Yamaguchi, N.; et al. Release of arachidonic acid by 2-arachidonoyl glycerol and HU210 in PC12 cells; roles of Src, phospholipase C and cytosolic phospholipase A(2)alpha. Eur. J. Pharmacol. 2008, 590, 1–11. [Google Scholar] [CrossRef] [PubMed]
  167. Smith, F.L.; Lohmann, A.B.; Dewey, W.L. Involvement of phospholipid signal transduction pathways in morphine tolerance in mice. Br. J. Pharmacol. 1999, 128, 220–226. [Google Scholar] [CrossRef] [Green Version]
  168. Williams, J.T.; Ingram, S.L.; Henderson, G.; Chavkin, C.; von Zastrow, M.; Schulz, S.; Koch, T.; Evans, C.J.; Christie, M.J. Regulation of µ-opioid receptors: Desensitization, phosphorylation, internalization, and tolerance. Pharmacol. Rev. 2013, 65, 223–254. [Google Scholar] [CrossRef]
  169. Skinner, M.K. Environmental epigenetic transgenerational inheritance and somatic epigenetic mitotic stability. Epigenetics 2011, 6, 838–842. [Google Scholar] [Green Version]
  170. Novikova, S.I.; He, F.; Bai, J.; Cutrufello, N.J.; Lidow, M.S.; Undieh, A.S. Maternal cocaine administration in mice alters DNA methylation and gene expression in hippocampal neurons of neonatal and prepubertal offspring. PLoS ONE 2008, 3, e1919. [Google Scholar] [CrossRef]
  171. Listos, J.; Talarek, S.; Gryzińska, M.; Listos, P.; Kędzierska, E.; Orzelska-Górka, J.; Łupina, M.; Kotlińska, J.H. Mephedrone exposure in adolescent rats alters the rewarding effect of morphine in adults. Eur. J. Pharmacol. 2017, 810, 63–69. [Google Scholar]
  172. Bird, A. DNA methylation patterns and epigenetic memory. Genes Dev. 2002, 16, 6–21. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  173. Hwang, C.K.; Song, K.Y.; Kim, C.S.; Choi, H.S.; Guo, X.H.; Law, P.Y.; Wei, L.N.; Loh, H.H. Evidence of endogenous mu opioid receptor regulation by epigenetic control of the promoters. Mol. Cell. Biol. 2007, 27, 4720–4736. [Google Scholar] [CrossRef] [PubMed]
  174. Hwang, C.K.; Kim, C.S.; Kim, D.K.; Law, P.Y.; Wei, L.N.; Loh, H.H. Up-regulation of the mu-opioid receptor gene is mediated through chromatin remodeling and transcriptional factors in differentiated neuronal cells. Mol. Pharmacol. 2010, 78, 58–68. [Google Scholar] [CrossRef] [PubMed]
  175. Mashayekhi, F.J.; Rasti, M.; Rahvar, M.; Mokarram, P.; Namavar, M.R.; Owji, A.A. Expression levels of the BDNF gene and histone modifications around its promoters in the ventral tegmental area and locus ceruleus of rats during forced abstinence from morphine. Neurochem. Res. 2012, 37, 1517–1523. [Google Scholar] [CrossRef] [PubMed]
  176. Sun, H.; Maze, I.; Dietz, D.M.; Scobie, K.N.; Kennedy, P.J.; Damez-Werno, D.; Neve, R.L.; Zachariou, V.; Shen, L.; Nestler, E.J. Morphine epigenomically regulates behavior through alterations in histone H3 lysine 9 dimethylation in the nucleus accumbens. J. Neurosci. 2012, 32, 17454–17464. [Google Scholar] [CrossRef] [PubMed]
  177. Ciccarelli, A.; Calza, A.; Santoru, F.; Grasso, F.; Concas, A.; Sassoè-Pognetto, M.; Giustetto, M. Morphine withdrawal produces ERK-dependent and ERK-independent epigenetic marks in neurons of the nucleus accumbens and lateral septum. Neuropharmacology 2013, 70, 168–179. [Google Scholar] [CrossRef]
  178. Liu, P.; Zhang, J.; Li, M.; Sui, N. Distinctive Roles of 5-aza-2′-deoxycytidine in Anterior Agranular Insular and Basolateral Amygdala in Reconsolidation of Aversive Memory Associated with Morphine in Rats. Front. Behav. Neurosci. 2016, 10, 50. [Google Scholar] [CrossRef]
  179. Zhang, J.J.; Han, J.; Sui, N. Okadaic acid blocks the effects of 5-aza-2-deoxycytidine on consolidation, acquisition and retrieval of morphine-induced place preference in rats. Neuropharmacology 2014, 86, 282–293. [Google Scholar] [CrossRef]
  180. Barrow, T.M.; Byun, H.M.; Li, X.; Smart, C.; Wang, Y.X.; Zhang, Y.; Baccarelli, A.A.; Guo, L. The effect of morphine upon DNA methylation in ten regions of the rat brain. Epigenetics 2017, 12, 1038–1047. [Google Scholar] [CrossRef] [Green Version]
