Dean / Bilsky / Negus Opiate Receptors and Antagonists

From Bench to Clinic
1. Auflage 2009
ISBN: 978-1-59745-197-0
Verlag: Humana Press
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, 757 Seiten

Reihe: Contemporary Neuroscience

Comprehensive and authoritative, Opioid Receptors and Antagonists: From Bench to Clinic offers neuroscientists, pharmacologists and interested clinicians a unique survey of the extensive and diverse research efforts currently employed with opioid antagonists to develop novel innovative drug therapies. Summarizes the present understanding of the chemistry, pharmacology and molecular biology of opioid receptors and their subtypes Highlights differences and similarities between the opioid pharmacology of animals and human Describes current and potential therapeutic areas for opioid antagonists, including substance abuse, alcohol and ingestive behaviors, behavioral disorders and other medical indications, supported by nonclinical and clinical evidence Focuses on the development of exciting and innovative drug delivery approaches that are being used with opioid antagonists for the above medical indications

Autoren/Hrsg.

Dean, Reginald

Bilsky, Edward J.

Negus, S. Stevens

Inhaltsverzeichnis

1;Preface;5
2;Foreword;7
2.1;Opiate Receptors and Antagonists;7
2.2;References;9
3;Contents;11
4;Contributors;16
5;Ultra-Low-Dose Opioid Antagonists Enhance Opioid Analgesia and Reduce Tolerance;23
5.1;1.1 Introduction;24
5.2;1.2 Preclinical Evidence of Enhanced Opioid Analgesia and Reduced Tolerance;24
5.3;1.3 Dose Effects and Dependency on Strain and Sex;26
5.4;1.4 Ultra-Low-Dose Naltrexone Effects on Neuropathic Pain and Cannabinoid Analgesia;28
5.5;1.5 Clinical Studies of Ultra-Low-Dose Opioid Antagonist Effects in Analgesia;29
5.6;1.6 Mechanism of Ultra-Low-Dose Opioid Antagonists;32
5.7;1.7 Conclusions;34
5.8;References;34
6;Upregulation of Opioid Receptors;38
6.1;2.1 Introduction;39
6.2;2.2 Opioid Receptor Upregulation Following Opioid Receptor Antagonist Administration;39
6.2.1;2.2.1 In Vivo Studies;39
6.2.2;2.2.2 In Vitro Studies;44
6.3;2.3 Functional Supersensitivity;45
6.4;2.4 Studies of the Molecular Mechanisms Involved in Antagonist-Induced Opioid Receptor Upregulation;46
6.5;2.5 Opioid Receptor Upregulation Induced by Nonopioid Drugs;52
6.6;2.6 Summary and Conclusions;56
6.7;References;58
7;Imaging Human Brain Opioid Receptors: Applications to Substance Use Disorders;64
7.1;3.1 Introduction;64
7.2;3.2 Mu Receptors;65
7.2.1;3.2.1 Ligands with muOR Affinity;65
7.2.2;3.2.2 Clinical Studies;66
7.2.2.1;3.2.2.1 Studies of Antagonists to Block Receptors in Healthy Humans;66
7.2.2.2;3.2.2.2 Opioid Dependence;67
7.2.2.3;3.2.2.3 Nonopioid Substance Use Disorders;71
7.2.2.3.1;Nicotine;71
7.2.2.3.2;Alcohol;71
7.2.2.3.3;Cocaine;73
7.3;3.3 Kappa Receptors;74
7.3.1;3.3.1 Ligands with kappaOR Affinity;74
7.3.2;3.3.2 Clinical Studies;74
7.4;3.4 Delta Receptors;75
7.4.1;3.4.1 Ligands with deltaOR Affinity;76
7.4.2;3.4.2 Clinical Studies;76
7.5;3.5 Conclusions;76
7.6;References;77
8;Opioid Receptor Antagonist-Mediated Signaling in the Immune System;85
8.1;4.1 Introduction;85
8.2;4.2 Opioid Receptor Expression in the Immune System;86
8.2.1;4.2.1 Opioid Receptors on Lymphocytes;87
8.2.2;4.2.2 Opioid Receptors on Granulocytes, Monocytes, and Macrophages;87
8.3;4.3 Opioid Receptor Antagonists: Effects on Immune Functions;88
8.3.1;4.3.1 Effects on T Cell Growth and Proliferation;88
8.3.2;4.3.2 Role in Thymocytes and Effect on Cellular Apoptosis;88
8.3.3;4.3.3 Effects on Cytokine Signaling;89
8.3.4;4.3.4 Effects on Phagocytic Functions;90
8.3.5;4.3.5 Effects on NK Function;90
8.3.6;4.3.6 Effects on Antibody Production;90
8.4;4.4 The Central Nervous System-Immune System Link;91
8.5;4.5 Opioid Receptor Signaling and Infection;92
8.6;4.6 Conclusions and Perspectives;92
8.7;References;93
9;The Chemistry and Pharmacology of Mu-Opioid Antagonists;99
9.1;5.1 Introduction;99
9.1.1;5.1.1 Opioid Background;100
9.1.2;5.1.2 Mu Opioid-Related Side Effects;100
9.2;5.2 When Is an Antagonist Called an Antagonist;101
9.2.1;5.2.1 The [35S]GTPGammaS Binding Assay;101
9.2.2;5.2.2 From In Vitro Antagonist Characterization to an In Vivo Model;101
9.3;5.3 Nalorphine, Naloxone, and Naltrexone: A History Lesson;103
