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

It has previously been shown that subchronic and acute administration of L-asparaginase and glutaminase inhibitors D-Aspartic acid (D-ASP) and prolyl-leucyl-glycinamide (PLG) intensifies and attenuates morphine (M) physical dependence, respectively, by the inhibition of ASP and glutamic acid (GLU) production, and subsequently their normal releases. Tizanidine (TIZ) has long been known to be an alpha 2-adrenoceptor agonist and inhibitor of ASP and GLU release. Therefore, in this study TIZ has been administered subchronically during the development of M physical dependence to rats in which M-containing pellets had been implanted or acutely 30 min before naloxone (NL)-induced abstinence syndrome. The subchronic administration of TIZ intensified NL-precipitated abstinence syndrome whereas its acute administration attenuated it, as did D-ASP and PLG. On the other hand, TIZ added into the medium prevented the in vitro M-dependent-made guinea pig ileum from contracting following NL application. Furthermore, TIZ stopped the already started contraction by NL of the M-dependent ileum, which completely relaxed later. These effects of TIZ on M-dependent ileum were antagonized by the alpha 2-adrenoceptor antagonist yohimbine. The intensification by subchronic TIZ administration of abstinence syndrome was attributed to the lesser release of ASP and GLU, which resulted in the larger blockade of M of ASPergic/GLUergic receptors due to the lesser release of their endogenous agonist ASP and GLU and consequently the higher upregulation of the receptors. The attenuation by acute TIZ administration of NL-precipitated abstinence syndrome was explained with lesser release of ASP and GLU and concomitantly the lesser stimulation of the receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of tizanidine on morphine physical dependence: attenuation and intensification. 135 95

The inhibition by opiates and the sudden normalization by opioid antagonists of the brain L-asparaginase activity (BAA) have previously been reported to be the main factors in the development of physical dependence and the manifestation of precipitated abstinence syndrome, respectively. As a result, L-asparaginase inhibitors D-aspartic acid and prolyl-leucyl-glycinamide (PLG) were separately given to mice and rats either just after morphine (M)-containing pellet implantation or 15 min before naloxone (NL)-precipitated abstinence syndrome. The animals treated in this manner were used to assess the intensity of the physical dependence and to determine the BAA. D-ASP or PLG administration following pellet implantation significantly increased all of the observed signs such as flying, jumping, wet dog shake and writhing. When D-ASP or PLG were given 15 min before precipitated abstinence they significantly decreased the number of the signs. The determination of the BAA showed significant decreases or increases more or less parallel to the severity of the physical dependence on M. The intensification of physical dependence by D-ASP or PLG given just after the pellet implantation was attributed to their additional inhibitory effect to that of M on the BAA at the beginning of the physical dependence development. The attenuating effect of BAA inhibitors D-ASP or PLG administered before precipitated abstinence was explained with the prevention of the increase in the BAA.
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PMID:Intensification and attenuation of morphine dependence by D-aspartic acid and PLG. 196 65

According to the hypothesis that the development of physical dependence on and tolerance to opiates depends on the inhibition by opiates of L-asparaginase and L-glutaminase activities in the brain, and the blockade by opiates of the aspartatergic/glutamatergic receptors especially NMDA, four female and fourty-four male heroin addicts were included in a double-blind clinical trial. Four mg chlorpromazine (CPZ) was administered every hour and 10 mg diazepam (DIA) every 6 hours to a group consisting of two female and nineteen male inpatients. The remaining subjects received 15 mg non-opioid antitussive dextromethorphan (DM) instead of CPZ. The withdrawn addicts were controlled twice a day and yawning, lacrimation, rhinorrhoea, perspiration, goose flesh, muscle tremor, dilated pupils, anorexia, joint and muscle aches, restlessness, insomnia, emesis, diarrhea, craving and rejection of smoking as abstinence syndrome signs were observed and rated on a scale of 1, 2 and 3 points according to their intensity. All signs, except perspiration and emesis, were significantly less intense in the group given DM + DIA than CPZ + DIA. The other plus points included the immediate stop of craving and the early onset of smoking in DM + DIA group. The results are considered to be supporting evidence for the hypothesis emphasizing the blockade of NMDA receptors by opiates in opiate addiction. Furthermore, the decrease caused by non-opioid NMDA antagonists in the responsiveness of NMDA receptors appears very promising for the treatment of opiate addicts.
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PMID:The treatment of heroin addicts with dextromethorphan: a double-blind comparison of dextromethorphan with chlorpromazine. 218 2

