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)

Mice of two strains, Crl:CD-1(1CR)Br and C57BL6, were exposed to nitrous oxide at concentrations of 50, 65 and 80 per cent for 34 or 68 hours. Cessation of nitrous oxide resulted in characteristic convulsions similar to those seen in alcohol withdrawal in all mice. These peaked in severity within 2-3 minutes after removal from nitrous oxide and declined over 6 hours. The severity and duration of these convulsions were related to the nitrous oxide concentration and duration of exposure. Naloxone or naltrexone produced no significant increase in severity of convulsions. The narcotic antagonists did not precipitate acute weight loss or characteristic jumping behaviour seen in animals dependent on opiates. These results demonstrate that chronic exposure to nitrous oxide results in development of physical dependence which resembles alcohol and not opiate dependence. Analgesia and physical dependence produced by nitrous oxide appear to be mediated through separate mechanisms.
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PMID:Physical dependence on nitrous oxide in mice: resemblance to alcohol but not to opiate withdrawal. 719 94

1 Dermorphin and Hyp6-dermorphin are the first representatives of a new class of potent opioid peptides occurring in amphibian skin. They present the unique feature of having a D-Ala residue incorporated in the peptide molecule. 2 Dermorphin displayed a potent depressive action on electrically stimulated contractions of the guinea-pig ileum and mouse vas deferens preparations. Dermorphin was respectively 57,294, 18 and 39 times more potent than Met-enkephalin, Leu-enkephalin, beta-endorphin, and morphine on the guinea-pig ileum opiate receptors. On the vas deferens receptors, dermorphin was about as potent as the enkephalins and 40 times more potent than morphine. Naloxone was a powerful antagonist to dermorphin in both preparations. 3 Dermorphin produced potent and long-lasting analgesia in mice by intravenous injection, and in rats by intracerebroventricular injection, the ED50 being here of the order of 13-23 pmol/rat. Morphine was 752 and 2170 times less potent, depending on the analgesia test used. At high intracerebroventricular doses analgesia was accompanied by catalepsy. 4 Intracerebroventricular infusion of dermorphin induced development of tolerance and precipitation of withdrawal symptoms upon administration of naloxone. Both tolerance and physical dependence was consistently less marked with dermorphin than with morphine. 5 The minimum sequence requirement for full dermorphin activity was represented by the N-terminal tetrapeptide. The presence of the D-Ala2-residue was of crucial importance.
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PMID:Pharmacological data on dermorphins, a new class of potent opioid peptides from amphibian skin. 719 58

A new met-enkephalin analogue (compound 82/205) was evaluated for its opioidergic activity in mice. The compound showed antinociception (warm water tail-flick test), tolerance, cross tolerance to morphine and physical dependence. The time course of antinociceptive effect of the compound was comparable to morphine. The antinociceptive ED50 (mumol kg-1, i.p.) values for the compound and morphine base were 5.31 and 7.59, respectively. Its antinociceptive effect was blocked by naloxone, beta-FNA (mu antagonist) and naloxonazine (mu1 antagonist) but not by ICI 174,864 (delta antagonist). Naloxone precipitated withdrawal jumpings were 2.6 times less in compound 82/205 treated mice than the morphine treated group. The new analogue compound 82/205 is a potent mu agonist antinociceptive with a possible weak dependence liability.
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PMID:Novel met-enkephalin analogue: a potent systemic mu agonist antinociceptive agent. 747 23

Chronic administration of narcotic mu opioid agonists results in tolerance and dependence. We propose that agonist stimulation causes a gradual conversion of mu receptors to a constitutively active state (mu*) as a key step in tolerance and physical dependence. We provide evidence in support of the existence of mu* in human neuroblastoma cells, SH-SY5Y, and mu* upregulation during morphine treatment. Naloxone blocked mu* activity, acting as an antagonist with negative intrinsic activity which accounts for its high potency in eliciting withdrawal. In contrast, the mu selective antagonist CTAP did not affect mu* activity but inhibited naloxone's effect. The protein kinase inhibitor H7 was found to suppress mu* formation, suggesting that mu* is phosphorylated. In a model of acute morphine tolerance/dependence in mice, H7 prevented naloxone induced withdrawal jumping and reversed morphine (antinociceptive) tolerance. CTAP caused only mild withdrawal and attenuated naloxone induced withdrawal, as predicted for an antagonist without negative activity. These results support a role for constitutive mu receptor activation in narcotic tolerance and dependence, affording potential separation of acute and chronic narcotic effects.
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PMID:Constitutive mu opioid receptor activation as a regulatory mechanism underlying narcotic tolerance and dependence. 751 10