  181. Chen, X.T.; Pitis, P.; Liu, G.; Yuan, C.; Gotchev, D.; Cowan, C.L.; Rominger, D.H.; Koblish, M.; Dewire, S.M.; Crombie, A.L.; et al. Structure-activity relationships and discovery of a G protein biased µ opioid receptor ligand, [(3-methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro-[4.5]de can-9-yl]ethyl})amine (TRV130), for the treatment of acute severe pain. J. Med. Chem. 2013, 56, 8019–8031. [Google Scholar] [CrossRef] [PubMed]
  182. Cheng, J.X.; Cheng, T.; Li, W.H.; Liu, G.X.; Zhu, W.L.; Tang, Y. Computational insights into the G-protein-biased activation and inactivation mechanisms of the μ opioid receptor. Acta Pharmacol. Sin. 2018, 39, 154–164. [Google Scholar] [CrossRef] [PubMed]
  183. Madariaga-Mazón, A.; Marmolejo-Valencia, A.F.; Li, Y.; Toll, L.; Houghten, R.A.; Martinez-Mayorga, K. Mu-Opioid receptor biased ligands: A safer and painless discovery of analgesics? Drug Discov. Today 2017, 22, 1719–1729. [Google Scholar] [CrossRef] [PubMed]
  184. Manglik, A.; Lin, H.; Aryal, D.K.; McCorvy, J.D.; Dengler, D.; Corder, G.; Levit, A.; Kling, R.C.; Bernat, V.; Hübner, H.; et al. Structure-based discovery of opioid analgesics with reduced side effects. Nature 2016, 537, 185–190. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  185. Negus, S.S.; Freeman, K.B. Abuse Potential of Biased Mu Opioid Receptor Agonists. Trends Pharmacol. Sci. 2018, 39, 916–919. [Google Scholar] [CrossRef]
  186. Ranjan, R.; Pandey, S.; Shukla, A.K. Biased Opioid Receptor Ligands: Gain without Pain. Trends Endocrinol. Metab. 2017, 28, 247–249. [Google Scholar] [CrossRef] [PubMed]
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 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.
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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 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.
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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).
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).
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Table 1. Agonists of µ receptors which are useful in clinical practices.
Table 1. Agonists of µ receptors which are useful in clinical practices.
Drug NamesStructural FormulaIndications
Alfentanil Ijms 20 04302 i001- anaesthesia in surgery [17]
Buprenorphine Ijms 20 04302 i002- relieve moderate-to-severe pain [18]
- substitute treatment for opioid addiction [19]
- Neonatal Abstinence Syndrome [20]
Butorphanol Ijms 20 04302 i003- treat moderate-to-severe pain [21]
- relieve acute morphine-induced pruritus [22]
Codeine Ijms 20 04302 i004- treatment of chronic cough [23]
- relief of moderate-to-severe pain [24]
- treat persistent diarrhoea [25]
Dextromethorphan Ijms 20 04302 i005- temporary relief of coughs without phlegm [26]
Diphenoxylate Ijms 20 04302 i006- acute and chronic diarrhoea of various origins [27]
- reduction in the amount of faecal fluid after ileostomy and colostomy [28]
Dihydrocodeine Ijms 20 04302 i007- treat moderate-to-severe pain [29]
- treat dry cough [29]
- treat diarrhoea [29]
Fentanyl Ijms 20 04302 i008- treatment of severe, chronic pain [30]
- used for surgical anaesthesia [30]
Hydrocodone Ijms 20 04302 i009- the management of pain severe enough to require daily, around-the-clock use [31]
Hydromorphone Ijms 20 04302 i010- relieve moderate-to-severe pain [32]
Laevodropropizine Ijms 20 04302 i011- treat dry cough [33]
Levorphanol Ijms 20 04302 i012- use in moderate-to-severe pain [34]
Loperamide Ijms 20 04302 i013- stop diarrhoea [35]
Meptazinol Ijms 20 04302 i014- relieve moderate-to-severe pain (among others, obstetrics) [36]
Methadone Ijms 20 04302 i015- treatment of opiate dependence [37]
- the treatment chronic, severe pain [38]
- treatment of neonatal abstinence syndrome [39]
Morphine Ijms 20 04302 i016- moderate-to-severe pain relief [40]
- used for procedural sedation [40]
- sporadically used as an antitussive drug [41]
- treatment of Neonatal Abstinence Syndrome [39]