9.3.1;5.3.1 Clinical Applications for Naltrexone;105
9.3.1.1;5.3.1.1 Alcohol;105
9.3.1.2;5.3.1.2 Opioid Detoxification;105
9.3.1.3;5.3.1.3 Feeding Behaviors;105
9.4;5.4 Irreversible Antagonists;105
9.4.1;5.4.1 Beta-Funaltrexamine;106
9.4.2;5.4.2 Dihydromorphinone and Dihydrocodeinone Derivatives;106
9.5;5.5 Reversible Antagonists;107
9.5.1;5.5.1 Quarternary Antagonists;107
9.5.1.1;5.5.1.1 Methylnaltrexone;108
9.5.1.2;5.5.1.2 Alvimopan;108
9.6;5.6 Other Structural Motifs as Mu Antagonists;108
9.6.1;5.6.1 Dmt-Tic Analogues;108
9.6.2;5.6.2 Somatostatin Analogues;109
9.6.3;5.6.3 Morphinans;109
9.6.4;5.6.4 Benzomorphans;109
9.6.5;5.6.5 Oripavines;110
9.7;5.7 Summary;110
9.8;References;111
10;Medicinal Chemistry of Kappa Opioid Receptor Antagonists;114
10.1;6.1 Introduction;114
10.2;6.2 SAR of Selective Nonpeptidic KOR Antagonists;116
10.2.1;6.2.1 SAR of norBNI;117
10.2.2;6.2.2 SAR of JDTic;125
10.2.3;6.2.3 SAR of MTHQ;125
10.3;6.3 Unusually Long Duration of Action of Current Selective KOR Antagonists;127
10.4;6.4 Future Directions;128
10.5;References;129
11;The Chemistry and Pharmacology of Delta Opioid Antagonists;134
11.1;7.1 Introduction;134
11.2;7.2 Classical delta-Opioid Antagonists;135
11.2.1;7.2.1 N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH;135
11.2.2;7.2.2 Naltrindole;136
11.2.3;7.2.3 H-Tyr-Tic-Phe-Phe-OH;136
11.2.4;7.2.4 [D-Ala2, Leu5, Cys6]enkephalin and [D-Ala2, Leu5, Ser6]enkephalin;138
11.2.5;7.2.5 5'-Isothiocyanate;139
11.2.6;7.2.6 Naltriben;139
11.2.7;7.2.7 7-Benzylidenenaltrexone;140
11.3;7.3 New delta-Opioid Antagonists;140
11.3.1;7.3.1 [(±)-KF4];140
11.3.2;7.3.2 Fluorescent delta-Antagonists;141
11.4;7.4 Clinical Applications of delta-Antagonists;142
11.4.1;7.4.1 Prevention of Morphine-Induced Antinociceptive Tolerance;142
11.4.2;7.4.2 Antitussive Properties;142
11.4.3;7.4.3 Ethanol Addiction;143
11.4.4;7.4.4 Cardiovascular Effects;145
11.5;7.5 Conclusion;146
11.6;References;146
12;Novel Opioid Antagonists with Mixed/Dual Selectivity;167
12.1;8.1 Introduction;168
12.2;8.2 Peptide Ligands Possessing Mixed Mu Agonist/Delta Antagonist Activity;169
12.3;8.3 Nonpeptide Ligands that Possess Mixed Agonist/Antagonist Activity;170
12.4;8.4 Conclusions;179
12.5;References;179
13;Experimental Utility and Clinical Potential of Irreversible Opioid Antagonists;182
13.1;9.1 Introduction;183
13.2;9.2 Insurmountable Antagonists Available for Mu-Opioid Receptors;184
13.2.1;9.2.1 Beta-Chlornaltrexamine;185
13.2.2;9.2.2 Beta-Funaltrexamine;185
13.2.3;9.2.3 Buprenorphine;185
13.2.4;9.2.4 Clocinnamox;186
13.2.5;9.2.5 Others;186
13.3;9.3 Experimental Utility;187
13.3.1;9.3.1 In Vitro Binding Parameters;187
13.3.2;9.3.2 Agonist Affinity and Efficacy Estimates;187
13.3.2.1;9.3.2.1 Agonist Affinity;188
13.3.2.2;9.3.2.2 Antagonist Affinities;190
13.3.2.3;9.3.2.3 Measures of Agonist Efficacy;190
13.3.2.4;9.3.2.4 Special Considerations;191
13.3.3;9.3.3 Receptor Turnover;192
13.3.4;9.3.4 Underlying Mechanisms of Tolerance and Dependence;193
13.4;9.4 Implications for Clinical Use;195
13.4.1;9.4.1 Clinical Experimental Utility;195
13.4.2;9.4.2 Implications for Therapeutics;197
13.5;9.5 Conclusions;198
13.6;References;198
14;Methylnaltrexone: A Peripherally Acting Opioid Antagonist;204
14.1;10.1 Introduction;204
14.2;10.2 Physical and Chemical Properties;205
14.3;10.3 Preclinical Development;205
14.3.1;10.3.1 Receptor Binding Activities;205
14.3.2;10.3.2 Acute Toxicity and Demethylation Studies;205
14.3.3;10.3.3 Opioid-Induced Emesis;206
14.3.4;10.3.4 Gut Motility and Opioids;207
14.4;10.4 Clinical Development;207
14.4.1;10.4.1 Safety and Tolerability;207
14.4.2;10.4.2 Absorption, Elimination, and Metabolism;208
14.4.3;10.4.3 Activity of Parenteral Methylnaltrexone in Healthy Volunteers;209
14.4.4;10.4.4 Activity of Oral Methylnaltrexone in Healthy Volunteers;210
14.4.5;10.4.5 Activity of Methylnaltrexone in Chronic Opioid Users;212
14.4.6;10.4.6 Methylnaltrexone in Long-Term Opioid Users with Advanced Medical Illness (44);214
14.4.7;10.4.7 Methylnaltrexone for Post-operative Ileus;216
14.4.8;10.4.8 First Phase III Trial: Methylnaltrexone in Chronic Opioid Users with Advanced Medical Illness;217
14.4.9;10.4.9 Second Phase III Trial: Methylnaltrexone in Chronic Opioid Users with Advanced Medical Illness;218
