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http://www.doctordeluca.com/Library/References/NaltexInducedOpiateSensitivity1.htm
Medline References: Naltrexone Induced Sensitivity to Opiates
Last Updated: 6/2001

 

1
UI - 2
AU - Miotto K
AU - McCann MJ
AU - Rawson RA
AU - Frosch D
AU - Ling W
AD - Matrix Center, Los Angeles, CA, USA
TI - Overdose, suicide attempts and death among a cohort of naltrexone- treated opioid addicts
AB - In a study evaluating naltrexone with either an intensive psychosocial protocol or standard community treatment for opioid dependence, 13 of 81 subjects overdosed within a 12-month period of study participation. There were four fatalities, one of which was a suicide. Among the nine nonfatal overdoses, there were four suicide attempts. Characteristics of subjects and naltrexone-taking are described
MH - Adult
MH - Depressive Disorder
MH - psychology
MH - Female
MH - Human
MH - Male
MH - Naltrexone
MH - adverse effects
MH - therapeutic use
MH - Narcotic Antagonists
MH - Narcotics
MH - poisoning
MH - Opioid-Related Disorders
MH - drug therapy
MH - mortality
MH - Psychiatric Status Rating Scales
MH - Psychotherapy
MH - Suicide,Attempted
MH - Support,U.S.Gov't,P.H.S.
RP - NOT IN FILE
NT - UI - 97323025LA - engRN - 0 (Narcotic Antagonists)RN - 0 (Narcotics)RN - 16590-41-3 (Naltrexone)PT - Clinical TrialPT - Journal ArticleID - DAO 7641/DA/NIDADA - 19970801IS - 0376-8716SB - IMCY - IRELANDJC - EBS
UR - PM:9179515
SO - Drug Alcohol Depend 1997 Apr 14 ;45(1-2):131-134

2
UI - 13
AU - Miotto K
AU - McCann MJ
AU - Rawson RA
AU - Frosch D
AU - Ling W
AD - Matrix Center, Los Angeles, CA, USA
TI - Overdose, suicide attempts and death among a cohort of naltrexone- treated opioid addicts
AB - In a study evaluating naltrexone with either an intensive psychosocial protocol or standard community treatment for opioid dependence, 13 of 81 subjects overdosed within a 12-month period of study participation. There were four fatalities, one of which was a suicide. Among the nine nonfatal overdoses, there were four suicide attempts. Characteristics of subjects and naltrexone-taking are described
MH - Adult
MH - adverse effects
MH - Depressive Disorder
MH - drug therapy
MH - Female
MH - Human
MH - Male
MH - mortality
MH - Naltrexone
MH - Narcotic Antagonists
MH - Narcotics
MH - Opioid-Related Disorders
MH - poisoning
MH - Psychiatric Status Rating Scales
MH - psychology
MH - Psychotherapy
MH - Suicide,Attempted
MH - Support,U.S.Gov't,P.H.S.
MH - therapeutic use
RP - NOT IN FILE
NT - UI - 97323025LA - engRN - 0 (Narcotic Antagonists)RN - 0 (Narcotics)RN - 16590-41-3 (Naltrexone)PT - Clinical TrialPT - Journal ArticleID - DAO 7641/DA/NIDADA - 19970801IS - 0376-8716SB - IMCY - IRELANDJC - EBS
UR - PM:9179515
SO - Drug Alcohol Depend 1997 Apr 14 ;45(1-2):131-134

