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)

mu-Opioid receptors mediate inhibition of the N-type calcium channel current in the human neuroblastoma cell line SH-SY5Y. We have previously shown that chronic exposure to morphine induces homologous tolerance to this effect. Here we show that chronic incubation with morphine (1 microM for three to seven days) does not, however, induce physical dependence at the level of the calcium channel current. Initial experiments were performed using the whole cell voltage-clamp technique. Chronically treated cells were bathed in superfusate which also contained morphine (1 microM). On washout of morphine the current amplitude increased by 12% and this was reversed by re-addition of morphine. Naloxone (1 microM) elicited a similar increase. However, this increase is most likely due to a reversal of the residual inhibitory effect of morphine on the calcium channel current rather than being a novel withdrawal response. Chronic exposure to morphine did not change the voltage-sensitivity of the calcium channel current or induce the appearance of a current sensitive to the L-type calcium channel agonists Bay K 8644 (3 microM) and S(+)-PN 202-791 (1 microM). In a further series of experiments the nystatin-perforated patch technique was employed in order to prevent washout of any L-type current in these cells. Under these conditions a Bay K 8644-sensitive, L-type current was unmasked following treatment with omega Conus Toxin GVIA. The peak current was depressed by omega Conus Toxin GVIA (1 microM) by approximately 90% both in control cells and cells chronically exposed to morphine. Now Bay K 8644 (3 microM) almost doubled the remaining current but the effect was equal in both groups of cells. It is concluded that chronic exposure to morphine does not induce physical dependence and a withdrawal syndrome in the human SH-SY5Y neuroblastoma cell line by changing either N-type or L-type calcium channel activity.
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PMID:Chronic exposure to morphine does not induce dependence at the level of the calcium channel current in human SH-SY5Y cells. 127 57

Naloxone, added after contractions induced by CCK-8 on the guinea pig ileum preparation, elicited a contraction attributed to the release of endogenous opioid which could inhibit the excitatory action of the peptide. With large concentrations of CCK-8, the preparation gave reproducible responses with time. Naloxone, added before the peptide, protracted the excitatory response to CCK-8, but not its height. Morphine decreased the response to CCK-8 but simultaneously raised the response to naloxone. The latter effect appeared very similar to the withdrawal contraction observed after brief exposure of the opioid in the guinea pig ileum to opioids. Clonidine, and alpha-2 adrenoceptor agonist, and nifedipine, a calcium channel antagonist, both known to interfere with tolerance and physical dependence, affected the excitatory response to CCK-8 and the subsequent response to naloxone in a different way.
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PMID:Some pharmacological characteristics of the guinea pig ileum opioid system activated by cholecystokinin. 169 57

Guinea-pig ileum stored for 30 min in Krebs solution and then mounted in Tyrode solution gave reproducible contracture responses to naloxone after brief exposure to morphine. The preparation lasted for several hours and a variety of pharmacological tests could be made. Clonidine, an alpha 2-adrenoceptor agonist, and nifedipine, a calcium channel antagonist, both known to interfere with tolerance and physical dependence, inhibited naloxone withdrawal contractures in a dose related way. Their action seemed to be receptor-mediated since yohimbine and Bay k 8644, respectively, reversed their inhibitory effect.
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PMID:Reproducible withdrawal contractions of isolated guinea-pig ileum after brief morphine exposure: effects of clonidine and nifedipine. 169 56

Prolonged ethanol administration causes upregulation of dihydropyridine-sensitive binding sites, thought to represent neuronal calcium channels, and these channels appear to play an important role in ethanol physical dependence. Dihydropyridine calcium channel antagonists, when given chronically with ethanol, prevent the development of tolerance to ethanol and the ethanol withdrawal syndrome. The upregulation of binding sites for these compounds was also prevented. Epileptiform activity has been described in isolated hippocampal slices after chronic ethanol treatment in vivo. This was prevented, stereoselectively, by the dihydropyridine calcium channel antagonist, isradipine, that did not affect the hyperexcitability produced in control slices by the GABAA antagonist, bicuculline.
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PMID:Calcium channel antagonists prevent adaptive responses to ethanol. 774 8

