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Neuroscience and Biobehavioral Reviews Feb 2021Since the discovery of pain relieving and rewarding properties of opiates such as morphine or heroin, the human mu-opioid system has been a target for medical research... (Review)
Review
Since the discovery of pain relieving and rewarding properties of opiates such as morphine or heroin, the human mu-opioid system has been a target for medical research on pain processing and addiction. Indeed, pain and pleasure act mutually inhibitory on each other and the mu-opioid system has been suggested as an underlying common neurobiological mechanism. Recently, research interest extended the role of the endogenous mu-opioid system beyond the hedonic value of pain and pleasure towards human social-emotional behavior. Here we propose a mu-opioid feedback model of social behavior. This model is based upon recent findings of opioid modulation of human social learning, bonding and empathy in relation to affiliative and protective tendencies. Fundamental to the model is that the mu-opioid system reinforces socially affiliative or protective behavior in response to positive and negative social experiences with long-term consequences for social behavior and health. The functional implications for stress, anxiety, depression and attachment behaviors are discussed.
Topics: Analgesics, Opioid; Feedback; Humans; Morphine; Receptors, Opioid, mu; Social Behavior
PubMed: 33359094
DOI: 10.1016/j.neubiorev.2020.12.013 -
Molecular Psychiatry Apr 2021Opioids, such as morphine, are clinic analgesics which induce euphoria. Morphine exposure modifies the excitability and functional interactions between neurons, while...
Opioids, such as morphine, are clinic analgesics which induce euphoria. Morphine exposure modifies the excitability and functional interactions between neurons, while the underlying cellular and molecular mechanisms, especially how morphine assembles heterogeneous interneurons (INs) in prelimbic cortex (PrL) to mediate disinhibition and reward, are not clear. Using approaches of optogenetics, electrophysiology, and cell type-specific RNA-seq, we show that morphine attenuates the inhibitory synaptic transmission from parvalbumin (PV)-INs onto pyramidal neurons in PrL via μ-opioid receptor (MOR) in PV-INs. Meanwhile, morphine enhances the inhibitory inputs from somatostatin (SST)-INs onto PV-INs, and thus disinhibits pyramidal neurons via δ-opioid receptor (DOR)-dependent Rac1 upregulation in SST-INs. We show that MOR in PV-INs is required for morphine-induced behavioral sensitization, while DOR as well as Rac1 activity in SST-INs is required for morphine-induced conditioned place preference and hyper-locomotion. These results reveal that SST- and PV-INs, functioning in PrL as a disinhibitory architecture, are coordinated by morphine via different opioid receptors to disinhibit pyramidal neurons and enhance reward.
Topics: Interneurons; Morphine; Parvalbumins; Pyramidal Cells; Reward
PubMed: 31413370
DOI: 10.1038/s41380-019-0480-7 -
Journal of Trace Elements in Medicine... Jul 2020Addiction is a pressing social problem worldwide and opioid dependence can be considered the strongest and most difficult addiction to treat. Mesolimbic and mesocortical... (Review)
Review
Addiction is a pressing social problem worldwide and opioid dependence can be considered the strongest and most difficult addiction to treat. Mesolimbic and mesocortical dopaminergic pathways play an important role in modulation of cognitive processes and decision making and, therefore, changes in dopamine metabolism are considered the central basis for the development of dependence. Disturbances caused by excesses or deficiency of certain elements have a significant impact on the functioning of the central nervous system (CNS) both in physiological conditions and in pathology and can affect the cerebral reward system and therefore, may modulate processes associated with the development of addiction. In this paper we review the mechanisms of interactions between morphine and zinc, manganese, chromium, cadmium, lead, fluoride, their impact on neural pathways associated with addiction, and on antinociception and morphine tolerance and dependence.
Topics: Animals; Humans; Morphine; Morphine Dependence; Neural Pathways; Transition Elements
PubMed: 32179426
DOI: 10.1016/j.jtemb.2020.126495 -
American Journal of Respiratory and... Dec 2021
Topics: Analgesics, Opioid; Fentanyl; Humans; Infusions, Intravenous; Intensive Care Units; Morphine
PubMed: 34644514
DOI: 10.1164/rccm.202109-2112ED -
Respiratory Physiology & Neurobiology Aug 2022We determined whether intravenous injections of the membrane-permeable ventilatory stimulants, D-cysteine ethyl ester (ethyl (2 S)- 2-amino-3-sulfanylpropanoate)...
D-cysteine ethyl ester and D-cystine dimethyl ester reverse the deleterious effects of morphine on arterial blood-gas chemistry and Alveolar-arterial gradient in anesthetized rats.