3
UI - 3
AU - White JM
AU - Irvine RJ
AD - Department of Clinical and Experimental Pharmacology, University of Adelaide, Australia
TI - Mechanisms of fatal opioid overdose
AB - There has been increasing recognition of the problem of fatal opioid overdose. This review examines the pharmacological basis of respiratory depression following opioid administration. Respiration is controlled principally through medullary respiratory centres with peripheral input from chemoreceptors and other sources. Opioids produce inhibition at the chemoreceptors via mu opioid receptors and in the medulla via mu and delta receptors. While there are a number of neurotransmitters mediating the control of respiration, glutamate and GABA are the major excitatory and inhibitory neurotransmitters, respectively. This explains the potential for interaction of opioids with benzodiazepines and alcohol: both benzodiazepines and alcohol facilitate the inhibitory effect of GABA at the GABAA receptor, while alcohol also decreases the excitatory effect of glutamate at NMDA receptors. Heroin and methadone are the major opioids implicated in fatal overdose. Heroin has three metabolites with opioid activity. Variation in the formation of these metabolites due to genetic factors and the use of other drugs could explain differential sensitivity to overdose. Metabolites of methadone contribute little to its action. However, variation in rate of metabolism due to genetic factors and other drugs used can modify methadone concentration and hence overdose risk. The degree of tolerance also determines risk. Tolerance to respiratory depression is less than complete, and may be slower than tolerance to euphoric and other effects. One consequence of this may be a relatively high risk of overdose among experienced opioid users. While agonist administration modifies receptor function, changes (usually in the opposite direction) also result from use of antagonists. The potential for supersensitivity to opioids following a period of administration of antagonists such as naltrexone warrants further investigation. While our understanding of the pharmacological basis of opioid-related respiratory depression has advanced, better understanding of the role of heroin metabolites, the metabolism of methadone, drug interactions and tolerance would all be of considerable value in knowing how best to respond to this problem
MH - chemically induced
MH - drug effects
MH - Drug Interactions
MH - Drug Tolerance
MH - etiology
MH - Human
MH - Naltrexone
MH - Narcotics
MH - Neurotransmitters
MH - Opioid-Related Disorders
MH - Overdose
MH - pharmacology
MH - physiology
MH - poisoning
MH - Respiration
MH - Respiratory Insufficiency
RP - NOT IN FILE
NT - UI - 20172421LA - engRN - 0 (Narcotics)RN - 0 (Neurotransmitters)RN - 16590-41-3 (Naltrexone)PT - Journal ArticlePT - ReviewPT - Review, TutorialDA - 20000407IS - 0965-2140SB - IMCY - ENGLANDJC - BM3
UR - PM:10707430
SO - Addiction 1999 Jul ;94(7):961-972

4
UI - 42
AU - Shah S
AU - Duttaroy A
AU - Chen BT
AU - Carroll J
AU - Yoburn BC
AD - Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Queens, NY 11439, USA
TI - The effect of mu-opioid receptor antisense on morphine potency and antagonist-induced supersensitivity and receptor upregulation
AB - The present study examined the effect of in vivo antisense oligodeoxynucleotide treatment on naltrexone (NTX)-induced functional supersensitivity and mu-opioid receptor up-regulation in mice. On day 1 mice were implanted S.C. with a NTX or placebo pellet and injected I.T. and I.C.V. with dH2O or oligodeoxynucleotides. The oligodeoxynucleotides were designed so that they were either perfectly complementary to the first 18 bases of the coding region of mouse mu- opioid receptor mRNA, or had one (Mismatch-1) or four (Mismatch-4) mismatches. On days 3, 5, 7, and 9, mice were again injected I.T. and I.C.V. with dH2O or one of the oligodeoxynucleotides. After the final injections on day 9, placebo and NTX pellets were removed, and 24 h later mice were tested for morphine analgesia or sacrificed for saturation binding studies ([3H]DAMGO). Naltrexone increased the analgesic potency of morphine in dH2O treated mice by approximately 70%. In binding studies, NTX significantly increased density of brain (approximately 60%) and spinal cord (approximately 140%) mu-opioid receptors without affecting affinity. The mu-opioid antisense and the oligodeoxynucleotide with one mismatch (Mismatch-1) significantly reduced the potency of morphine by approximately twofold in placebo- treated mice. The oligodeoxynucleotide with four mismatches (Mismatch- 4) did not significantly alter morphine potency. When placebo-treated mice were treated with either the antisense to the mouse mu-opioid receptor, Mismatch-4 or Mismatch-1 there were no significant changes in the density of mu-opioid receptors. Thus, mu-opioid antisense significantly reduced morphine potency without changing mu-opioid receptor density. When NTX and oligodeoxynucleotide treatments were combined, there was no change in NTX-induced supersensitivity and mu- opioid receptor upregulation. These data suggest that opioid antagonist- induced supersensitivity and upregulation of mu-opioid receptors does not involve changes in gene expression
MH - Animal
MH - antagonists & inhibitors
MH - Dose-Response Relationship,Drug
MH - drug effects
MH - Male
MH - Mice
MH - Morphine
MH - Naltrexone
MH - Oligonucleotides,Antisense
MH - pharmacology
MH - Receptors,Opioid,mu
MH - Sensitivity and Specificity
MH - Support,U.S.Gov't,P.H.S.
MH - Up-Regulation (Physiology)
RP - NOT IN FILE
NT - UI - 97275030LA - engRN - 0 (Oligonucleotides, Antisense)RN - 0 (Receptors, Opioid, mu)RN - 57-27-2 (Morphine)PT - Journal ArticleID - DA 04185/DA/NIDADA - 19970718IS - 0361-9230SB - IMCY - UNITED STATESJC - B5M
UR - PM:9128924
SO - Brain Res Bull 1997 ;42(6):479-484

