LS Q.

Opioids IIContributors

M.W. Adler, O.F.X. Almeida, P.L. Bailey, A.J. BertalmioR.J. Bicknell, H.U. Bryant, T.F. Burks, C. Castellano, S.G. CellaG. Comitini, S.J. Cooper, A. Cowan, A.I. Faden, H.L. FieldsJ. Florez, K.M. Foley, C.P. France, E.B. Geller, A.R. GenazzaniA.B. Grossman, Ji-Sheng Han, J.W. Holaday, A. HurleI.B. Introini-Collison, D.L. Kilpatrick, T.C. Kirkham, W. KromerV. Locatelli, J.L. McGaugh, L. McLoughlin, S. MedbakM.J. Millan, E.E. Miiller, D. Naber, F. Nyberg, C.P. O'BrienF. Petraglia, F. Porreca, R. Przewlocki, R. SchulzK. Schwarz-Stevens, T.S. Shippenberg, C. Stein, F.C. TortellaE.L. Way, G. Winger, J.H. Woods, T.L. Yaksh

Editor: Albert Herz

Section Editors: H. Akil and E.J. Simon

Springer-VerlagBerlin Heidelberg New York London ParisTokyo Hong Kong Barcelona Budapest

Contents

Section E: Pharmacology and Behavior

CHAPTER 31

Brainstem Mechanisms of Pain Modulation: Anatomy and PhysiologyH.L. FIELDS. With 4 Figures 3

A. Introduction: Central Versus Peripheral Antinociceptive Action . . . 3B. Spinal and Supraspinal Opioid Antinociception 3C. Pain-Modulating Systems 4

I. Midbrain Periaqueductal Gray 41. Afferents to the PAG 62. Outflow from the PAG 7

II. The Dorsolateral Pontomesencephalic Tegmentum 7III. The Rostral Ventromedial Medulla 7

1. Physiology of RVM Neurons 82. Opioid Actions on RVM Neurons 83. Intrinsic Circuitry of the RVM; Neural Mechanism

of Opioid Analgesia 10IV. Projections from Brainstem Nociceptive Modulating Nuclei

to the Dorsal Horn 11V. Dorsal Horn Circuitry Underlying Brainstem Inhibition

of Nociceptive Transmission 121. Direct Inhibition of Projection Neurons 122. Inhibition of Excitatory Interneurons 133. Excitation of an Inhibitory Interneuron 13

D. Physiological Activation of Pain-Modulating Circuits 14References 15

CHAPTER 32

Supraspinal Opioid Receptors in AntinociceptionF. PORRECA and T.F. BURKS 21

A. Introduction 21I. Definitions and Terms 22

XVI Contents

B. Involvement of Opioid u-Receptors in SupraspinalAntinociception 24I. Subtypes of Opioid u-Receptors: \i^ Hypothesis 29

C. Involvement of Opioid K-Receptors in SupraspinalAntinociception 31I. Subtypes of Opioid K-Receptors: Antinociceptive Studies 35

D. Involvement of Opioid 8-Receptors in SupraspinalAntinociception 36I. Recent Advances in Understanding the Role of 5-Receptors

in Supraspinal Antinociception: Subtypes of 8-Receptors 38E. Involvement of Opioid e-Receptors in Supraspinal Antinociception 41F . Synthesis 42References 44

CHAPTER 33

The Spinal Actions of OpioidsT.L. YAKSH 53

A. Introduction 53B. Historical Overview 53C. Opioid Binding in Spinal Cord 54

I. Spinal Gray 54II. Sensory Nerves 55

D. Electrophysiological Effects of Spinal Opioids 56I. Primary Afferent Axons 56

II. Dorsal Root Ganglia 57III. Central Afferent Terminals 58IV. Dorsal Horn Neurons 60

1. Systemic Drug Administration 602. Iontophoretic Drug Administration 623. Topically Applied Opioids 63

V. Ventral Horn Neurons 64E. Behavioral Effects of Spinal Opioids 64

I. Pharmacology 661. Agonist Activity • 662. Antagonist Activity 663. Role of Intrinsic Activity 694. Synergy 705. Tolerance 70

