Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278080 (physical dependence)
 1,658 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have shown that chronic, forced exposure to opiates produces specific biochemical adaptations in the ventral tegmental area (VTA) and nucleus accumbens (NAc). The functional consequences of these adaptations have been hypothesized to contribute to certain motivational aspects of drug addiction. In this study, the possibility that similar adaptations could occur in response to intermittent heroin self-administration was tested by comparing homogenates of VTA and NAc from rats self-administering heroin, rats receiving yoked injections of heroin, and rats receiving yoked injections of saline (controls). Tyrosine hydroxylase (TH) immunoreactivity was increased (31-38%) in the VTA and decreased (11%) in the NAc of heroin-exposed rats relative to controls. Heroin exposure also increased cAMP-dependent protein kinase (PKA) activity in both particulate (19-27%) and soluble (17-20%) fractions of the NAc, and decreased (16-17%) the level of Gi alpha immunoreactivity in this brain region. In contrast, no significant biochemical changes were found in the substantia nigra or caudate-putamen, indicating a selective effect on the mesolimbic dopamine system. Overall, adaptations in the VTA and NAc of heroin-exposed rats were similar to, but generally smaller in magnitude than, adaptations produced by chronic morphine administration. However, in contrast to morphine-treated animals, heroin-exposed animals failed to display overt signs of opiate physical dependence, suggesting that adaptations in motivational systems may occur more readily than adaptations in brain regions associated with physical dependence.
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PMID:Biochemical adaptations in the mesolimbic dopamine system in response to heroin self-administration. 886 61

Neuropathic pain has been suggested to be resistant to treatment with opiates. Such perceived lack of opioid responsiveness may be due to the dose-range over which specific opioid compounds have been studied as well as the efficacy of these compounds. Dihydroetorphine is a novel opiate that demonstrates significantly greater analgesic potency compared to morphine, and which also demonstrates diminished capacity for producing physical dependence in laboratory animals. The present study compared the intravenous (i.v.) efficacy, potency and duration of action of dihydroetorphine, fentanyl, heroin and morphine in producing anti-allodynic actions in a rat model of neuropathic pain (ligation of the L5/L6 nerve roots). All compounds produced significant anti-allodynic activity with dihydroetorphine being the most potent (A50 of 0.2 microg kg(-1), i.v.). Morphine was approximately 7440 times less potent than dihydroetorphine while heroin and fentanyl were approximately 163.5 and 6.9 times less potent in producing anti-allodynic actions. Dihydroetorphine also showed a maximal effect at 0.6 microg kg(-1) in all animals tested, while 100 microg kg(-1) was required for heroin to produce a maximal effect. Fentanyl and morphine did not elicit a maximum anti-allodynic response (74 and 76% maximum possible effect (%MPE), respectively). As expected, fentanyl showed a relatively brief duration of action (approximately 20 min at the highest tested dose), while dihydroetorphine and morphine demonstrated anti-allodynic actions for up to 45 min. Heroin had the longest duration of action, producing significant anti-allodynic effects for up to 90 min. These data show that dihydroetorphine and heroin produce potent and long-lasting anti-allodynic actions in this model. Additionally, in contrast to morphine and fentanyl, both dihydroetorphine and heroin were able to achieve a maximal response. The remarkable potency, maximal efficacy and duration of action of these compounds, particularly dihydroetorphine, suggests that these compounds may warrant further examination as potential therapeutic treatments for neuropathic pain states.
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PMID:Anti-allodynic actions of intravenous opioids in the nerve injured rat: potential utility of heroin and dihydroetorphine against neuropathic pain. 978 70

The major pharmacological effects of heroin can be traced back to some structural properties of the morphine molecule. The analgesic effects of heroin derive from the two active metabolites, 6-O-acetylmorphine and morphine, which bind specifically to the mu-opioid receptors of the central nervous system. mu-receptors also mediate other pharmacological actions of heroin i.e. respiratory depression, euphoria and physical dependence. Heroin is more potent and faster acting than morphine as an analgesic drug. Presently, there is a considerable dispute whether heroin should be legalized for the treatment of pain in terminal cancer. Chronic administration of heroin results in the development of tolerance. It is characterized by a shortened duration and decreased intensity of the analgesic, euphoric, sedative and other CNS-depressant effects. Tolerance to opioids is due to increased adaptation of the cells which changes their receptor sites after chronic exposure to the drug. Toxicity of heroin depends markedly on the route of administration in animal studies. Variable composition of street heroin or sudden loss of tolerance can cause fatal heroin overdose of addicts. Respiratory arrest is the most common reason for death among heroin addicts.
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PMID:[Heroin, part III: the pharmacology of heroin]. 1511 43

