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)

The clinical pharmacology of fentanyl and alfentanil was examined in opioid-experienced volunteers with agonist and antagonist sensitivity measures. Two studies used within-subject, placebo-controlled, crossover designs. In study 1, fentanyl (0.125, 0.25 mg/70 kg i.v.) was followed at 0, 20, 60 and 180 min by naloxone (10 mg/70 kg i.m.). Agonist effects during 180-min and 0-min (control; simultaneous fentanyl-naloxone i.v. infusion) challenge sessions were compared. Fentanyl rapidly constricted pupils, depressed respiration and produced subjective "high" and opiate symptoms lasting 60 to 120 min, depending on the measure. Naloxone precipitated withdrawal symptoms of comparable intensity at each challenge point. In study 2, fentanyl (0.125, 0.25 mg/70 kg i.v.), alfentanil (1, 2 mg/70 kg i.v.) and saline were followed at 1 and 6 hr by naloxone (10 mg/70 kg i.m.). Agonist effects were examined during 6-hr challenge sessions. The two drugs produced a comparable range of effects with similar peak magnitude for 0.125 mg/70 kg fentanyl and 1 mg/70 kg alfentanil and for 0.25 mg/70 kg fentanyl and 2 mg/70 kg alfentanil. Alfentanil's duration of action was brief ( < 60 min). Withdrawal was precipitated at 6 hr only after 0.25 mg/70 kg fentanyl. These findings support typical mu opioid characteristics (pleasurable subjective effects, physical dependence) for both drugs, differential duration of action (fentanyl > alfentanil) and peak effects consistent with a 1:8 (fentanyl/alfentanil) potency ratio.
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PMID:Comparative clinical pharmacology of short-acting mu opioids in drug abusers. 866 83

One purpose of this study was to characterize the acute effects of the partial mu-opioid agonist buprenorphine administered to human subjects undergoing maintenance treatment with ascending doses of morphine. A second purpose was to examine the development of tolerance, cross-tolerance and physical dependence under the same morphine maintenance conditions. Six opioid-dependent volunteers were treated chronically with ascending morphine doses of 15, 30, 60 and 120 mg/day. Each morphine dosing level was maintained for 2 weeks, with test drugs administered during the second week of maintenance of each morphine dose. Both morphine (30 mg i.m.) and buprenorphine (6 mg i.m.) constricted pupils and produced reports of opioid-like subjective effects. The magnitude of these effects was inversely related to the morphine maintenance dose, with no effects being detected at higher maintenance levels. Naloxone (0.3 mg) produced little effect at lower morphine maintenance doses but precipitated withdrawal at higher maintenance doses. Buprenorphine failed to precipitate withdrawal even when subjects were treated with 120 mg/day morphine. These findings indicate that dose-dependent tolerance to morphine, cross-tolerance to buprenorphine and physical dependence develop during morphine maintenance. The finding that buprenorphine does not act as an antagonist under these dosing conditions further supports the clinical observation that there are conditions under which patients dependent on short-acting opioids can be comfortably transferred directly to buprenorphine maintenance treatment.
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PMID:Buprenorphine, morphine and naloxone effects during ascending morphine maintenance in humans. 876 38

The severity of naloxone-precipitated withdrawal in rats infused intravenously with morphine at the rates of 2.5, 5 and 10 mg/kg/hr over various time periods was investigated. Plasma morphine concentration reached a constant and rate-dependent level at 1 hr after the start of morphine infusion, and this level was maintained until the termination of infusion. Naloxone (2.0 mg/kg, s.c.) was challenged 18 hr after infusion was stopped, and the withdrawal was evaluated by plasma corticosterone (PCS) increase, diarrhea and body weight loss. The incidence of naloxone-precipitated withdrawal signs was related to both the infusion rate and duration of morphine infusion. The duration of morphine infusion (ET50) needed to elicit naloxone-precipitated PCS increase and diarrhea in 50% of the rats was inversely related to the morphine infusion rates, but the total amount of infused morphine (EA50) that elicited naloxone-precipitated withdrawals in 50% of rats was the same at all infusion rates. These results suggest that the total amount of morphine infused may play an important role in the development of acute physical dependence on morphine rendered by continuous intravenous morphine infusion for 1-8 hr.
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PMID:Possible involvement of the total amount of morphine infused in the development of acute morphine dependence in rats. 882 85