F . Spinal Opioids in Humans 71G. Mechanisms Underlying the Analgesic Actions of Spinal Opioids... 72H. Effects of Spinal Opiates on Visceral and Somatomotor

and Autonomic Function 74I. Motor Function 74

Contents XVII

II. Genitourinary Function 75III. Gastrointestinal Function 75IV. Cardiovascular Function 75

J. Concluding Comments 76References 76

CHAPTER 34

Peripheral Mechanisms of Opioid AnalgesiaC. STEIN 91

A. Introduction 91B. Animal Studies 91

I. Criteria for Evaluation 91II. Exogenous Ligands 92

III. Endogenous Ligands 93IV. Mechanisms 93

1. Role of Inflammation 932. Opioid Peptides in the Periphery 963. Opioid Receptors in the Periphery 974. Conclusions 98

C. Human Studies 98I. Criteria for Evaluation 98

II. Effects of Opioid Agonists in the Periphery 99HI. Conclusions 100

References 100

CHAPTER 35

Acupuncture and Stimulation Produced AnalgesiaJI-SHENG HAN. With 4 Figures 105

A. Introduction t 105B. Strategies for Research on the Involvement of Opioids

in Acupuncture Analgesia 106C. Naloxone Blockade of Acupuncture Analgesia 107

I. Frequency of Electroacupuncture 107II. Intensity of Electroacupuncture 108III. Timing of Naloxone Administration 108

D. Mediation of Low and High Frequency ElectroacupunctureAnalgesia by Different Varieties of Opioid Peptides 109

I. Specific Opioid Antagonists and Their Effects on EAA 109II. Cross-Tolerance Study 109

III. Antibody Microinjection Study 110IV. Radioimmunoassay of Rat Spinal Perfusate I l l

XVIII Contents

V. Radioimmunoassay of Human Lumbar CSF I l lVI. The Role of p-Endorphin in Mediating the Effect of EA 112

VII. Neural Pathways Mediating Low and High Frequency EAA 112VIII. Alternating Low and High Frequency

EA Stimulation .: 1141. Interaction of MEK and DYN A in the Spinal Cord 1142. The Effect of Alternating Low and High Frequency

EA Stimulation 114IX. Optimal EA Frequency for the Rabbit 116

E. Apparent Balance Between Opioids and Antiopioidsin Pain Control 116I. The Putative Antiopioids and the Development

of EA Tolerance 116II. CCK-8 as an Antiopioid Substance 116

F . Other Forms of Stimulation Which May Produce Opioid Analgesia 117I. Transcutaneous Electric Nerve Stimulation 117

II. Strong Noxious Stimulation and Stressful Stimulation 118HI. Brain Stimulation 119

G. General Discussion and Conclusions 120References 121

CHAPTER 36

Multiple Opioid Systems and Chronic PainM.J. MlLLAN 127

A. Introduction: Multiple Opioid Systems 127B. The Nature of Chronic Pain: Animal Models 130

I. Types of Chronic Pain 130II. Models of Chronic Pain 132

C. Response of Opioid Systems in Animal Models of Pain 133I. Pro-Opiomelanocortin: P-Endorphin 133

II. Pro-Enkephalin: Met-Enkephalin 134III. Pro-Dynorphin: Dynorphin 136

D. Response to Opioid Agonists and Antagonists in Models of Pain . . . 139I. Paradoxical Naloxone-Induced Antinociception 139