5
UI - 93
AU - Ayesta FJ
AU - Ableitner A
AU - Emmett-Oglesby MW
AU - Herz A
AU - Shippenberg TS
AD - Department of Neuropharmacology, Institute Max-Planck of Psychiatry, Planegg-Martinsried, Federal Republic of Germany
TI - Paradoxical effect of chronic fentanyl treatment on naltrexone-induced supersensitivity and upregulation
AB - The present study sought to evaluate the influence of chronic opioid antagonist treatment upon the discriminative stimulus and analgesic effects of the opioid receptor agonist fentanyl. Male Wistar rats were trained to discriminate fentanyl (0.04 mg/kg) from saline in a two- lever food reinforced paradigm. After acquisition of the discrimination, they were implanted with osmotic minipumps which delivered either naltrexone (0.07 mg/h) or distilled water, and the sensitivity of discrimination was assessed at various times after pump removal. The influence of chronic naltrexone treatment upon the antinociceptive effects of fentanyl was assessed in drug-naive (control) rats and in rats which had received fentanyl in the same dosage schedule as those in drug discrimination experiments. Chronic infusion of naltrexone for 7 days did not modify the dose-response curve for the fentanyl vs. saline discrimination. Algesiometric tests revealed a significant increase in the antinociceptive effect of fentanyl in control rats after naltrexone treatment. In contrast, such supersensitivity was not observed in rats which had previously received fentanyl injections. Autoradiographic data revealed a naltrexone- induced upregulation of mu opioid receptors in control animals. Paradoxically, this effect was significantly increased in fentanyl- pretreated rats. These data suggest that prior drug experience can affect the development of antagonist-induced supersensitivity to the behavioral actions of opioid agonists. Furthermore, it would appear that after chronic agonist treatment the phenomena of opioid receptor upregulation and functional supersensitivity are dissociated
MH - Analgesia
MH - Animal
MH - Autoradiography
MH - Behavior,Animal
MH - Discrimination Learning
MH - Dose-Response Relationship,Drug
MH - drug effects
MH - Drug Hypersensitivity
MH - Drug Interactions
MH - drug therapy
MH - etiology
MH - Fentanyl
MH - Male
MH - Naltrexone
MH - Narcotics
MH - Nociceptors
MH - pharmacology
MH - Rats
MH - Rats,Inbred Strains
MH - Support,Non-U.S.Gov't
MH - Time Factors
MH - Up-Regulation (Physiology)
RP - NOT IN FILE
NT - UI - 92113902LA - engRN - 0 (Narcotics)RN - 16590-41-3 (Naltrexone)RN - 437-38-7 (Fentanyl)PT - Journal ArticleDA - 19920218IS - 0022-3565SB - IMCY - UNITED STATESJC - JP3
UR - PM:1731036
SO - J Pharmacol Exp Ther 1992 Jan ;260(1):168-174

