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)

Long-term administration of opiates leads to changes in the effects of these drugs, including tolerance, sensitization and physical dependence. There is, as yet, incomplete understanding of the neural mechanisms that underlie these phenomena. Tolerance, sensitization and physical dependence can be considered adaptive processes similar to other experience-dependent changes in the brain, such as learning and neural development. There is considerable evidence demonstrating that N-methyl-D-aspartate (NMDA) receptors and downstream signaling cascades may have an important role in different forms of experience-dependent changes in the brain and behavior. This review will explore evidence indicating that NMDA receptors and downstream messengers may be involved in opiate tolerance, sensitization and physical dependence. This evidence has been used to develop a cellular model of NMDA receptor/opiate interactions. According to this model, mu opioid receptor stimulation leads to a protein kinase C-mediated activation of NMDA receptors. Activation of NMDA receptors leads to influx of calcium and activation of calcium-dependent processes. These calcium-dependent processes have the ability to produce critical changes in opioid-responsive neurons, including inhibition of opioid receptor/second messenger coupling. This model is similar to cellular models of learning and neural development in which NMDA receptors have a central role. Together, the evidence suggests that the mechanisms that underlie changes in the brain and behavior produced by long-term opiate use may be similar to other central nervous system adaptations. The experimental findings and the resulting model may have implications for the treatment of pain and addiction.
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PMID:The neurobiology of opiate tolerance, dependence and sensitization: mechanisms of NMDA receptor-dependent synaptic plasticity. 1282 26

Cough is an important defensive reflex of the airway and a common symptom of respiratory disease. After an upper respiratory tract virus infection, cough is transient, but is more persistent with conditions such as asthma, rhinosinusitis, gastroesophageal reflux, chronic obstructive pulmonary disease (COPD) and lung cancer. Treatment directed at these conditions may improve cough, but there remains a need to control cough directly. The most effective antitussives are opioids, such as morphine, codeine or pholcodeine, but they produce side effects including drowsiness, nausea, constipation and physical dependence. Opioids such as k- and d-opioid receptor agonists, non-opioids such as nociceptin, neurokinin and bradykinin receptor antagonists, vanilloid receptor VR(1) antagonists, blockers of sodium-dependent channels, and maxi-K calcium-dependent channel activators of afferent nerves may all represent novel antitussives and this needs to be confirmed in clinical trials.
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PMID:Current and future prospects for drugs to suppress cough. 1291 74

Cough is an important defensive reflex of the airway and also a common symptom of respiratory disease. Cough after common respiratory virus infection is transient but is more persistent when associated with conditions such as asthma, rhinosinusitis, gastro-oesophageal reflux, chronic obstructive pulmonary disease and lung cancer. Persistent cough may be due to peripheral and/or central sensitisation of cough reflexes initiated by cough receptors, rapidly adapting receptors or nociceptors. Treatment directed at associated conditions such as asthma (with anti-inflammatories) and gastro-oesophageal reflux (with proton-pump inhibitors) improve cough. There remains a need to use drugs that suppress the neural activity of cough (termed nonspecific), as treatments directed at the clinical cause(s) of the underlying cough (termed specific) may not be effective. The most effective indirect antitussives are opioids such as morphine, codeine or pholcodeine, but they produce side effects such as drowsiness, nausea, constipation and physical dependence. Opioids such as kappa- and delta-receptor agonists, non-opioids such as nociceptin, neurokinin and bradykinin receptor antagonists, cannabinoids, vanilloid receptor-1 antagonists, blockers of Na+-dependent channels, and large conductance Ca2+-dependent K+-channel activators of afferent nerves may represent novel antitussives.
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PMID:Drugs to suppress cough. 1570 18

We investigated how functional changes in high voltage-gated calcium channels (HVCCs) occurred in the cerebral cortex of mouse with ethanol physical dependence. The continuous treatment of mice with ethanol vapor for 8 days significantly increased the expressions of alpha1C, alpha1D, and alpha2/delta1 subunits of L-type HVCCs in association with decreased level of beta4 subunit of L-type HVCCs, although alpha1A and alpha1B subunits of P/Q- and N-type HVCCs, respectively, showed no alterations. [(3)H]Diltiazem binding to the particulate fractions increased with increased Bmax value and no changes of Kd value. These results indicate that ethanol physical dependence accompanies the up-regulation of L- type HVCCs, which is due to increased expression of alpha1C, alpha1D, and alpha2/delta1 subunits.
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PMID:Ethanol physical dependence is accompanied by up-regulated expression of L-type high voltage-gated calcium channel alpha1 subunits in mouse brain. 1578 Oct 65