The development of physical dependence on opiates appears to involve an inhibition by opiates of L-asparaginase and glutaminase, and the blockade by opiates of aspartatergic (ASPergic)/glutamatergic (GLUergic) receptors. Ketamine (K) (0.5 or 1 mg/kg) or dextromethorphan (DM) (1 or 2 mg/kg), both of which are known to decrease the responsiveness of ASPergic/GLUergic receptors, were administered to the three morphine (M)-containing pellets implanted rats prior to 2 mg/kg naloxone (NL) injection. Whereas 0.5 mg/kg K showed no significant effect on abstinence syndrome signs, 1 mg/kg K and 1 mg/kg DM significantly attenuated some of the signs. The attenuation or prevention of all the signs were observed after 2 mg/kg DM administration. Almost complete prevention was seen from the second minute on during the ten-minute observation period. As ASP and GLU antagonists K and DM have this antagonizing effect on the precipitated abstinence syndrome signs, the manifestation of abstinence syndrome may mainly result from the normalization of ASP and GLU production because of the disinhibition by NL of the enzymes and the stronger stimulation of ASPergic/GLUergic receptors which have no opiate blockade after NL injection.
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PMID:Suppression by ketamine and dextromethorphan of precipitated abstinence syndrome in rats. 234 61

The activities of the brain L-asparaginase and angiotensin converting enzyme (ACE), and the plasma cortisol level were found to be decreased in the rats implanted with morphine (M) containing pellets. Even though 10 mg/kg of naloxone (N) itself showed an inhibitory effect on ACE it abolished the inhibitions seen in the M dependent rats five min following subcutaneous injection. The chronic administration of L-aspartic acid (ASP) during the development of physical dependence or just before the N injection prevented the increase of the plasma cortisol caused by N. It is concluded that in addition to the inhibition of the brain L-asparaginase activity which was previously hypothesized to be the main reason of the development of physical dependence on opiates as a result of the related experimental and clinical data, the inhibition by M of the brain ACE activity may take part in the development of physical dependence. With regard to the plasma cortisol level, the concomitant administration of ASP with M blocks, to a great extent, the development of physical dependence on opiate. The single dose of ASP administration before N injection prevents the effect of N, the manifestation of abstinence syndrome.
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PMID:Brain asparaginase, ACE activity and plasma cortisol level in morphine dependent rats: effect of aspartic acid and naloxone. 302 85

According to the hypothesis implying that the main reason of physical dependence on opiate is the inhibition of brain L-asparaginase activity and L-aspartic acid gradually decreases compulsory opiate intake so that physical dependence disappears by itself, 31 opiate addicts were given 8 g L-aspartic acid for 7 days after withdrawal from opiate and appearance of abstinence syndrome signs. The attenuations by L-aspartic acid of the abstinence syndrome signs were statistically compared with those obtained from other 12 opiate addicts received daily 50 mg chlorpromazine + 60 mg diazepam which have long been used to suppress abstinence syndrome because of their multiple receptor blocking and sedative effects. The intensity and duration of 13 signs out of 16 ones were found to be significantly more alleviated and shortened in the addicts treated with L-aspartic acid.
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PMID:Comparison of the suppressive effects of L-aspartic acid and chlorpromazine + diazepam treatments on opiate abstinence syndrome signs in men. 381 27