We determined whether intravenous injections of the membrane-permeable ventilatory stimulants, D-cysteine ethyl ester (ethyl (2 S)- 2-amino-3-sulfanylpropanoate) (D-CYSee) and D-cystine dimethyl ester (methyl (2 S)- 2-amino-3-[[(2 S)- 2-amino-3-methoxy-3-oxopropyl]disulfanyl] propanoate) (D-CYSdime), could overcome the deleterious actions of intravenous morphine on arterial blood pH, pCO, pO and sO, and Alveolar-arterial (A-a) gradient (i.e., the measure of exchange of gases in the lungs) in Sprague Dawley rats anesthetized with isoflurane. Injection of morphine (2 mg/kg, IV) caused pronounced reductions in pH, pO and sO accompanied by elevations in pCO all which are suggestive of diminished ventilation, and elevations in A-a gradient, which suggests a mismatch of ventilation-perfusion. Subsequent boluses of D-cysteine ethyl ester (2 ×100 μmol/kg, IV) or D-cystine dimethyl ester (2 ×50 μmol/kg, IV) rapidly reversed of the negative actions of morphine on pH, pCO, pO and sO and A-a gradient. Similar injections of D-cysteine (2 ×100 μmol/kg, IV) were without effect, whereas injections of D-cystine (2 ×50 μmol/kg, IV) produced a modest reversal. Our data show that D-cysteine ethyl ester and D-cystine dimethyl ester readily overcome the deleterious effects of morphine on arterial blood gas (ABG) chemistry and A-a gradient by mechanisms that may depend upon their ability to rapidly enter cells. As a result of their known ability to enter the brain, lungs, muscles of the chest wall, and most likely the major peripheral chemoreceptors (i.e., carotid bodies), the effects of the thiolesters on changes in ABG chemistry and A-a gradient elicited by morphine likely involve central and peripheral mechanisms. We are employing target prediction methods to identify an array of in vitro and in vivo methods to test potential functional proteins by which D-CYSee and D-CYSdime modulate the effects of morphine on breathing.
Topics: Animals; Cysteine; Cystine; Morphine; Rats; Rats, Sprague-Dawley
PubMed: 35447347
DOI: 10.1016/j.resp.2022.103912 -
Nature Communications Feb 2021Roughly half of the drug overdose-related deaths in the United States are related to synthetic opioids represented by fentanyl which is a potent agonist of mu-opioid...
Roughly half of the drug overdose-related deaths in the United States are related to synthetic opioids represented by fentanyl which is a potent agonist of mu-opioid receptor (mOR). In recent years, X-ray crystal structures of mOR in complex with morphine derivatives have been determined; however, structural basis of mOR activation by fentanyl-like opioids remains lacking. Exploiting the X-ray structure of BU72-bound mOR and several molecular simulation techniques, we elucidated the detailed binding mechanism of fentanyl. Surprisingly, in addition to the salt-bridge binding mode common to morphinan opiates, fentanyl can move deeper and form a stable hydrogen bond with the conserved His297, which has been suggested to modulate mOR's ligand affinity and pH dependence by previous mutagenesis experiments. Intriguingly, this secondary binding mode is only accessible when His297 adopts a neutral HID tautomer. Alternative binding modes may represent a general mechanism in G protein-coupled receptor-ligand recognition.
Topics: Analgesics, Opioid; Fentanyl; Ligands; Models, Molecular; Molecular Dynamics Simulation; Morphine; Receptors, Opioid, mu; Structure-Activity Relationship
PubMed: 33579956
DOI: 10.1038/s41467-021-21262-9 -
Pharmacology Research & Perspectives Aug 2023Morphine induces spinal 5-hydroxytryptamine (5-HT) release, but the role and mechanism of the spinal 5-HT release induced by morphine are not well understood. The...
Morphine induces spinal 5-hydroxytryptamine (5-HT) release, but the role and mechanism of the spinal 5-HT release induced by morphine are not well understood. The purpose of this study was to define the role and mechanism of spinal 5-HT release induced by oral morphine. We also examined whether persistent pain affected the spinal 5-HT release induced by oral morphine. Spinal 5-HT release was measured using microdialysis of lumbar cerebrospinal fluid (CSF). Two opioids, morphine and oxycodone, were orally administered and 5-HT release was measured in awake rats. Naloxone and β-funaltrexamine (β-FNA) were used to determine whether the effect of morphine on 5-HT release was mediated by opioid receptor activation. To study persistent pain, a formalin test was used. At 45 min after oral morphine administration, the formalin test was started and spinal 5-HT release was measured. Oral morphine, but not oral oxycodone, increased 5-HT release at the spinal cord to approximately 4000% of the baseline value. This effect of morphine was not antagonized by either naloxone or β-FNA at a dose that antagonized the antinociceptive effect of morphine. Formalin-induced persistent pain itself had no effect on spinal 5-HT release but enhanced the oral morphine-induced spinal 5-HT release. Oral morphine-induced spinal 5-HT release was not mediated by opioid receptor activation. Spinal 5-HT induced by oral morphine did not play a major role in the antinociceptive effect of morphine in the hot plate test. Persistent pain increased oral morphine-induced spinal 5-HT release.