The effects of some adenosine agonists and calcium channel antagonists on the induction of tolerance to and dependence on barbital in mice have been studied. The concurrent administration of barbital and one of the following adenosine agonists, D- or L-phenylisopropyl adenosine, cyclopentyl adenosine and chloroadenosine, or the adenosine antagonists theophylline or 8-phenyltheophylline did not change the intensities of tolerance to and dependence on the barbiturate. N-ethylcarboxamide adenosine administered during the period of chronic administration of barbital significantly reduced the withdrawal syndrome. The administration of the calcium channel antagonists diltiazem, verapamil or nifedipine was also ineffective in altering the processes of tolerance and physical dependence when given concomitantly with barbital. Abstinence behavior was significantly reduced when mice were treated during the first 48 h of withdrawal from the barbiturate with either L-phenylisopropyl adenosine, N-ethylcarboxamide adenosine, nifedipine or verapamil. These results are discussed in relation to the attenuation of tolerance to and dependence on benzodiazepines induced by similar treatments.
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PMID:Purinergic drugs and calcium channel antagonists attenuate the withdrawal syndrome from barbital. 786 69

The effects of calcium channel inhibitors on ethanol intake and dependence in Wistar rats were studied. Nifedipine and isradipine were suspended in 1% Tween 40 saline solution and administered ip 60 min prior to testing. Audiogenic seizure response evaluation was performed after 5 days of ethanol treatment. Both nifedipine and isradipine significantly reduced the intensity score of convulsions and, in doses of 2.5 and 5.0 mg/kg, respectively, abolished them. Both drugs significantly reduced ethanol preference and intake in the high preference group of animals. Our results support the observations that certain dihydropyridine derivatives are capable of attenuating both ethanol preference and physical dependence.
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PMID:Comparative study of nifedipine and isradipine in animal models of ethanol dependence. 811 82

We have shown previously that the dihydropyridine calcium channel antagonist nitrendipine, given chronically, prevents the development of ethanol tolerance and physical dependence. The present study examines the effects on barbiturate tolerance and physical dependence. Nitrendipine, given acutely during withdrawal, provided little protection against barbiturate withdrawal, as measured by convulsive behaviour on handling. When nitrendipine was given chronically concurrently with the barbiturate, a prolonged protection against the withdrawal syndrome was seen. Acute nitrendipine significantly increased the latency of seizures in response to the partial benzodiazepine inverse agonist FG7142 during barbiturate withdrawal, but there was no effect on the seizure incidence in response to bicuculline. Chronic treatment with nitrendipine did not alter the development of tolerance to the ataxic or general anaesthetic actions of barbiturates, but evidence was found of a possible interaction between nitrendipine and pentobarbitone, which may have been pharmacokinetic. The results suggest that neuronal calcium channels may be involved to some degree in the development of the changes responsible for barbiturate withdrawal, but to a less extent than found previously for ethanol dependence.
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PMID:Dihydropyridine-sensitive calcium channels and barbiturate tolerance and withdrawal. 820 88

Physical dependence on alcohol was observed previously at the cellular level in cultured IM-9 human lymphoblast cells. To answer the question whether physical dependence can also develop in neurones and to investigate the neuronal processes involved in the development of alcohol dependence and withdrawal symptoms, cultures of cortical neurones were adapted to alcohol. Morphological characteristics of neurones were not altered during the chronic (3-day) repeated (once per day) ethanol (50-100 mM) treatment, whereas obvious signs of neuronal damage were seen after the following 24 h of alcohol-withdrawal. The extent of the damage, quantitated by measuring the release of lactate dehydrogenase (LDH) into the culture media, was dependent on the concentration of ethanol in the medium during adaptation. LDH-release induced by alcohol-withdrawal was significantly reduced by re-addition of ethanol, as well as by administration of non-competitive (MK-801) or NR2B selective (threo-ifenprodil) N-methyl-D-aspartate (NMDA) receptor antagonists. The sigma ligand haloperidol and the L-type voltage sensitive calcium channel blocker nimodipine were also effective, whereas the effect of the gamma-aminobutyric acid type A (GABA(A)) receptor agonist muscimol was not significant. Furthermore, chronic ethanol treatment potentiated the NMDA induced neurotoxicity and the ability of acute alcohol to inhibit LDH-release in response to NMDA. According to these results, (i) the phenomenon of alcohol-dependence can be observed at the level of neurones and (ii) NMDA receptors seem to play a central role in the development of ethanol dependence and in neurotoxicity induced by alcohol-withdrawal.
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PMID:Cytotoxic effect of alcohol-withdrawal on primary cultures of cortical neurones. 1113 80