14.5;10.5 Other Potential Roles of Methylnaltrexone in Clinical Practice;221
14.5.1;10.5.1 Opioid-Induced Delay in Gastric Emptying;221
14.5.2;10.5.2 Opioid-Induced Urinary Retention;221
14.5.3;10.5.3 Opioid-Induced Subjective Effects;222
14.5.4;10.5.4 Maintaining the Cough Reflex After Opioids;222
14.5.5;10.5.5 Opioid-Induced Immunosuppression;222
14.5.6;10.5.6 Constipation Associated with Functional Bowel Disorders;223
14.5.7;10.5.7 Inhibition of Angiogenesis;223
14.6;10.6 Summary;223
14.7;Conflict of Interest Disclaimer;224
14.8;References;224
15;Opioid Antagonist Effects in Animal Models Related to Opioid Abuse: Drug Discrimination and Drug Self-Administration;228
15.1;11.1 Introduction;229
15.2;11.2 Animal Models of Abuse-Related Drug Effects;229
15.2.1;11.2.1 The 3-Term Contingency;229
15.2.2;11.2.2 Drug Discrimination Procedures;230
15.2.3;11.2.3 Drug Self-Administration Procedures;231
15.2.4;11.2.4 Procedures to Study Drug Dependence and Withdrawal;232
15.3;11.3 Effects of Opioid Antagonists in Assays of Drug Discrimination;233
15.3.1;11.3.1 Discriminative Stimulus Effects of Opioid Agonists;233
15.3.2;11.3.2 Antagonism of the Discriminative Stimulus Effects of Opioid Agonists;233
15.3.3;11.3.3 Discriminative Stimulus Effects of Opioid Antagonists;236
15.4;11.4 Effects of Opioid Antagonists in Assays of Drug Self-Administration;237
15.4.1;11.4.1 Effects of Opioid Agonists As Consequent Stimuli;237
15.4.2;11.4.2 Effects of Opioid Antagonists on Opioid Agonist Self-Administration;237
15.4.3;11.4.3 Effects of Opioid Antagonists as Consequent Stimuli;239
15.5;11.5 Effects of Opioid Antagonists in Opioid-Dependent Subjects;240
15.5.1;11.5.1 Dependence Associated with Opioid Agonist Treatment;240
15.5.2;11.5.2 Effects of Antagonists in Dependent Subjects: Drug Discrimination Studies;240
15.5.3;11.5.3 Effects of Antagonists in Dependent Subjects: Drug Self-Administration Studies;242
15.5.3.1;11.5.3.1 Effects on Self-Administration of Opioid Agonists;242
15.5.3.2;11.5.3.2 Effects As Consequent Stimuli;244
15.6;11.6 Summary and Implications for Clinical Studies;245
15.7;References;246
16;Naltrexone for Initiation and Maintenance of Opiate Abstinence;254
16.1;12.1 Overview of Opiate Dependence Pharmacotherapy;254
16.2;12.2 Opiate Detoxification;255
16.2.1;12.2.1 Range of Pharmacotherapies;255
16.2.2;12.2.2 Rapid Opiate Detoxification;255
16.2.2.1;12.2.2.1 Naltrexone Combined with Alpha-2 Agonists;255
16.2.2.2;12.2.2.2 Naltrexone Combined with Buprenorphine;256
16.2.3;12.2.3 Ultrarapid Opiate Detoxification;257
16.3;12.3 Naltrexone Maintenance of Opiate Abstinence;258
16.3.1;12.3.1 Opiate Receptor Antagonists;258
16.3.2;12.3.2 Naltrexone Maintenance;259
16.3.2.1;12.3.2.1 Naloxone Challenge, Naltrexone Induction, and Naltrexone Maintenance Dosing;259
16.3.2.2;12.3.2.2 Safety and Side Effect Profile;259
16.3.2.3;12.3.2.3 Efficacy in Clinical Use;260
16.3.2.4;12.3.2.4 Depot Naltrexone;261
16.3.2.5;12.3.2.5 Pharmacological Adjuncts to Improve Compliance (Lofexidine/Fluoxetine);263
16.3.2.6;12.3.2.6 Behavioral Platforms to Improve Compliance;264
16.3.2.7;12.3.2.7 Patient Selection;265
16.4;12.4 Conclusion;266
16.5;References;266
17;Ultra-Low-Dose Naltrexone Decreases Dependence and Addictive Properties of Opioids;273
17.1;13.1 Introduction;274
17.2;13.2 Ultra-Low-Dose Naltrexone or Naloxone Reduces Somatic Withdrawal in Rodents;274
17.3;13.3 Ultra-Low-Dose Naltrexone Reduces Affective Withdrawal in Rodents;276
17.4;13.4 Reduced Physical Dependence in Clinical Trial of Oxytrex Versus Oxycodone;277
17.5;13.5 Ultra-Low-Dose Naltrexone Reduces the Rewarding Properties of Opioids;278
17.6;13.6 Ultra-Low-Dose Naltrexone Reduces the Rewarding Potency of Intravenous Oxycodone and Blocks Relapse to Oxycodone Seeking in Rats;281
17.7;13.7 Conclusions;283
17.8;References;285
18;Can a Combination Formulation Containing a Neutral Opiate Antagonist Decrease the Abuse of mu-Agonist Opiates;288
18.1;14.1 Prescription Opiate Abuse in the United States – An Emerging Epidemic;289
18.1.1;14.1.1 US Trends in Ambulatory Care Opioid Prescribing from 1993 to 2003;291
18.1.2;14.1.2 Opioid Basal Signaling, Inverse Agonists, and Neutral Antagonists;292
18.2;14.2 Potential Advantages of 6beta-naltrexol in Decreasing Abuse of Prescription Opiates;294