Topics: Animals; Rats; Receptors, Opioid; Serotonin; Oxycodone; Morphine; Analgesics, Opioid; Naloxone; Pain
PubMed: 37488088
DOI: 10.1002/prp2.1119 -
Neuroscience Dec 2022Morphine and other opioid analgesics are the drugs of election to treat moderate-to-severe pain, and they elicit their actions by binding to the opioid receptors....
Morphine and other opioid analgesics are the drugs of election to treat moderate-to-severe pain, and they elicit their actions by binding to the opioid receptors. Cocaine is a potent inhibitor of dopamine, serotonin, and noradrenaline reuptake, as it blocks DAT, the dopamine transporter, causing an increase in the local concentration of these neurotransmitters in the synaptic cleft. The molecular effects of these drugs have been studied in specific brain areas or nuclei, but the systemic effects in the whole organism have not been comprehensively analyzed. This study aims to analyze the transcriptomic changes elicited by morphine (10 uM) and cocaine (15 uM) in zebrafish embryos. An RNAseq assay was performed with tissues extracts from zebrafish embryos treated from 5 hpf (hours post fertilization) to 72 hpf, and the most representative deregulated genes were experimentally validated by qPCR. We have found changes in the expression of genes related to lipid metabolism, chemokine receptor ligands, visual system, hemoglobins, and metabolic detoxification pathways. Besides, morphine and cocaine modified the global DNA methylation pattern in zebrafish embryos, which would explain the changes in gene expression elicited by these two drugs of abuse.
Topics: Animals; Morphine; Zebrafish; Cocaine; Transcriptome; Receptors, Opioid
PubMed: 36404518
DOI: 10.1016/j.neuroscience.2022.10.017 -
Addiction Biology May 2024Opioid addiction is a relapsing disorder marked by uncontrolled drug use and reduced interest in normally rewarding activities. The current study investigated the impact...
Opioid addiction is a relapsing disorder marked by uncontrolled drug use and reduced interest in normally rewarding activities. The current study investigated the impact of spontaneous withdrawal from chronic morphine exposure on emotional, motivational and cognitive processes involved in regulating the pursuit and consumption of food rewards in male rats. In Experiment 1, rats experiencing acute morphine withdrawal lost weight and displayed somatic signs of drug dependence. However, hedonically driven sucrose consumption was significantly elevated, suggesting intact and potentially heightened reward processing. In Experiment 2, rats undergoing acute morphine withdrawal displayed reduced motivation when performing an effortful response for palatable food reward. Subsequent reward devaluation testing revealed that acute withdrawal disrupted their ability to exert flexible goal-directed control over reward seeking. Specifically, morphine-withdrawn rats were impaired in using current reward value to select actions both when relying on prior action-outcome learning and when given direct feedback about the consequences of their actions. In Experiment 3, rats tested after prolonged morphine withdrawal displayed heightened rather than diminished motivation for food rewards and retained their ability to engage in flexible goal-directed action selection. However, brief re-exposure to morphine was sufficient to impair motivation and disrupt goal-directed action selection, though in this case, rats were only impaired in using reward value to select actions in the presence of morphine-paired context cues and in the absence of response-contingent feedback. We suggest that these opioid-withdrawal induced deficits in motivation and goal-directed control may contribute to addiction by interfering with the pursuit of adaptive alternatives to drug use.
Topics: Animals; Substance Withdrawal Syndrome; Reward; Motivation; Male; Goals; Morphine; Rats; Morphine Dependence; Narcotics; Conditioning, Operant
PubMed: 38706098
DOI: 10.1111/adb.13393 -
Molecules (Basel, Switzerland) Jun 2023Opioids are considered the most effective analgesics for the treatment of moderate to severe acute and chronic pain. However, the inadequate benefit/risk ratio of... (Review)
Review
Opioids are considered the most effective analgesics for the treatment of moderate to severe acute and chronic pain. However, the inadequate benefit/risk ratio of currently available opioids, together with the current 'opioid crisis', warrant consideration on new opioid analgesic discovery strategies. Targeting peripheral opioid receptors as effective means of treating pain and avoiding the centrally mediated side effects represents a research area of substantial and continuous attention. Among clinically used analgesics, opioids from the class of morphinans (i.e., morphine and structurally related analogues) are of utmost clinical importance as analgesic drugs activating the mu-opioid receptor. In this review, we focus on peripheralization strategies applied to -methylmorphinans to limit their ability to cross the blood-brain barrier, thus minimizing central exposure and the associated undesired side effects. Chemical modifications to the morphinan scaffold to increase hydrophilicity of known and new opioids, and nanocarrier-based approaches to selectively deliver opioids, such as morphine, to the peripheral tissue are discussed. The preclinical and clinical research activities have allowed for the characterization of a variety of compounds that show low central nervous system penetration, and therefore an improved side effect profile, yet maintaining the desired opioid-related antinociceptive activity. Such peripheral opioid analgesics may represent alternatives to presently available drugs for an efficient and safer pain therapy.
Topics: Humans; Analgesics, Opioid; Morphinans; Pain; Analgesics; Morphine; Receptors, Opioid, mu
PubMed: 37375318
DOI: 10.3390/molecules28124761