Morphine dependence is a long lasting form of neuronal plasticity. Naloxone-precipitated morphine withdrawal, a model of opioid dependence, induces brain region-specific changes in activator protein-1 (AP-1) transcription factor gene expression. Rapid increases in c-fos, fos-B, jun-B, and c-jun mRNA levels accompany withdrawal, with the relative level of induction correlating with the severity of physical dependence. Altered patterns of c-fos mRNA expression were limited to neuronal circuits mediating stress responses, motivation, and cognition. AP-1 DNA-binding activity and dimer composition also exhibited regulation after withdrawal, presumably as a result of both transcriptional and post-translational events. Thus, morphine dependence results in the alteration of diverse, brain region-specific, signal transcription pathways involving AP-1 transcription factors.
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PMID:Precipitated morphine withdrawal stimulates multiple activator protein-1 signaling pathways in rat brain. 783 31

In acute dependence, signs and symptoms of opioid withdrawal are precipitated when an opioid antagonist (naloxone) is administered following acute (e.g. single dose) pretreatment with a mu agonist. This study examined the influence of amount of previous opioid exposure, both immediate and remote, on intensity of precipitated withdrawal effects in an acute dependence model. Two groups of subjects, opioid abusers (n = 20) and nonabusers (n = 20), received either one 15 mg/70 kg IM morphine pretreatment or two such pretreatments spaced 24 h apart. Naloxone challenge (30 mg/70 kg) followed 4.33 h after the second pretreatment. There were clear effects of morphine pretreatment condition (single versus repeated 15 mg) on the intensity of precipitated withdrawal responses elicited by naloxone. More intense effects were seen after the repeated pretreatment, suggesting that physical dependence escalates with repeated opioid exposures spaced at appropriate intervals. Subjects with an opioid abuse history reported greater liking of agonist drug effects than did nonabusers, whereas nonabusers reported more sedating effects. However, an opioid abuse history did not influence the intensity of precipitated withdrawal symptoms and signs. The latter finding suggests that a previous opioid exposure history does not dramatically modulate initial stages of physical dependence development during subsequent opioid exposure episodes.
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PMID:Opioid physical dependence development: effects of single versus repeated morphine pretreatments and of subjects' opioid exposure history. 784 9

Elevation of plasma corticosterone (PCS) has been used as an indicator of morphine withdrawal, but it is not clear whether the magnitude of elevation is related to the intensity of the dependence. The dose-dependent effects of naloxone on PCS and body weight were studied in male Sprague-Dawley rats rendered physically dependent on morphine by injecting increasing doses of 40-120 mg/kg/day, s.c. twice daily for 1-6 days. Naloxone (0.01-2.0 mg/kg, s.c.) was administered 3 hr after the last morphine administration. Naloxone elevated PCS levels in a dose-dependent manner in all groups treated with morphine, and the elevation was correlated with the number of days of morphine treatment. Naloxone also reduced dose-dependently the body weight in all groups treated with morphine; in this case, a reverse correlation was obtained between the body weight changes and the PCS levels. It was confirmed that PCS elevation is a quantitative sign of naloxone-precipitated morphine withdrawal and that the elevation is indicative of the degree of morphine physical dependence.
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PMID:Quantitative properties of plasma corticosterone elevation induced by naloxone-precipitated withdrawal in morphine-dependent rats. 786 10

We examined the effect of morphine pretreatment spacing on intensity of subsequent precipitated withdrawal response to test the hypothesis that withdrawal intensity would be inversely related to pretreatment spacing. Subjects were ten nondependent male volunteers who reported using opioids an average of 2.5 times per week. Three IM morphine injections (each 18 mg/70 kg) were administered during each of four experimental conditions. The experimental conditions involved spacing injections at 12-, 24-, 48- or 72-h intervals. Naloxone (10 mg/70 kg IM) was administered 24 h after the last morphine exposure. A comparison condition was included in which a naloxone challenge was given at 24 h following a single IM morphine pretreatment (18 mg/70 kg). Subject rated measures of symptoms and observer-rated measures of signs indicated that withdrawal intensity was inversely related to the morphine spacing interval and in particular that intensity of withdrawal precipitated after three pretreatments spaced at 12-h intervals was greater than that precipitated after a single morphine pretreatment. Physiological data supported a more intense withdrawal response in the 12-h spacing condition and provided evidence of overshoot on blood pressure and skin temperature measures. These findings are pertinent to the transition between acute and chronic physical dependence; they suggest that there is a temporal window during which repeated opioid administrations result in escalation of physical dependence but that dependence levels after widely spaced multiple exposures may be no greater than after a single exposure.
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PMID:Opioid physical dependence development in humans: effect of time between agonist pretreatments. 787 Oct 65