18.3;14.3 Assessing the Neutral Antagonist Propertiesof 6beta-Naltrexol;295
18.4;References;296
19;Effects of Opioid Antagonists on the Abuse-Related Effects of Psychomotor Stimulants and Nicotine;298
19.1;15.1 Introduction;299
19.2;15.2 Pharmacology of Psychomotor Stimulants;299
19.3;15.3 Influence of Psychomotor Stimulants on Opioid Gene Expression;300
19.4;15.4 Animal Models of Addiction;300
19.4.1;15.4.1 Drug Self-Administration;300
19.4.2;15.4.2 Reinstatement of Drug Seeking;301
19.4.3;15.4.3 Conditioned Place Preference;301
19.4.4;15.4.4 Intracranial Self-Stimulation;302
19.5;15.5 Nonselective Opioid Receptor Antagonists;302
19.5.1;15.5.1 Drug Self-Administration;302
19.5.2;15.5.2 Conditioned Place Preference;304
19.5.3;15.5.3 Intracranial Self-Stimulation;306
19.5.4;15.5.4 Neurochemistry;307
19.6;15.6 Selective MOPr Antagonists;309
19.6.1;15.6.1 Drug Self-Administration;309
19.6.2;15.6.2 Neurochemistry;310
19.7;15.7 Selective DOPr Antagonists;311
19.7.1;15.7.1 Drug Self-Administration;311
19.7.2;15.7.2 Conditioned Place Preference;312
19.7.3;15.7.3 Intracranial Self-Stimulation;313
19.7.4;15.7.4 Neurochemistry;313
19.8;15.8 Selective KOPr Antagonists;313
19.8.1;15.8.1 Drug Self-Administration;314
19.8.2;15.8.2 Conditioned Place Preference;314
19.8.3;15.8.3 Intracranial Self-Stimulation;315
19.8.4;15.8.4 Neurochemistry;315
19.9;15.9 Conclusions;316
19.10;References;317
20;Potential Use of Opioid Antagonists in the Treatment of Marijuana Abuse and Dependence;324
20.1;16.1 Introduction;325
20.2;16.2 Historical Evolution of Research on Cannabinoids;325
20.3;16.3 Effects of Opioid Antagonists in Animal Models of cap delta 9-THC Abuse and Dependence;326
20.3.1;16.3.1 Effects of Opioid Antagonists on cap delta 9-THC-Induced Changes in Dopamine Neurotransmission;326
20.3.2;16.3.2 Effects of Opioid Antagonists on THC Discrimination;328
20.3.3;16.3.3 Effects of Opioid Antagonists on the Cannabinoid Withdrawal Syndrome;329
20.3.4;16.3.4 Effects of Opioid Antagonists on THC-Induced CPPs;329
20.3.5;16.3.5 Effects of Opiates Antagonists on Intravenous Drug Self-Administration;331
20.4;16.4 Research in Human Subjects;332
20.4.1;16.4.1 Current Clinical Research with Humans;332
20.4.2;16.4.2 Future Directions for Clinical Research;334
20.5;16.5 Conclusions;334
20.6;References;335
21;Naltrexone in Smoking Cessation: A Review of the Literature and Future Directions;340
21.1;17.1 Introduction;340
21.1.1;17.1.1 Opioid Mediation of Smoking Behavior;341
21.2;17.2 Human Laboratory Studies of Naltrexone and Acute Smoking;341
21.3;17.3 Clinical Trials;346
21.4;17.4 Sources of Individual Differencesin Response to Naltrexone;350
21.4.1;17.4.1 Sex Differences;350
21.4.2;17.4.2 Depression History and Symptoms;351
21.4.3;17.4.3 Cessation-Related Weight Gain;351
21.4.4;17.4.4 Alcohol Drinking Patterns;352
21.4.5;17.4.5 Genetic Variants;352
21.5;17.5 Future Directions and Ongoing Research;353
21.6;References;353
22;Opioid Antagonists and Ethanol’s Ability to Reinforce Intake of Alcoholic Beverages: Preclinical Studies;358
22.1;18.1 Introduction: Alcoholism is a Problem with a Long History;358
22.2;18.2 A Scientific Revolution in Theory of Addictions;362
22.3;18.3 The Revolution and Alcoholism;363
22.4;18.4 Tolerance to Naltrexone’s Effects;369
22.5;18.5 Secondary Reinforcers That Strengthen the Habit to Drink and Their Opioid Involvement;372
22.6;18.6 Specificity of Naltrexone;377
22.6.1;18.6.1 Overlap with Eating Disorders;377
22.6.2;18.6.2 Overlap with Analgesia;379
22.6.3;18.6.3 Kind of Opioid Receptors;379
22.7;18.7 Opioids and Sex of the Drinker;381
22.8;18.8 Combining Drugs to Achieve Better Outcomes of Treatments;382
22.9;18.9 Theory Incorporating the Lessons of the Revolution;383
22.10;References;384
23;Clinical Use of Opioid Antagonists in the Treatment of Alcohol Dependence;393
23.1;19.1 Introduction;394
23.2;19.2 Evidence for the Clinical Use of Opioid Antagonists in the Treatment of Alcohol Dependence;395
23.2.1;19.2.1 Translation from Basic Science to Clinical Utility;395
23.2.2;19.2.2 Human Laboratory Models of Heavy Drinking;395
23.3;19.3 Opiate Antagonist Clinical Trials;398
23.3.1;19.3.1 Early Clinical Trials – Initial Efficacy and Questions;398
23.3.2;19.3.2 The COMBINE Study in the US;400
23.4;19.4 Factors that Affect Naltrexone Efficacy;402