Heroin and morphine exposure can cause physical dependence, with symptoms manifesting during their withdrawal. Inter-individual differences in symptom frequency during morphine withdrawal are a common finding that, in rodents, is demonstrably attributable to genotype. However, it is not known whether inter-individual differences characterize heroin withdrawal, and whether such variation can be similarly influenced by genotype. Therefore, we injected mice of ten inbred strains with acute and chronic heroin doses and compared their jumping frequencies, a common index of withdrawal magnitude, during naloxone-precipitated withdrawal. The data revealed significant strain frequency differences (range after acute and chronic heroin injection: 0-104 and 0-142 jumps, respectively) and substantial heritability (h(2)=0.94 to 0.96), indicating that genetic variance is associated with heroin withdrawal. The rank order of strain sensitivity for acute and chronic heroin withdrawal jumping, and for the current heroin and previous morphine strain data, were significantly correlated (r=0.75-0.94), indicating their genetic and, ultimately, physiological commonality. These data suggest that the genetic liability to heroin dependence remains constant across a period of heroin intake, and that heroin and morphine dependence may benefit from common treatment strategies.
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PMID:A survey of acute and chronic heroin dependence in ten inbred mouse strains: evidence of genetic correlation with morphine dependence. 1847 45

Heroin is an illicit, highly addictive drug. It is either the most abused or the most rapidly acting member of opioids. Abusers describe a feeling of a surge of pleasurable sensation, named as "rush" or "high". Repeated administration of high doses of heroin results in the induction of physical dependence. Physical dependence refers to an altered physiological state produced by chronic administration of heroin which necessitates the continued administration of the drug to prevent the appearance of a characteristic syndrome, the opioid withdrawal or abstinence syndrome. Withdrawal symptoms may occur within a few hours after the last administration of heroin. Symptoms of the withdrawal include restlessness, insomnia, drug craving, diarrhea, muscle and bone pain, cold flashes with goose bumps, and leg movements. Major withdrawal symptoms peak between 48 and 72 hours after the last dose of heroin and subside after about a week. At this time, weakness and depression are pronounced and nausea and vomiting are common. Nevertheless, some chronic addicts have shown persistent withdrawal signs for many months or even years. Heroin addiction is considered as a behavioural state of compulsive drug use and a high tendency to relapse after periods of abstinence. It is generally accepted that compulsive use and relapse are typically associated with the status of heroin craving or heroin hunger that are difficult to define but appear to be powerful motivational significance in the addiction process. The route of administering heroin varies largely and may indicate the degree of seriousness of the individual's addiction. Intravenous administration seems to be the predominant method of heroin use, but recently a shift in heroin use pattern has been found, i.e. from injection to sniffing and smoking. Frequent injections coupled with widespread sharing of syringes increase the risk of contracting HIV, hepatitis B, C and other blood-borne infectious diseases. Long-term use of heroin has also severe medical consequences such as scarred veins, bacterial infections of blood vessels, liver and kidney diseases, and lung complications.
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PMID:[Heroin addiction]. 2232 4

Heroin, a mu agonist, acts through the mu opioid receptor. The mu opioid receptor gene, OPRM1, undergoes extensive alternative splicing, creating an array of splice variants that are conserved from rodent to humans. Increasing evidence suggests that these OPRM1 splice variants are pharmacologically important in mediating various actions of mu opioids, including analgesia, tolerance, physical dependence, rewarding behavior, as well as addiction. In the present study, we examine expression of the OPRM1 splice variant mRNAs in the medial prefrontal cortex (mPFC), one of the major brain regions involved in decision-making and drug-seeking behaviors, of male human heroin abusers and male rats that developed stable heroin-seeking behavior using an intravenous heroin self-administration (SA) model. The results show similar expression profiles among multiple OPRM1 splice variants in both human control subjects and saline control rats, illustrating conservation of OPRM1 alternative splicing from rodent to humans. Moreover, the expressions of several OPRM1 splice variant mRNAs were dysregulated in the postmortem mPFCs from heroin abusers compared to the control subjects. Similar patterns were observed in the rat heroin SA model. These findings suggest potential roles of the OPRM1 splice variants in heroin addiction that could be mechanistically explored using the rat heroin SA model.
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PMID:Dysregulated expression of the alternatively spliced variant mRNAs of the mu opioid receptor gene, OPRM1, in the medial prefrontal cortex of male human heroin abusers and heroin self-administering male rats. 3250 72