cAMP response-element binding protein (CREB), a transcription factor involved in learning, memory and drug addiction, is phosphorylated by calcium-calmodulin-dependent protein kinase IV (CaMKIV). Here, we show that CaMKIV-knockout (KO) mice developed less analgesic tolerance after chronic morphine administration with no alteration in physical dependence or acute morphine-induced analgesia. The increase in phosphorylated CREB expression observed in wild-type mice after chronic morphine was absent in CaMKIV-KO mice, while there was no difference in the expression or phosphorylation of the micro-opioid receptor between groups. Morphine-treated CaMKIV-KO mice showed less G-protein uncoupling from the micro-opioid receptor than did wild-type mice, while uncoupling was similar in control wild-type and KO mice. In addition, morphine reduced inhibitory transmission to a greater degree in CaMKIV-KO mice than in controls after chronic morphine exposure. Our results provide novel evidence for the role of CaMKIV in the development of opioid analgesic tolerance but not physical dependence.
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PMID:Evidence for a role of CaMKIV in the development of opioid analgesic tolerance. 1663 62

Previous reports revealed up-regulation of L-type high voltage-gated calcium channels (HVCCs) in mouse brains with ethanol physical dependence. We investigated mechanisms of enhancement of L-type HVCC function using mouse cerebrocortical neurons exposed to 50 mM ethanol for 3 days and the brains of mouse physically dependent on ethanol. Ethanol facilitated 30 mM KCl-stimulated (45)Ca(2+) influx in dose- and duration-dependent manners, which was abolished by nifedipine, an inhibitor specific to L-type HVCCs, but not by inhibitors for other types of HVCCs. Increase in [(3)H]PN200-110 binding to the particulate fractions from the ethanol-treated neurons was due to increased B(max) value with no changes in K(d) value. Western blot analysis showed the increased expression of alpha1C, alpha1D, and alpha2/delta1 subunits with decreased beta4 subunit expression and no changes in expressions of alpha1A, alpha1B, alpha1F, and alpha2 subunits. A similar pattern of the changes in the expression of these subunits of L-type HVCCs were observed in the cerebral cortex from mouse with ethanol physical dependence. These results indicate that sustained ethanol exposure to the neurons induces up-regulation of L-type HVCCs, which is due to increased expressions of alpha1C, alpha1D, and alpha2/delta1 subunits, and produces no alterations in P/Q- and N-type HVCC functions.
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PMID:Increase in expression of alpha1 and alpha2/delta1 subunits of L-type high voltage-gated calcium channels after sustained ethanol exposure in cerebral cortical neurons. 1703 Oct 67

As functional changes in L-type high voltage-gated calcium channels (HVCCs) are recognized to be one of the major neurochemical modifications occurring in brains of animals with morphine physical dependence, this study attempts to examine whether regional difference in the expressions of HVCC subunits are produced in the brains under such pathological conditions. Scatchard analysis of [(3)H]PN200-110 binding showed increased Bmax values in the cerebral cortex and the mesolimbic region including the nucleus accumbence, which are brain regions participating in the development of morphine physical dependence, but not in the cerebellum. In the former two brain regions, alpha1C and alpha1D subunits of L-type HVCCs and alpha2/delta1 subunit increased, although decreases of alpha1B and alpha2/delta1 subunits were observed in the cerebellum. A single dose of morphine did not change the expression of any of the HVCC subunits. These results indicate that the increased L-type HVCC subunits in the cerebral cortex and mesolimbic region participate in the development of morphine physical dependence.
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PMID:Regional differences of L-type high voltage-gated calcium channel subunit expression in the mouse brain after chronic morphine treatment. 1791 66