23.4.1;19.4.1 Treatment Adherence;402
23.4.2;19.4.2 Long Acting Injectable Naltrexone;403
23.5;19.5 Longer-Term Follow-up of Individuals Treated with Naltrexone;404
23.6;19.6 Patient Variables Affecting Response;404
23.7;19.7 Side Effects and Clinical Use;405
23.8;19.8 Summary;405
23.9;References;406
24;Preclinical Effects of Opioid Antagonists on Feeding and Appetite;409
24.1;20.1 Introduction;409
24.2;20.2 Opioid Antagonist Effects upon Palatable and Hedonic Aspects of Food Intake;410
24.2.1;20.2.1 Behavioral Role of General and Specific Opioid Antagonists;410
24.2.1.1;20.2.1.1 General Opioid Antagonist Effects;410
24.2.1.2;20.2.1.2 Opioid Receptor Subtype Antagonist Effects;411
24.2.1.3;20.2.1.3 Central Sites of Action of General and Specific Opioid Antagonists;411
24.2.2;20.2.2 Molecular Role of General and Specific Opioid Antagonists;412
24.3;20.3 Opioid Antagonist Effects upon Homeostatic Regulatory Challenges;412
24.3.1;20.3.1 Behavioral Role of General and Specific Opioid Antagonists;412
24.3.1.1;20.3.1.1 General Opioid Antagonist Effects;412
24.3.1.2;20.3.1.2 Opioid Receptor Subtype Antagonist Effects;412
24.3.1.3;20.3.1.3 Central Sites of Action of General and Specific Opioid Antagonists;413
24.3.2;20.3.2 Molecular Role of General and Specific Opioid Antagonists;413
24.3.2.1;20.3.2.1 Neurochemical Changes;413
24.3.2.2;20.3.2.2 Knockout and Antisense Effects;414
24.4;20.4 Opioid Antagonist Effects upon Body Weight Regulation;414
24.4.1;20.4.1 Behavioral Role of General and Specific Opioid Antagonists in Chronic and Obesity Studies;414
24.4.1.1;20.4.1.1 General Opioid Antagonist Effects;414
24.4.1.2;20.4.1.2 Opioid Receptor Subtype Antagonist Effects;415
24.4.2;20.4.2 Molecular Role of General and Specific Opioid Antagonists in Chronic and Obesity Studies;415
24.4.2.1;20.4.2.1 Neurochemical Changes;415
24.4.2.2;20.4.2.2 Knockout and Antisense Effects;416
24.5;20.5 Opioid Antagonist Effects upon Pharmacologically Elicited Feeding Responses;416
24.5.1;20.5.1 Behavioral Role of General and Specific Opioid Antagonists;416
24.5.1.1;20.5.1.1 General Opioid Antagonist Effects;416
24.5.1.2;20.5.1.2 Opioid Receptor Subtype Antagonist Effects;416
24.5.1.3;20.5.1.3 Central Sites of Action of General and Specific Opioid Antagonists;417
24.5.2;20.5.2 Molecular Role of General and Specific Opioid Antagonists;418
24.6;20.6 Conclusions;418
24.7;References;419
25;CNS Opiate Systems and Eating Disorders;429
25.1;21.1 Definitions;429
25.2;21.2 Incidence and Prevalence;430
25.3;21.3 Diagnostic Criteria;430
25.3.1;21.3.1 Anorexia Nervosa;430
25.3.2;21.3.2 Bulimia Nervosa;430
25.4;21.4 Anorexia Versus Starvation;431
25.5;21.5 Clinical Research on Anorexia and Opioids;431
25.6;21.6 Anorexia Nervosa: An Addictive Disorder?;432
25.7;21.7 Metabolic Response to Caloric Restriction;433
25.8;21.8 Case Studies and Clinical Trials;437
25.9;21.9 Summary;440
25.10;References;441
26;Potential Utility of Kappa Ligands in the Treatment of Mood Disorders;444
26.1;22.1 Background;444
26.2;22.2 Kappa Antagonists;446
26.2.1;22.2.1 History;446
26.2.2;22.2.2 Mechanisms;448
26.2.3;22.2.3 Complexities;449
26.2.4;22.2.4 Clinical Studies;450
26.2.5;22.2.5 Summary;451
26.3;22.3 Kappa Agonists;451
26.3.1;22.3.1 History;451
26.3.2;22.3.2 Mechanisms;453
26.3.3;22.3.3 Complexities;453
26.3.4;22.3.4 Clinical Studies;454
26.3.5;22.3.5 Summary;455
26.4;22.4 The Future of Kappa Ligands in the Study and Treatment of Mood Disorders;456
26.5;References;458
27;Opioid Antagonists in the Treatment of Pathological Gambling and Kleptomania;464
27.1;23.1 Introduction;464
27.2;23.2 Clinical Presentation;465
27.2.1;23.2.1 Pathological Gambling;465
27.2.2;23.2.2 Kleptomania;465
27.3;23.3 Addiction Model and Etiological Issues;466
27.3.1;23.3.1 Addiction Model;466
27.3.2;23.3.2 Genetics of Addiction;466
27.4;23.4 Neurobiology;467
27.4.1;23.4.1 Dopamine;467
27.4.2;23.4.2 Opioid System;468
27.4.3;23.4.3 Neuroimaging Studies;468
27.5;23.5 Treatment;469
27.5.1;23.5.1 Opioid Antagonists;470
27.5.2;23.5.2 Safety of Opioid Anatgonists;471
27.6;23.6 Conclusions;472
27.7;References;472
28;Efficacy of Opioid Antagonists in Attentuating Self-Injurious Behavior;476
28.1;24.1 Introduction;477
28.2;24.2 Overview;479
28.2.1;24.2.1 The Biological Stress System Pain, Pleasure, and SIB;479