The effect of acute and chronic morphine administration on calbindin-D28K (calbindin) gene expression has been studied. One group of adult male rats received a single injection of morphine (10 mg/kg, s.c.) or saline and were sacrificed 1 or 4 h later. Another group was injected with escalating doses of morphine sulfate twice daily for 15 days to induce tolerance and physical dependence. Rats were sacrificed 1 h after the last injection. In a third group, the effect of naloxone-precipitated withdrawal on gene expression in morphine-addicted rats was also analyzed 1 h after naloxone (1 mg/kg, i.p.). The cerebellum and remaining brain (minus the cerebellum) were removed, and total RNA was extracted and used for analysis. Calbindin mRNA levels in cerebellum were decreased to 30%-40% control at 1 and 4 h after a single morphine injection. Co-administration of the opiate antagonist, naloxone, reversed the effect of morphine. Tolerance developed to the acute effects in that levels were not altered significantly 1 h after morphine injection in chronically-treated rats. Unlike the cerebellum, calbindin mRNA in the remainder of the brain (minus the cerebellum) was unchanged 1 and 4 h following morphine administration to drug-naive rats, but was increased more than 2-fold compared to controls 1 h after morphine injection in chronically treated animals. Naloxone-precipitated withdrawal caused a small (20%) but significant decrease in calbindin mRNA in the cerebellum, with no change in the brain (minus the cerebellum).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of calbindin-D28K gene expression in response to acute and chronic morphine administration. 802 77

Previous studies measuring opioid inhibition of cyclic adenosine monophosphate in SH-SY5Y cells supported the hypothesis that continuous agonist stimulation causes a gradual conversion of the mu opioid receptor to a sensitized or constitutively active state termed mu*. Conversion to mu* was prevented by the kinase inhibitor H7, but not its close analog H8. Naloxone was proposed to act as a negative antagonist (inverse agonist) blocking mu* activity, whereas D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) appeared to act as a neutral antagonist having no effect on mu* activity. Initial in vivo results indicated that mu* activity may play a role in narcotic tolerance and dependence (Wang et al., Life Sci. 54: PL339-PL350 1994). Our study explores the pharmacology of H7 and H8, naloxone and CTAP in mice after induction of acute tolerance and dependence induced by a single s.c. dose of morphine (100 mg/kg). Physical dependence was defined by withdrawal jumping induced by i.p. naloxone injections 4 hr after the morphine dose, the time of maximal physical dependence. Neither H7 nor H8 (50 nmol or less) induced jumping, affected morphine antinociception or produced significant behavioral effects, when injected by the intracerebroventricular (i.c.v.) or intrathecal (i.th.) routes. When given 30 min before the naloxone challenge, H7, but not H8, significantly reduced naloxone jumping by i.c.v. injection. Administration of naloxone into the central nervous system, rather than by i.p. administration, required coinjection by both i.c.v. and i.th. routes to elicit full withdrawal jumping (30 nmol at each site). In contrast, the putative neutral antagonist CTAP caused little withdrawal jumping when coinjected i.c.v. and i.th., as expected if modulation of mu* activity played a role in dependence. However, CTAP was capable of partially reversing naloxone (i.p.) induced jumping when given either i.c.v. or i.th., indicating that CTAP competes with naloxone at mu*. Moreover, these results demonstrate that both spinal and supraspinal sites are required for full opioid withdrawal jumping in mice. Antinociceptive tolerance was also evaluated by determining the response to morphine in the 55 degrees C warm-water tail-flick test. Morphine pretreatment (100 mg/kg, s.c., -5 hr) produced antinociceptive tolerance as shown by a 2.7-fold increase in the calculated morphine A50 value. Tolerance was reversed by H7, but not H8, treatment (50 nmol, i.c.v., -30 min). These results are consistent with the hypothesis that a sensitized or constitutively active mu* state plays a role in narcotic tolerance and dependence.
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PMID:Effects of naloxone and D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 and the protein kinase inhibitors H7 and H8 on acute morphine dependence and antinociceptive tolerance in mice. 861 58


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