6
UI - 109
AU - Yoburn BC
AU - Kreuscher SP
AU - Inturrisi CE
AU - Sierra V
AD - Department of Pharmaceutical Sciences, College of Pharmacy & Allied Health Professions, St. John's University, Jamaica, NY 11439
TI - Opioid receptor upregulation and supersensitivity in mice: effect of morphine sensitivity
AB - Mice of the Swiss-Webster strain obtained from two suppliers (Taconic, Charles River) were found to differ in their sensitivity to morphine. Mice from Taconic were approximately two-fold more sensitive to the analgesic and lethal effects of morphine compared to the Charles River mice. In a third strain, C3H/HEN, morphine was found to be more than 2.5 times more potent in producing analgesia than in the Charles River mice. Binding studies showed that the Taconic mice and C3H/HEN mice had approximately 40% and 60%, respectively, more specific [3H]naloxone binding sites in brain than did the less sensitive Charles River mice. When treated with chronic naltrexone for 8 days the analgesic potency of morphine was increased by approximately 90% for both Swiss-Webster mice and by 20% for the C3H/HENs. [3H]Naloxone binding was increased by 45-50% in the Swiss-Webster strains, but by only 33% in C3H/HEN mice. These data indicate that receptor upregulation is directly related to increases in morphine potency. Further, these findings suggest that initial sensitivity to morphine can determine the degree of functional supersensitivity and relative receptor upregulation produced by chronic opioid antagonist treatment
MH - Analgesia
MH - Animal
MH - Brain
MH - Dose-Response Relationship,Drug
MH - drug effects
MH - Male
MH - metabolism
MH - Mice
MH - Mice,Inbred C3H
MH - Morphine
MH - Naloxone
MH - Naltrexone
MH - pharmacology
MH - Receptors,Opioid
MH - Support,Non-U.S.Gov't
MH - Support,U.S.Gov't,P.H.S.
RP - NOT IN FILE
NT - UI - 89297174LA - engRN - 0 (Receptors, Opioid)RN - 465-65-6 (Naloxone)RN - 57-27-2 (Morphine)PT - Journal ArticleID - DA 04157/DA/NIDADA - 19890801IS - 0091-3057SB - IMCY - UNITED STATESJC - P3Q
UR - PM:2544906
SO - Pharmacol Biochem Behav 1989 Mar ;32(3):727-731