28.2.2;24.2.2 Pain and the Endogenous Opioid System;479
28.2.3;24.2.3 Pleasure (Addiction) and the Endogenous Opioid System;479
28.2.4;24.2.4 Stress and the Endogenous Opioid System;480
28.3;24.3 Efficacy of Opiate Blockers in the Treatment of SIB;480
28.3.1;24.3.1 Acute Effects of Naltrexone;480
28.3.2;24.3.2 Long-Term Effects of Naltrexone Treatments;483
28.4;24.4 Endogenous Opioid Levels Predict Response to Opiate Blockers;484
28.5;24.5 Conclusions;486
28.6;References;487
29;Pharmacotherapeutic Effects of Opioid Antagonists in Alcohol-Abusing Patients with Schizophrenia;492
29.1;25.1 Introduction;492
29.2;25.2 Opioid Antagonist Use in Schizophrenia;493
29.3;25.3 Opioid Antagonist Treatment in Alcohol Dependence;494
29.4;25.4 Opiate Antagonist Treatment in Patients with Alcohol Dependence and Psychiatric Comorbidity;495
29.5;25.5 Opiate Antagonist Treatment in Patients with Alcohol Dependence and Schizophrenia;497
29.6;25.6 Conclusions;499
29.7;References;500
30;Current Issues in the Use of Opioid Antagonists (Naltrexone for Opiate Abuse: A Re-Educational Tool as Well as an Effective Drug);503
30.1;26.1 Introduction;504
30.2;26.2 Overview and History;504
30.3;26.3 Testing-Out and Other Aspects of Naltrexone’s Ability to Block Opiates;507
30.4;26.4 Breakthrough and Pseudo-Breakthrough;511
30.5;26.5 Toxicity and Side Effects: The Myth of Serious Hepatotoxicity;512
30.6;26.6 Side Effects or Withdrawal Effects?;513
30.7;26.7 Receptor Up-Regulation and Supersensitivity After Naltrexone Discontinuation;514
30.8;26.8 Local Tissue Reactions;515
30.9;26.9 Scheduled and Unscheduled Removal of Implants and Dealing with Severe Pain in Patients with Active Depot Naltrexone;516
30.10;26.10 Compliance;517
30.11;26.11 Comparisons with Disulfiram;518
30.12;26.12 Special Techniques for Maximising Success and Minimising Distress and Drop-Out in the Transition from Opiates to Naltrexone;519
30.13;26.13 Psychological Aspects of Treatment with Naltrexone Implants;520
30.14;26.14 Naltrexone Politics;521
30.15;26.15 The Future;522
30.16;References;522
31;Emergency Room Use of Opioid Antagonists in Drug Intoxication and Overdose;527
31.1;27.1 Introduction;527
31.2;27.2 Naloxone;530
31.2.1;27.2.1 Pharmacology;530
31.2.2;27.2.2 Therapeutic Uncertainties;531
31.2.2.1;27.2.2.1 Receptor Binding;531
31.2.2.2;27.2.2.2 Acute Complications;532
31.2.2.3;27.2.2.3 Acute Withdrawal Symptoms;542
31.2.2.4;27.2.2.4 Renarcotization;542
31.2.2.5;27.2.2.5 Summary;542
31.2.3;27.2.3 Effect of Dose and Route of Naloxone on Response Rate;543
31.2.4;27.2.4 Effect of Dose and Route of Naloxone on AWS;544
31.2.5;27.2.5 Effect of Dose and Route of Naloxone on Recurrence of Toxicity;545
31.2.6;27.2.6 Timing of Complications;546
31.2.7;27.2.7 Research Difficulties;546
31.2.8;27.2.8 Summary;547
31.3;27.3 The Long-Acting Opioid Antagonists: Nalmefene and Naltrexone;549
31.4;References;550
32;Kappa-Opioid Antagonists as Pruritogenic Agents;556
32.1;28.1 Introduction;556
32.2;28.2 Effects of Kappa Antagonists on Overt Behavior;557
32.2.1;28.2.1 Initial Observations with norBNI;557
32.2.2;28.2.2 Findings with GNTI;557
32.3;28.3 Experimental Protocol;558
32.4;28.4 Results;560
32.5;28.5 Perspective;561
32.6;References;562
33;Clinical Effect of Opioid Antagonists on Clinical Pruritus;565
33.1;29.1 Introduction;565
33.1.1;29.1.1 The Sensation of Pruritus;565
33.1.2;29.1.2 Neurophysiology of Pruritus;566
33.1.3;29.1.3 Pathophysiology of Pruritus;566
33.1.4;29.1.4 Is Central Sensitization for Itch a Common Pathway in Diseases Characterized by this Symptom;567
33.2;29.2 Opioidergic Neurotransmission and Pruritus;568
33.2.1;29.2.1 Etiology of the Pruritus of Cholestasis;568
33.2.2;29.2.2 Opioidergic Neurotransmission in Cholestasis;568
33.2.3;29.2.3 The Liver as a Source of Endogenous Opioids in Hepatic Disease;569
33.3;29.3 Fundamental Studies Towards Clinical Trials of Opiate Antagonists for the Treatment of the Pruritus of Cholestasis;569
33.3.1;29.3.1 Behavioral Methodology to Study Scratching;570
33.3.2;29.3.2 Instruments to Study Scratching Behavior;570
33.3.3;29.3.3 Insight from Behavioral Studies in Pruritus;571
33.3.4;29.3.4 Behavioral Studies from Animal Models of Scratching;572
33.4;29.4 Clinical Trials of Opiate Antagonists for the Treatment of Pruritus;573