Nalbuphine Ijms 20 04302 i017- itching treatment [42]
- recommended for weak-to-moderately severe pain [42]
- sedation [43]
- anaesthesia [44]
Nalmefene Ijms 20 04302 i018- reduction of alcohol consumption [45]
Naloxone Ijms 20 04302 i019- Treatment of poisoning, overdose of opioid substances [46]
- reversal of undesirable effects from opioid used during anaesthesia [47]
- counteracting the occurrence of opioid-induced constipation [48]
- substitute treatment of opioid dependence [49]
Naltrexone Ijms 20 04302 i020- treatment of alcoholism [50]
Oxycodone Ijms 20 04302 i021- treatment of opioid-induced constipation [48]
- pain treatment [51]
Pentazocine Ijms 20 04302 i022- treatment of moderate-to-severe pain [52]
- a preanaesthetic or preoperative medication [52]
Pethidine Ijms 20 04302 i023- the treatment of moderate-to-severe pain [53]
- used as an adjunct to preoperative medications to reduce shivering [53]
- relief of childbirth pain [54]
Remifentanil Ijms 20 04302 i024- relief of childbirth pain [54]
- treatment of moderate-to-severe pain [55]
- providing anaesthesia and sedation [55]
Sulfentanil Ijms 20 04302 i025- management of moderate-to-severe pain [56]
- anaesthesia [56]
Tapentadol Ijms 20 04302 i026- to help relieve moderate-to-severe pain [57]
Tilidine Ijms 20 04302 i027- treatment of pain [58]
Tramadol Ijms 20 04302 i028- treat moderate-to-severe chronic pain [59]
- relief of childbirth pain [59]
- anaesthesia [60]
- premature ejaculation [61]
Table 2. The experimental procedures in particular phases of addiction.
Table 2. The experimental procedures in particular phases of addiction.
Experimental Procedures for Phases of Addiction
Morphine dependence is obtained commonly by chronic administration of increasing doses (from 10 to 50–100 mg/kg) of morphine, twice a day for 5–9 consecutive days.
Morphine withdrawal is obtained in morphine dependent animals either by discontinuation of chronic morphine administration or via administration of an opioid receptor antagonist, such as naloxone, at a range of doses from 1 to 6 mg/kg. The severity of morphine withdrawal symptoms is analyzed on the basis of the number of withdrawal episodes, such as jumpings, paw tremors, teeth chattering, wet dog shakes and diarrhoea.
Morphine tolerance is obtained by repeated administration of the same dose of morphine (10 mg/kg) for several (3–7) consecutive days. Commonly, it is analyzed by comparison of the reaction of animals on nociceptive stimulus, recorded on the first and last day of morphine administration. Morphine tolerance commonly is measured in behavioural tests, such as the tail immersion test or the hot plate test.
Morphine-induced behavioral sensitization is related closely to the environment in which the addictive substance is taken and reflects morphine-seeking behavior in studied animals. It is obtained by administration of a challenge dose of morphine (at range of 1–10 mg/kg) in morphine dependent animals after several days (7–10) of a morphine-free period. It is measured as an increase in locomotor activity of animals, rarely as the enhanced rewarding effect.

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Listos, J.; Łupina, M.; Talarek, S.; Mazur, A.; Orzelska-Górka, J.; Kotlińska, J. The Mechanisms Involved in Morphine Addiction: An Overview. Int. J. Mol. Sci. 2019, 20, 4302.

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Listos J, Łupina M, Talarek S, Mazur A, Orzelska-Górka J, Kotlińska J. The Mechanisms Involved in Morphine Addiction: An Overview. International Journal of Molecular Sciences. 2019; 20(17):4302.

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Listos, Joanna, Małgorzata Łupina, Sylwia Talarek, Antonina Mazur, Jolanta Orzelska-Górka, and Jolanta Kotlińska. 2019. "The Mechanisms Involved in Morphine Addiction: An Overview" International Journal of Molecular Sciences 20, no. 17: 4302.

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