7
UI - 111
AU - Warren PH
AU - Morse WH
AD - Laboratory of Psychobiology, Harvard Medical School, Boston, Massachusetts
TI - Environmental determinants of enhanced sensitivity to the behavioral effects of naltrexone
AB - Dose-effect curves for naltrexone were determined in three squirrel monkeys studied sequentially under four different schedule conditions: a schedule of shock postponement; a fixed-interval schedule of shock presentation; a fixed-ratio schedule of food presentation; and a fixed- ratio schedule of stimulus-shock termination. In general, responding under the shock-postponement or the fixed-interval schedules was decreased minimally by doses of naltrexone up to 30 mg/kg, and these effects were not altered appreciably after daily injections of naltrexone under the fixed-interval schedule. Under the fixed-ratio schedule of food presentation naltrexone (0.3 to 10 mg/kg) produced dose-related decreases in responding, and after repeated daily injections of naltrexone the dose-effect curve was shifted more than 3- fold to the left. Under the fixed-ratio schedule of stimulus-shock termination, however, this supersensitivity to naltrexone was not apparent: responding was decreased appreciably only after 17.6 mg/kg of naltrexone. When the fixed-ratio schedule of food presentation was reinstated, the supersensitivity to naltrexone observed previously under this schedule was not evident initially, but reappeared quickly in two of the monkeys. The greater rate-decreasing effects of naltrexone under the fixed-ratio schedules compared to the other schedules may reflect a dependency related to the control rate of responding. Supersensitivity to naltrexone occurred only under the fixed-ratio schedule of food presentation and could be reversed temporarily by intervening exposure to the schedule of stimulus-shock termination. These results extend earlier findings that the behavioral effects of drugs can be dependent upon both past and present environmental influences
MH - Animal
MH - Conditioning (Psychology)
MH - Dose-Response Relationship,Drug
MH - drug effects
MH - Male
MH - Naltrexone
MH - pharmacology
MH - Reinforcement Schedule
MH - Saimiri
MH - Support,U.S.Gov't,P.H.S.
RP - NOT IN FILE
NT - UI - 89141476LA - engRN - 16590-41-3 (Naltrexone)PT - Journal ArticleID - DA00499/DA/NIDAID - DA02658/DA/NIDAID - MH07658/MH/NIMHID - etcDA - 19890403IS - 0022-3565SB - IMCY - UNITED STATESJC - JP3
UR - PM:2918471
SO - J Pharmacol Exp Ther 1989 Feb ;248(2):546-551

8
UI - 112
AU - Rothman RB
AU - Bykov V
AU - Long JB
AU - Brady LS
AU - Jacobson AE
AU - Rice KC
AU - Holaday JW
AD - Laboratory of Clinical Science, NIMH, Bethesda, MD 20892
TI - Chronic administration of morphine and naltrexone up-regulate mu-opioid binding sites labeled by [3H][D-Ala2,MePhe4,Gly-ol5]enkephalin: further evidence for two mu-binding sites
AB - A variety of data support the hypothesis of an opiate receptor complex composed of distinct, yet interacting mu and delta binding sites (termed mu cx and delta cx to indicate binding sites 'in the complex'), in addition to independent mu and delta binding sites, termed mu ncx and delta ncx, to indicate binding sites 'not in the complex'. Ligand binding studies using membranes and slide-mounted sections of rat brain support the hypothesis that the irreversible mu-antagonist beta- funaltrexamine (FNA) selectively alkylates the opiate receptor complex, altering the binding of mu agonists to the mu cx binding site and the binding of [3H][D-Ala2,D-Leu5]enkephalin to the delta cx site. Previous studies demonstrated that the chronic administration of morphine to rats selectively 'upregulates' the opiate receptor complex. In contrast, the chronic administration of naltrexone upregulates several types of opioid receptors, including kappa, the delta ncx binding site, and multiple binding sites labeled by mu agonists. A prediction based upon these observations is that, using [3H][D-Ala2,MePhe4,Gly- ol5]enkephalin to label mu binding sites, chronic morphine should upregulate only the mu cx binding site, whereas chronic naltrexone should additionally up-regulate the mu ncx binding site. In this study we test and confirm this hypothesis, using sensitivity to FNA to define the mu cx binding site. The implications of these data for models of the opioid receptors and the mechanism(s) of tolerance and dependence are discussed
MH - analogs & derivatives
MH - Animal
MH - Benzomorphans
MH - Brain
MH - Enkephalin,Ala(2)-MePhe(4)-Gly(5)-
MH - Enkephalins
MH - In Vitro
MH - Male
MH - metabolism
MH - Morphine
MH - Naltrexone
MH - Narcotic Antagonists
MH - pharmacology
MH - Rats
MH - Rats,Inbred Strains
MH - Receptors,Opioid
MH - Receptors,Opioid,kappa
MH - Receptors,Opioid,mu
RP - NOT IN FILE
NT - UI - 89231946LA - engRN - 0 (Benzomorphans)RN - 0 (Enkephalins)RN - 0 (Narcotic Antagonists)RN - 0 (Receptors, Opioid)RN - 0 (Receptors, Opioid, kappa)RN - 0 (Receptors, Opioid, mu)RN - 100929-53-1 (Enkephalin, Ala(2)-MePhe(4)-Gly(5)-)RN - 16590-41-3 (Naltrexone)RN - 57-27-2 (Morphine)RN - 72782-05-9 (beta-funaltrexamine)RN - 75684-07-0 (bremazocine)PT - Journal ArticleDA - 19890620IS - 0014-2999SB - IMCY - NETHERLANDSJC - EN6
UR - PM:2540993
SO - Eur J Pharmacol 1989 Jan 24 ;160(1):71-82