33.4.1;29.4.1 Opiate Antagonists for the Treatment of the Pruritus of Cholestasis;573
33.4.2;29.4.2 Opiate Antagonists for the Treatment of the Pruritus of Uremia;574
33.4.3;29.4.3 Opiate Antagonists for the Treatment of the Pruritus of Skin Diseases;575
33.5;29.5 Summary;575
33.6;References;578
34;Effects of Opioid Antagonists on L-DOPA-Induced Dyskinesia in Parkinson’s Disease;582
34.1;30.1 Introduction;583
34.1.1;30.1.1 L-DOPA-Induced Dyskinesia;583
34.2;30.2 Enhanced Opioid Neurotransmission is Associated with l-DOPA-Induced Dyskinesia;583
34.2.1;30.2.1 PPE-B Expression;584
34.2.2;30.2.2 PPE-A Expression;584
34.3;30.3 A Role for Opioid Transmission in the Expression of Established LID;586
34.4;30.4 Preclinical Studies Using Opioid Receptor Antagonists to Suppress the Expression of l-DOPA-Induced Dyskinesia in Animal Models of PD;587
34.5;30.5 Clinical Studies of Potential of Opioid Receptor Antagonists to Reduce Expression of LID in PD Patients;588
34.6;30.6 Role of Opioid Peptides in Development (‘Priming’) of LID;588
34.7;30.7 The Future for Opioid Receptor Antagonists in LID?;589
34.8;References;589
35;Endocrine Effects of Opioid Antagonists;594
35.1;31.1 Introduction;594
35.2;31.2 Opioid Antagonist Effects on the HPG Axis;596
35.2.1;31.2.1 Naltrexone Stimulates Release of LH;596
35.2.1.1;31.2.1.1 Clinical Studies of the HPG Axis;596
35.2.1.2;31.2.1.2 Preclinical Studies of the HPG Axis;601
35.3;31.3 Opioid Antagonist Effects on the HPA Axis;602
35.3.1;31.3.1 Clinical Studies of Opioid Effects on the HPA Axis;604
35.3.2;31.3.2 Preclinical Studies of Opioid Effects on the HPA Axis;605
35.4;31.4 Opioid Effects on Prolactin;606
35.4.1;31.4.1 Clinical Studies of Opioid Effects on Prolactin;607
35.4.2;31.4.2 Preclinical Studies of Opioid Effects on Prolactin;608
35.5;31.5 Summary of the Effects of Opioid Agonists and Antagonists on the HPG and HPA Axis and Prolactin;609
35.6;References;610
36;Opioid Antagonists in Traumatic Shock:Animal and Human Studies;618
36.1;32.1 Introduction;618
36.2;32.2 Role of Beta-Endorphin in Cardiovascular Function and Immune Depression Following Traumatic Shock;619
36.2.1;32.2.1 Role of Beta-Endorphin in Cardiovascular Depression Following Traumatic Shock;619
36.2.2;32.2.2 Role of Beta-Endorphin in Immune Depression Following Traumatic Shock in Rats;620
36.3;32.3 Opioid Receptors Associated with Traumatic Shock;622
36.4;32.4 Antishock Effects of Opioid Antagonists;626
36.4.1;32.4.1 Nonselective Opioid Receptor Antagonists;626
36.4.2;32.4.2 Specific Opioid Receptor Antagonists;630
36.4.2.1;32.4.2.1 Effects of TRH on Traumatic Shock;630
36.4.2.2;32.4.2.2 Effects of Delta- and Kappa-Opioid Receptor Antagonists on Traumatic Shock;630
36.5;32.5 Conclusion and Perspective;632
36.6;References;633
37;The Efficacy of Opioid Antagonists Against Heatstroke-Induced Ischemia and Injury in Rats;637
37.1;33.1 Introduction;637
37.2;33.2 Materials and Methods;638
37.2.1;33.2.1 Experimental Animals;638
37.2.2;33.2.2 Induction of Heatstroke;639
37.2.3;33.2.3 Experimental Group;639
37.2.4;33.2.4 Physiological and Biochemical Parameter Monitoring;639
37.2.5;33.2.5 Measurement of Extracellular Glutamate, Glycerol, Lactate/Pyruvate, NOx , and DHBA in the Striatum;640
37.2.6;33.2.6 Measurement of CBF, Brain O2, and Brain Temperature;640
37.2.7;33.2.7 Measurement of Baroreflex Sensitivity;641
37.2.8;33.2.8 Neuronal Damage Score;641
37.2.9;33.2.9 Statistical Analysis;641
37.3;33.3 Experimental Results;641
37.3.1;33.3.1 CTAP or Naltrexone Increases both Latency and Survival Time During Heatstroke;641
37.3.2;33.3.2 CTAP or Naltrexone Attenuates Heatstroke-Induced Cerebrovascular Dysfunction During Heatstroke;642
37.3.3;33.3.3 CTAP Attenuates Heatstroke-Induced Hypercoagulable State;642
37.3.4;33.3.4 CTAP Attenuates Heatstroke-Induced Cellular Injury and Organ Dysfunction;642
37.3.5;33.3.5 CTAP Attenuates Heatstroke-Induced Activated Inflammation;644
37.3.6;33.3.6 CTAP Attenuates Heatstroke-Induced Overproduction of NOx and DHBA;644
37.4;33.4 Discussion, Conclusions, and Perspectives;646
37.4.1;33.4.1 Discussion;646
37.4.2;33.4.2 Conclusions;648
37.4.3;33.4.3 Perspectives;649
37.5;References;650
38;A Review of the Opioid System in Cancer Patients and Preliminary Results of Opioid Antagonists in the Treatment of Human Neoplasms;653