The locus coeruleus (LC) is a major noradrenergic nucleus in the brain. The activity of the LC neurons is chronically regulated by opioids. So far, very little is known about the morphological changes induced by chronic treatment with opioids. In the present study, the effects of chronic treatment with morphine and dihydroetorphine, a new narcotic analgesic with lower physical dependence potential than morphine, were investigated on the ultrastructure of the rat LC. Rats received saline or increasing doses of morphine or dihydroetorphine for 5 days by twice daily subcutaneous injections. Withdrawal was precipitated in half of the opioid-treated rats by a single intraperitoneal injection of naloxone 4 h after the last injections of opioids. The ultrastructure of the LC was examined by electron microscopy. Results showed that chronic morphine treatment induced a marked injury to the LC neurons. The primary changes in the cell body were the indentation of nuclei, the fragmentation and degranulation of rough endoplasmic reticulum, as well as the disaggregation of polyribosomes. Myelinoid bodies were seen in the processes. An accumulation of presynaptic vesicles was observed in some of the terminals which formed synaptic junctions with the LC neurons as compared to the normal controls. Naloxone-precipitated withdrawal from morphine did not stop the morphine-induced injury on the LC neurons except that less accumulation of presynaptic vesicles occurred. Chronic dihydroetorphine treatment only induced a slight change in the ultrastructure of the LC neurons. These results indicate that the LC neurons are more vulnerable to chronic treatment with morphine than to that with dihydroetorphine.
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PMID:Ultrastructural changes in rat locus coeruleus induced by chronic opioids. 925 84

The effect of intracerebroventricular (i.c.v.) treatment with antisense oligodeoxynucleotide (A-oligo) to delta opioid receptor mRNA on the morphine-induced place preference and naloxone-precipitated jumping was examined in morphine-dependent mice. Morphine (5 mg/kg, s.c.) produced a significant place preference. I.c.v. pretreatment with A-oligo (0.01-1 microg/mouse) dose-dependently attenuated this morphine (5 mg/kg, s.c.)-induced place preference, while mismatched oligodeoxynucleotide (M-oligo; 1 microg/mouse, i.c.v.) was ineffective. Naloxone (3 mg/kg, s.c.) precipitated jumping in morphine-dependent mice. I.c.v. pretreatment with A-oligo (1 microg/mouse) attenuated this naloxone (3 mg/kg, s.c.)-precipitated jumping in morphine-dependent mice, while M-oligo (1 microg/mouse, i.c.v.) was ineffective. These data demonstrate that the selective reduction in supraspinal delta opioid receptor function caused by pretreatment with A-oligo attenuated the morphine-induced place preference and naloxone-precipitated jumping in morphine-dependent mice, suggesting that the rewarding effect of and physical dependence on morphine may be modulated by central delta opioid receptors.
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PMID:Antisense oligodeoxynucleotide to delta opioid receptors attenuates morphine dependence in mice. 930 58

The administration of morphine and fentanyl by continuous intravenous infusion has been shown to produce analgesic tolerance and physical dependence in human neonates. In animals, daily repeated morphine bolus injections is a common method of inducing neonatal rat tolerance and dependence. Yet this method differs from the intravenous route reported to affect human neonates. Alzet osmotic minipumps were implanted in postnatal day 14 rats to provide a continuous morphine infusion more closely mimicking the clinical picture. Rats remained naive or were infused with saline or morphine (0.7 mg/kg/h) for 72 h. Morphine's antinociceptive potency was similar between naive and saline-infused animals, while morphine-infused animals were tolerant. Gender did not contribute to the degree of tolerance observed. Naloxone precipitated withdrawal in the morphine pump-implanted rats was similar to that reported by others. Thus, minipumps provide a useful model for assessing the tolerance and dependence liability of different opioids.
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PMID:Characterization of neonatal rat morphine tolerance and dependence. 953 10

The present study was carried out to investigate the relative involvement of spinal opioid receptors in the development of physical dependence on intrathecal (i.t.) butorphanol in comparison with i.t. morphine. Dependence was induced by continuous i.t. infusion of butorphanol (52 nmol/h) and morphine (26 nmol/h) for 4 days in male Sprague-Dawley rats. Naloxone, CTOP, naltrindole, and nor-binaltorphimine (nor-BNI) were administered i.t. to precipitate behavioral signs of withdrawal. Administration of i.t. naloxone produced a significantly greater increase in the profile of withdrawal signs in i.t. morphine dependence than that in i.t. butorphanol dependence. An i.t. nor-BNI challenge elicits behavioral signs of withdrawal only in rats dependent on i.t. butorphanol, but not in rats dependent on i.t. morphine. CTOP administered i.t. precipitated withdrawal signs in i.t. morphine dependence that were greater than that in i.t. butorphanol dependence. An i.t. treatment with naltrindole produced equivalent signs of withdrawal in both i.t. butorphanol- and morphine-dependent rats. These results suggest that continuous i.t. butorphanol results in the development of less physical dependence than that of i.t. morphine. Spinal kappa- rather than delta- and mu-opioid receptors play a major role in the development of i.t. butorphanol dependence, whereas spinal mu-opioid receptors play a more important role than delta-opioid receptors in i.t. morphine dependence.
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PMID:Relative involvement of spinal opioid receptors in physical dependence on intrathecal butorphanol and morphine. 970 Sep 74

