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)

Chronic benzodiazepine treatment elicits adaptive responses in the CNS, seen behaviorally as functional tolerance and physical dependence. Experiments are described in which a radioreceptor assay is used to follow benzodiazepine activity in CSF samples during daily flurazepam treatment of cats. Tolerance is evident even after the second dose, despite increasing CSF drug activity, showing a large and rapidly developing functional tolerance. Other studies are discussed which also show tolerance within 24 hours of initiating benzodiazepine treatment. In contrast, a spontaneous withdrawal syndrome is usually seen only after prolonged treatment with high doses. However, physical dependence can also be studied by precipitating abstinence with a benzodiazepine antagonist, such as Ro15-1788. Cats were treated daily with flurazepam, then Ro15-1788 was given and abstinence signs were recorded. Abstinence could be precipitated 24 hours after beginning treatment, and dependence was nearly maximal after 7 days. Dependence developed during treatment with as little as 0.5 mg/kg flurazepam, which is near threshold for any behavioral response. Chronic diazepam caused the same dependence as flurazepam. Thus, the development of tolerance and physical dependence both show a remarkably rapid adaptation of the CNS in response to benzodiazepines.
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PMID:Time course for development of benzodiazepine tolerance and physical dependence. 285 77

Clinically, patients with Delirium Tremens (DT) and acute alcohol hallucinosis (impending DT) appear excited with vivid false perception. Cerebral blood flow and eeg correspondingly point to hyperexcitability in the CNS during these conditions. Clinical trials with barbital treatment in alcohol withdrawal shows that the amount of drug and the drug plasma concentration is the same no matter whether the physical signs of withdrawal are accompanied by hallucinations and clouding of consciousness. The psychotic signs in DT and acute alcoholic hallucinosis develops after many years of alcoholism as does seizures. We hypothesize that physical withdrawal is determined by the degree of physical dependence developed during the most recent drinking period whereas the psychotic signs and seizures are due to a cumulated CNS hyperactivity developed over many years of repeated alcohol intoxication and withdrawal. Changes of electrolyte concentrations in plasma or CSF do not play an important role in the pathogenesis of DT and related clinical states except that changes in calcium and inorganic phosphate metabolism indirectly point to changes in membrane excitability. A new model for a study of rapidly repeated intoxication and withdrawal episodes in rats has shown that repetition of episodes augments the convulsive component of withdrawal whereas the non-convulsive signs are dependent on the most recent episode only. The augmentation of the convulsive component correlates with regional differences in brain glucose consumption. Furthermore, synaptic proteins and acidic phospholipids may be involved in the development of CNS hyperexcitability during alcohol withdrawal. In conclusion both clinical and experimental studies indicate that severe alcohol withdrawal reactions may consist of two components: 1) Physical withdrawal signs determined by recent physical dependence. 2) A long term cumulated CNS hyperexcitability relating to seizures and psychotic signs during withdrawal. This state is elicited by alcohol withdrawal but it represents a cumulated and permanent or long lasting CNS dysfunction in alcoholics. The precise biochemical/pathophysiological mechanisms for the development of the two-component dysfunction still remain to be clarified in detail.
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PMID:Delirium tremens and related clinical states: psychopathology, cerebral pathophysiology and psychochemistry: a two-component hypothesis concerning etiology and pathogenesis. 306 44

The cerebrospinal fluid-contacting nucleus (CSF-CN) may influence actual composition of the CSF for non-synaptic signal transmission via releasing or absorbing bioactive substances, which distributes and localizes in the ventral periaqueductal central gray of the brainstem. Previous studies demonstrated that CSF-CN was involved in neuropathic pain and morphine dependence. Thus, to identify whether extracellular signal-regulated kinase 5 (ERK5) distributed in the CSF-CN and its function on the formation and development of morphine physical dependence, morphine withdrawal-like behavioral test and immunofluorescent technique were used in this research. Morphine was subcutaneously injected by an intermittent and escalating procedure to induce physical dependence, which was measured by withdrawal symptoms. In this study, we found that horseradish peroxidase-conjugated toxin subunit B/p-ERK5 double-labeled neurons expressed in the CSF-CN of normal rats. ERK5 signaling pathway was remarkably activated by naloxone-precipitated withdrawal in the CSF-CN. Moreover, selective attenuation of p-ERK5 expression in the CSF-CN by lateral ventricle injection of BIX02188 could significantly relieve morphine withdrawal symptom. These findings confirmed that the activation of p-ERK5 in the CSF-CN might contribute to morphine physical dependence.
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PMID:Extracellular signal-regulated kinase 5 in the cerebrospinal fluid-contacting nucleus contributes to morphine physical dependence in rats. 2314 93