38.1;34.1 Introduction;654
38.2;34.2 Opioid Receptors;654
38.3;34.3 Opioid-Cannabinergic System Interactions;655
38.4;34.4 Opioid System-Pineal Interactions;656
38.5;34.5 Immunomodulatory Effects of Opioid Agonists and Antagonists;657
38.6;34.6 Oncostatic Properties of Opioid Agonists and Antagonists;658
38.7;34.7 Clinical Investigations of Opioid and Cannabinoid Systems;660
38.8;34.8 Clinical Investigation of the Opioid System in Cancer Patients;660
38.9;34.9 Clinical Studies with Opioid Antagonists in Human Neoplasms;661
38.10;34.10 Future Perspectives with Opioid Antagonists in Cancer Therapy;662
38.11;References;663
39;Nonclinical Pharmacology of VIVITROL®: A Monthly Injectable Naltrexone for the Treatment of Alcohol Dependence;666
39.1;35.1 Introduction;667
39.2;35.2 Extended-Release Formulation of Naltrexone;669
39.3;35.3 Medisorb Formulation of Extended-Release Naltrexone (XR-NTX);669
39.3.1;35.3.1 Process for Formulating Medisorb Naltrexone Microspheres;670
39.3.2;35.3.2 Microsphere Release Mechanism;670
39.3.3;35.3.3 Selection of a Lead Formulation;670
39.3.3.1;35.3.3.1 In Vitro Release of Naltrexone from Microspheres;672
39.3.3.2;35.3.3.2 In Vivo Pharmacokinetic and Pharmacodynamic Evidence of Efficacy in Rats;672
39.3.3.2.1;Brain Mu-Opioid Receptor Changes;675
39.3.3.2.2;Suppression of Morphine Antinociception by XR-NTX: Extent of Opioid Receptor Blockade;676
39.3.3.2.3;Overriding the Blockade of Antinociceptive Actions of Opioids in Rats Treated with XR-NTX;679
39.3.3.3;35.3.3.3 Pharmacokinetic Profile of XR-NTX in Nonhuman Primates;681
39.3.4;35.3.4 Preclinical Summary;681
39.3.5;References;683
40;The Development of Sustained-Release Naltrexone and Clinical Use in Treating Opiate Dependence;686
40.1;36.1 Introduction;687
40.1.1;36.1.1 Opioid Dependence and Consequences;687
40.1.1.1;36.1.1.1 Epidemiology;687
40.1.1.2;36.1.1.2 Treatment for Heroin Use;687
40.1.2;36.1.2 Oral Naltrexone;688
40.1.2.1;36.1.2.1 Pharmacology of Naltrexone;688
40.1.2.2;36.1.2.2 Clinical Experience with Oral Naltrexone;688
40.1.2.3;36.1.2.3 Sustained-Release Naltrexone Preparations;689
40.1.2.4;36.1.2.4 Sustaining Therapeutic Levels;689
40.1.2.5;36.1.2.5 Biodegradability;690
40.1.2.6;36.1.2.6 Tissue Compatibility;690
40.1.2.7;36.1.2.7 Newer Formulations;691
40.2;36.2 Mode of Administration: Sustained-Release Preparation;692
40.3;36.3 Other Considerations;693
40.4;36.4 Merits of Depot Preparations;694
40.5;36.5 Polydrug Use;694
40.6;36.6 Accidental Opioid Overdose Following Treatment Cessation;695
40.7;36.7 Pain Management: Antagonism of Opiates;695
40.8;36.8 Concluding Comments;695
40.9;References;696
41;The Development of ProNeura Technology for the Treatment of Addictions;700
41.1;37.1 Introduction;700
41.2;37.2 Opioid Dependence;701
41.2.1;37.2.1 Overview of Opioid Dependence and Treatments;701
41.2.2;37.2.2 Overview of Buprenorphine and Use in Opioid Dependence;702
41.2.3;37.2.3 Limitations of Current Delivery and the Need for Long-Term Release Formulations;703
41.2.4;37.2.4 Probuphine: Continuous, Long-Term Delivery of Buprenorphine;704
41.2.5;37.2.5 Probuphine: Preclinical Studies;705
41.2.6;37.2.6 Probuphine: Clinical Studies;707
41.3;37.3 Alcoholism;709
41.3.1;37.3.1 Overview of Alcoholism and Treatments;709
41.3.2;37.3.2 Overview of Nalmefene and Use in Alcoholism;711
41.3.3;37.3.3 Limitations of Current Delivery and the Need for Long-Term Release Formulation;712
41.3.4;37.3.4 ProNeura Nalmefene Implants: Continuous, Long-Term Delivery of Nalmefene;713
41.4;37.4 Conclusions;715
41.5;References;715
42;Development of Opioid Transdermal Delivery Systems;720
42.1;38.1 Opioid Antagonists;721
42.2;38.2 Full and Partial Opioid Agonists;733
42.3;38.3 Conclusion;735
42.4;References;735
43;Intranasal Naloxone for Treatment of Opioid Overdose;740
43.1;39.1 Introduction;740
43.2;39.2 Pharmacological Basis for IN Use;742
43.3;39.3 The Evidence Regarding Use in Opioid Overdose Emergencies;742
43.3.1;39.3.1 Effectiveness;742
43.3.2;39.3.2 Adverse Events;744
43.3.3;39.3.3 Other Benefits;744
43.3.4;39.3.4 Gaps in the Evidence;745
43.4;39.4 Discussion;745
43.4.1;39.4.1 Current Place in Treatment;745
43.4.2;39.4.2 Potential Future Place in Treatment Systems;746
43.4.3;39.4.3 Unresolved Issues;747
43.5;References;748
44;Index;751