The cross-tolerance and convergent dependence between morphine and the cannabimimetic agent R(+)-[2,3-dihydro-5-methyl-3[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-+ ++benzoxazin-yl]-(1-naphthalenyl) methanone mesylate (WIN 55,212-2) were assessed in vitro on guinea-pig ileum. To induce tolerance and dependence the myenteric plexus-longitudinal muscle was incubated at 37 degrees C for 5 h with a fixed concentration representing the IC50 for each compound. Myenteric plexus-longitudinal muscle exposed to WIN 55,212-2 (5 x 10(-8) M) was less sensitive to its inhibitory effect on electrically evoked contractions than naive myenteric plexus-longitudinal muscle. The exposure to cannabinoid induced a parallel rightward shift in the lower part of the concentration-response curve of WIN 55,212-2 and a marked reduction in the maximal inhibitory effect of the drug. Myenteric plexus-longitudinal muscle tolerant to WIN 55,212-2 was subsensitive to the inhibitory effect of morphine on the twitch response. The cross-tolerance between WIN 55,212-2 and morphine was bidirectional. In fact, after 5 h the morphine (10(-7) M)-incubated myenteric plexus-longitudinal muscle was less sensitive to the inhibitory effect of WIN 55,212-2. The tissue tolerant to morphine or WIN 55,212-2 was tested for the presence of physical dependence. Naloxone (10(-5) M) produced a typical withdrawal contracture in morphine-tolerant myenteric plexus-longitudinal muscle which could be reduced by a 15-min pretreatment with WIN 55,212-2 (5 X 10(-8) M). In contrast, SR141716 (10(-6) M) [N-(piperidino)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyr azole-carboxamide], a concentration which fully antagonized the inhibitory effect of WIN 55,212-2 (10(-7) M) in control preparations, did not produce significant contracture in WIN 55,212-2-tolerant myenteric plexus-longitudinal muscle. The mechanisms underlying the cross-tolerance and convergent dependence remain to be ascertained.
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PMID:Cross-tolerance and convergent dependence between morphine and cannabimimetic agent WIN 55,212-2 in the guinea-pig ileum myenteric plexus. 1044 86

We investigated the antinociceptive effect of FR140423, 3-(difluoromethyl)-1-(4-methoxyphenyl)-5-[4-(methylsulfinyl)phenyl] pyrazole, in the tail-pinch test in mice, and evaluated the mechanism of action using various opioid receptor antagonists. P.o. and i.t. injection of FR140423 exerted dose-dependent antinociceptive activities with ED50 values of 21 mg/kg and 3.1 microg/mouse, respectively. However, i.c.v. injection of FR140423 did not show an antinociceptive effect. The antinociceptive effects of FR140423 were completely abolished by naloxone and naltrindole but not by naloxonazine, beta-funaltrexamine and nor-binaltorphimine. FR140423 did not affect any opioid receptor binding in mouse spinal membranes at concentrations up to 100 microM in vitro. Naloxone-induced jumping and diarrhea tests for morphine-like physical dependence of FR140423 gave negative results. These results suggest that FR140423 can induce antinociception by acting on the spinal but not the supraspinal site, and that spinal delta-opioid systems indirectly play a role in the antinociception produced by FR140423 in mice.
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PMID:Antinociceptive properties of FR140423 mediated through spinal delta-, but not mu- and kappa-, opioid receptors. 1051 65

The influence of an inhibitor of cAMP-dependent protein kinase and protein kinase C, H-7 [1-(5-isoquinolinesulfonyl)-2-methylpiperazine], on naloxone (an opioid receptor antagonist)-precipitated withdrawal signs and changes in levels of dopamine (DA) and its metabolites in morphine- or butorphanol-dependent rats was investigated. Animals were infused continuously with morphine (a mu-opioid receptor agonist) or butorphanol (a mu/delta/kappa mixed opioid receptor agonist) for 3 days. Naloxone precipitated withdrawal syndrome and decreased the levels of DA in the cortex, striatum, and midbrain; 3, 4-dihydroxyphenylacetic acid (DOPAC) in the cortex, striatum, limbic areas, and midbrain; and homovanilic acid (HVA) in the striatum, limbic areas, and midbrain regions. In animals rendered dependent on butorphanol, the results obtained were similar to those of morphine-dependent rats except for the changes in DOPAC levels. Concomitant infusion of H-7 and opioid blocked both the expression of withdrawal signs and the decreases in DA, DOPAC, and HVA levels in a dose-dependent manner. These results suggest that the enhancement of cAMP-dependent protein kinase and/or protein kinase C activity accompanying the increase of DA neuron activity during continuous infusion of opioids leads to an abrupt reduction in levels of DA and its metabolites precipitated by naloxone, which is intimately involved in the expression of physical dependence on opioids.
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PMID:A protein kinase inhibitor, H-7, blocks naloxone-precipitated changes in dopamine and its metabolites in the brains of opioid-dependent rats. 1092 15


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