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)

Analgesics such as morphine are toxic drugs that kill by producing respiratory depression. Further morphine-like drugs produce a high level of physical dependence and are highly reinforcing in some subjects. A systematic search, conducted over the last 50 years, for safer and less addicting analgesic has revealed that opioid analgesics act on different types of opioid receptors (mu, kappa, and sigma), and that they may function as mixed agonist-antagonists or as partial agonists. Thus some mixed agonists function as competitive antagonists at the mu receptor and as partial or strong agonists at the kappa or sigma receptor. When mixed agonists produce the same pharmacologic effects (eg, analgesia) by acting on different receptors, they invoke the principle of receptor dualisms. Drugs that produce agonist (analgesic) effects by acting on the kappa receptors are an order of magnitude safer than the mu agonists and produce a lesser degree of physical dependence than strong mu agonists. Thus safer, less addicting analgesics have been produced that act either as agonist-antagonists or by being partial agonists.
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PMID:Clinical evidence for different narcotic receptors and relevance for the clinician. 301 58

The present study investigated the role of NMDA (N-methyl-D-aspartate) receptors in the hypersusceptibility to seizures induced by the benzodiazepine inverse agonist DMCM (methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate) during diazepam withdrawal in mice, using behavioral and biochemical approaches. The seizure threshold of DMCM was markedly decreased during diazepam withdrawal, reflecting withdrawal hyperexcitability in response to physical dependence. The decrease in the seizure threshold of DMCM in diazepam-withdrawn mice was inhibited by the non-competitive NMDA receptor antagonists MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cycloheptan-5,10-imine maleate; 50 microg/kg, s.c.) and ifenprodil (20 mg/kg, i.p.). The effective doses of these compounds were lower than those required to prevent DMCM-induced seizures in chronically vehicle-treated mice. Since MK-801 and ifenprodil do not only bind to NMDA receptors but also to sigma receptors, the present study also investigated the effects of sigma receptor ligands. The decrease in the seizure threshold of DMCM in diazepam-withdrawn mice was not modified by the sigma receptor agonist, (+)-pentazocine (5 mg/kg, s.c.), or the sigma receptor antagonist, NE-100 (N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride; 5 mg/kg, i.p.). Furthermore, the latency to the expression of wild running induced by intracerebroventricular administration of NMDA (60 ng/mouse) was also significantly lower in diazepam-withdrawn mice than in vehicle-treated control mice. On the other hand, there was no difference in the spermidine concentration between vehicle-treated control and diazepam-withdrawn mice. In a receptor binding experiment, the Bmax value for [3H]-MK-801 binding was significantly increased in cerebrocortical tissues from diazepam-withdrawn mice, while the Kd value did not change in either group. However, the acute addition of a high concentration of diazepam (10 and 100 microM) in vitro did not alter [3H]-MK-801 binding in cerebrocortical membrane preparations. The behavioral experiments suggest that NMDA receptor antagonists may suppress benzodiazepine withdrawal responses, while the biochemical study reveals upregulation of the NMDA receptor, which may play an important role in the hypersusceptibility to DMCM-induced seizure in diazepam-withdrawn mice.
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PMID:Hypersusceptibility to DMCM-induced seizures during diazepam withdrawal in mice: evidence for upregulation of NMDA receptors. 955 Mar 3