Administration of opioids to alleviate moderate to severe acute pain and chronic cancer pain is an established management process. However, advancements in clinical pharmacologic research have shown that opioids are also effective in chronic noncancerous pain. Many patients properly treated for prolonged periods with opioids develop tolerance and subsequently, physical dependence. This process is not necessarily harmful to the patient and will not cause the patient to develop an addiction (properly defined as psychologic dependence). For many patients who have been on opioid therapy for months or years, analgesic effectiveness tragically becomes less. In addition, opioid-induced constipation can be severe and cause pain; patients do not develop tolerance to this adverse reaction. Therefore, such issues become a management problem and require additional intervention. Currently, many different classes of drugs can serve as effective adjuncts to opioids for treatment of pain. Adding adjunctive medication to opioid therapy improves pain management primarily by nonopioid mechanisms of action. Clinical outcomes of such combinations include greater analgesia and attenuation of opioid-induced adverse reactions such as nausea and vomiting, constipation, sedation, and respiratory depression. Adjuncts include acetaminophen, antiarrhythmics, anticonvulsants, antidepressants, antipsychotics, baclofen, benzodiazepines, capsaicin, calcium channel blockers, clonidine hydrochloride, central nervous system stimulants, corticosteroids, local anesthetics, N-methyl-D-aspartate receptor antagonists, nonsteroidal antiinflammatory drugs, pentoxifylline, and scopolamine. Some adjuncts (eg, acetaminophen) are routinely used today, whereas others (eg, nifedipine [calcium channel blocker]) are used on a limited basis but have great potential for more widespread application. All professionals (eg, nurses, pharmacists, physicians, physicians' assistants, social workers, members of the clergy) involved in treating patients with unresolved pain recognize this to be an extraordinary and delicate time. It is when patients are likely to request physicians to provide some method to accelerate their death. Thus, inadequate analgesia can become a suicidogen, ie, any factor that causes a patient to want to commit suicide. Incorporation of adjuncts to opioid therapy can serve to lessen pain and improve quality of life for a suffering patient.
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PMID:Adjuncts to opioid therapy. 1235 36

ZC88 is a novel non-peptide N-type voltage-sensitive calcium channel blocker synthesized by our institute. In the present study, the oral analgesic activity of ZC88 in animal models of acute and neuropathic pain, and functional interactions between ZC88 and morphine in terms of analgesia, tolerance and dependence were investigated. In mice acetic acid writhing tests, ZC88 (10-80 mg/kg) administered by oral route showed significant antinociceptive effects in a dose-dependent manner. The ED50 values of ZC88 were 14.5 and 14.3 mg/kg in male and female mice, respectively. In sciatic nerve chronic constriction injury rats, mechanical allodynia was ameliorated by oral administration of ZC88 at doses of 14, 28 and 56 mg/kg, suggesting ZC88 relieved allodynic response of neuropathic pain. When concurrently administered with morphine, ZC88 (20-80 mg/kg) dose-dependently potentiated morphine analgesia and attenuated morphine analgesic tolerance in hot-plate tests. ZC88 also prevented chronic exposure to morphine-induced physical dependence and withdrawal, but not morphine-induced psychological dependence in conditioned place preference model. These results suggested that ZC88, a new non-peptide N-type calcium channel blocker, had notable oral analgesia and anti-allodynia for acute and neuropathic pain. ZC88 might be used in pain relief by either application alone or in combination with opioids because it enhanced morphine analgesia while prevented morphine-induced tolerance and physical dependence.
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PMID:Analgesic activity of ZC88, a novel N-type voltage-dependent calcium channel blocker, and its modulation of morphine analgesia, tolerance and dependence. 1837 13


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