9
UI - 131
AU - Tempel A
AU - Gardner EL
AU - Zukin RS
TI - Neurochemical and functional correlates of naltrexone-induced opiate receptor up-regulation
AB - The neurochemical and functional correlates of opioid receptor up- regulation after chronic antagonist administration in vivo and of down- regulation after withdrawal of antagonist were examined. Total brain opioid receptors increased 1.9-fold by day 8 of naltrexone administration, after which no further increase was observed; the newly synthesized or unmasked receptors exhibited an enhanced sensitivity to guanyl nucleotide modulation. Withdrawal from chronic naltrexone treatment resulted in a return to nearly control levels of receptor density and guanyl nucleotide sensitivity in a period of 6 days. These results suggest that up-regulation is accompanied by an increased coupling of the receptors to the inhibitory guanyl nucleotide binding protein (Ni) and that down-regulation involves the dissociation of the receptor/Ni complex. In experiments designed to target opiate receptor subtypes, long-term treatment with naltrexone was found to produce a coordinated up-regulation of brain mu and delta receptors, but did not cause a significant change in the density or affinity of kappa or sigma receptors. These findings indicate that the kappa and sigma opiate receptor classes may be subject to independent control mechanisms. Chronic naltrexone treatment also resulted in an enhanced morphine- induced analgesia. This result indicates that a functional supersensitivity occurs as a result of the selective up-regulation of mu and delta receptors. After withdrawal from naltrexone, supersensitivity to morphine-induced analgesia decreased monotonically and, in parallel to opioid receptor density, to prenaltrexone treatment levels within 6 days. Together, these results suggest a functional significance for antagonist-induced mu and delta opiate receptor up- regulation
MH - Analgesia
MH - analogs & derivatives
MH - Animal
MH - Brain
MH - Brain Chemistry
MH - drug effects
MH - Guanosine Triphosphate
MH - Male
MH - metabolism
MH - Morphine
MH - Naloxone
MH - Naltrexone
MH - Pain
MH - pharmacology
MH - physiopathology
MH - Rats
MH - Rats,Inbred Strains
MH - Receptors,Opioid
MH - Support,Non-U.S.Gov't
MH - Support,U.S.Gov't,Non-P.H.S.
MH - Support,U.S.Gov't,P.H.S.
MH - Time Factors
RP - NOT IN FILE
NT - UI - 85107709LA - engRN - 0 (Receptors, Opioid)RN - 16590-41-3 (Naltrexone)RN - 465-65-6 (Naloxone)RN - 57-27-2 (Morphine)RN - 86-01-1 (Guanosine Triphosphate)PT - Journal ArticleID - DA 00069/DA/NIDAID - DA 01843/DA/NIDAID - HD 07154/HD/NICHDDA - 19850321IS - 0022-3565SB - IMCY - UNITED STATESJC - JP3
UR - PM:2982011
SO - J Pharmacol Exp Ther 1985 Feb ;232(2):439-444

 

Alexander DeLuca, M.D., FASAM.
Copyright 1999. All rights reserved.                               [Top of Page]
Revised: June 16, 2001.
Dr. DeLuca's Website