The aim of this study is to examine how sustained exposure to two 1,4-benzodiazepines (BZDs) with different action period, diazepam and brotizolam, and a 1,5-BZD, clobazam, affects L-type high voltage-gated calcium channel (HVCC) functions and its mechanisms using primary cultures of mouse cerebral cortical neurons. The sustained exposure to these three BZDs increased [(45)Ca2+] influx, which was due to the enhanced [(45)Ca2+] entry through L-type HVCCs but not through of Cav2.1 and Cav2.2. Increase in [(3)H]diltiazem binding after the exposure to these three BZDs was due to the increase in the binding sites of [(3)H]diltiazem. Western blot analysis showed increase of Cav1.2 and Cav1.3 in association with the increased expression of alpha2/delta1 subunit. Similar changes in [(3)H]diltiazem binding and L-type HVCC subunit expression were found in the cerebral cortex from mouse with BZD physical dependence. These results indicate that BZDs examined here have the potential to increase L-type HVCC functions mediated via the enhanced expression of not only Cav1.2 and Cav1.3 but also alpha2/delta1 subunit after their sustained exposure, which may participate in the development of physical dependence by these BZDs.
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PMID:Up-regulation of L-type high voltage-gated calcium channel subunits by sustained exposure to 1,4- and 1,5-benzodiazepines in cerebrocortical neurons. 1794 10

Long-term alcohol exposure gives rise to development of physical dependence on alcohol in consequence of changes in certain neurotransmitter functions. Accumulating evidence suggests that the glutamatergic neurotransmitter system, especially the N-methyl-D-aspartate (NMDA) type of glutamate receptors is a particularly important site of ethanol's action, since ethanol is a potent inhibitor of the NMDA receptors (NMDARs) and prolonged ethanol exposition leads to a compensatory "upregulation" of NMDAR mediated functions supposedly contributing to the occurrence of ethanol tolerance, dependence as well as the acute and delayed signs of ethanol withdrawal.Recently, expression of different types of NMDAR subunits was found altered after long-term ethanol exposure. Especially, the expression of the NR2B and certain splice variant forms of the NR1 subunits were increased in primary neuronal cultures treated intermittently with ethanol. Since NMDA ion channels with such an altered subunit composition have increased permeability for calcium ions, increased agonist sensitivity, and relatively slow closing kinetics, the abovementioned alterations may underlie the enhanced NMDAR activation observed after long-term ethanol exposure. In accordance with these changes, the inhibitory potential of NR2B subunit-selective NMDAR antagonists is also increased, demonstrating excellent potency against alcohol withdrawal-induced in vitro cytotoxicity. Although in vivo data are few with these compounds, according to the effectiveness of the classic NMDAR antagonists in attenuation, not only the physical symptoms, but also some affective and motivational components of alcohol withdrawal, novel NR2B subunit selective NMDAR antagonists may offer a preferable alternative in the pharmacotherapy of alcohol dependence.
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PMID:Role of altered structure and function of NMDA receptors in development of alcohol dependence. 1836 2

Signs of physical dependence as a consequence of long-term drug use and a moderate abuse liability limit benzodiazepine clinical usefulness. Growing evidence suggests a role for voltage-gated calcium channel (VGCC) regulation in mediating a range of chronic drug effects from drug withdrawal phenomena to dependence on a variety of drugs of abuse. High voltage-activated (HVA) calcium currents were measured in whole-cell recordings from acutely isolated hippocampal CA1 neurons after a 1-week flurazepam (FZP) treatment that results in withdrawal-anxiety. An approximately 1.8-fold increase in Ca(2+) current density was detected immediately after and up to 2 days but not 3 or 4 days after drug withdrawal. Current density was unchanged after acute desalkyl-FZP treatment. A significant negative shift of the half-maximal potential of activation of HVA currents was also observed but steady-state inactivation remained unchanged. FZP and diazepam showed use- and concentration-dependent inhibition of Ca(2+) currents in hippocampal cultured cells following depolarizing trains (FZP, IC(50) = 1.8 microM; diazepam, IC(50) = 36 microM), pointing to an additional mechanism by which benzodiazepines modulate HVA Ca(2+) channels. Systemic preinjection of nimodipine (10 mg/kg), an L-type (L)-VGCC antagonist, prevented the benzodiazepine-induced increase in alpha-amino-3-hydroxy-5-methylisoxasole-4-propionic acid receptor (AMPAR)-mediated miniature excitatory postsynaptic current in CA1 neurons 2 days after FZP withdrawal, suggesting that AMPAR potentiation, previously linked to withdrawal-anxiety may require enhanced L-VGCC-mediated Ca(2+) influx. Taken together with prior work, these findings suggest that enhanced Ca(2+) entry through HVA Ca(2+) channels may contribute to hippocampal AMPAR plasticity and serve as a potential mechanism underlying benzodiazepine physical dependence.
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PMID:Chronic benzodiazepine administration potentiates high voltage-activated calcium currents in hippocampal CA1 neurons. 1881 92


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