II. Acute and Chronic Administration of Agonists 141E. Mechanisms Underlying Response of Opioid Systems 143

I. c-fos and Intracellular Ca2+ 143II. Primary Afferent Transmitters 145

F . Summary and Concluding Comments 147References 149

Contents XIX

CHAPTER 37

Gastrointestinal Effects of OpioidsW. KROMER. With 1 Figure 163

A. Introduction 163B. Motility 163

I. Esophagus 163II. Stomach 163

III. Pylorus 164IV. Small Intestine 164

1. In Vivo and In Vitro Studies on Opioid Agonistsand Antagonists 164

2. Apparent Species Differences and the Duality inOpioid Actions 165

3. Types of Opioid Receptors Involved In Vitro and In Vivo 1664. Cellular Opioid Mechanisms 1675. Location and Functional Role of Opioid Receptors 1696. Central Opioid Effects on Gut Motility 1727. Tolerance and Dependence 172

V. Choledochoduodenal Sphincter, Sphincter of Oddi, andIleocecal Sphincter 173

VI. Colon 174VII. Anal Sphincter 174

C. Gastric Acid Secretion 175I. In Vitro and In Vivo Studies 175

II. Central Opioid Effects 175III. Opioid Receptor Types Involved 176

D. Mucosal Integrity 176E. Water and Electrolyte Secretion 177

I. The Antisecretory Effect of Opioids 177II. The Contribution of Opioid Receptor Types to the

Peripheral Effect on Net Chloride Secretion 177III. Central Antisecretory Opioid Actions 178IV. The Antidiarrheal Action of Loperamide 179V. Opioid Effects on the Gastrointestinal Immune System 180

F . Pancreatic Exocrine Secretion 180G. Conclusions 180References 182

XX Contents

CHAPTER 38

Role of Endogenous Opioids in Central Cardiovascular Regulationand DysregulationA.I. FADEN ; 191

A. Introduction 191B. Cardiovascular Actions of Systemically or Centrally

Administered Opioids 191I. Site of Administration 191

II. Anesthetic State 192III. Respiratory State 192IV. Species 193V. Type of Opioid 193

C. Effects of Opioid Receptor Antagonists or Opioid ReceptorRegulation on Cardiovascular Function 194

D. Role of Endogenous Opioids and Opioid Receptors in Shock 195E. Role of Endogenous Opioids and Opioid Receptors in

Hypertension 197F . Overview 199References 199

CHAPTER 39

Physiological Functions of Opioids: Temperature RegulationM.W. ADLER and E.B. GELLER 205

A. Introduction 205B. Effects of Exogenously Administered Opioid Substances 205

I. Factors Influencing the Effect on Body Temperature 2051. Species, Strain, Gender, Age 2052. Restraint, Stress, Environment 2073. Drug, Dose, Route, Chronic Administration 211

II. Effects of Receptor-Selective Opioids 2131. u-Agonists and -Antagonists 2132. 8-Agonists and -Antagonists 2163. K-Agonists and -Antagonists 2184. a-Agonists and -Antagonists 219

C. Mechanisms Involved in Actions of Opioids on Body Temperature 219I. Basic Concepts in Thermoregulation 219

II. Mechanisms of Heat Production in Opioid-InducedHyperthermia 221

III. Mechanisms of Heat Loss in Opioid-Induced Hypothermia . . . . 222D. Role of Endogenous Opioid System in Thermoregulation 223

I. Hypotheses 2231. Opioid Antagonism 223

Contents XXI

2. Differentiation Among Receptors 2253. Role in Hibernation 2254. Mechanism of Action 2265. Interactions with Neurotransmitters and Other

Neuropeptides 226E. Summary 228References 229

CHAPTER 40

Opioid Mechanisms in the Control of Food Consumptionand Taste PreferencesS.J. COOPER and T.C. KIRKHAM 239

A. Introduction 239B. Opioids and Palatability 240

I. Sweet Taste Preference 2411. Opioid Antagonist Studies 2412. Opioid Agonist Studies 2413. Opioid Receptor Deficiency 243

II. Salt Taste Preference 243HI. Sucrose Sham Feeding 244IV. Electrical Stimulation-Induced Feeding 245V. Food Preferences 246

VI. Human Eating Studies 248VII. Opioid Receptor Types and Feeding Responses 248

VIII. Summary 7 250C. Endogenous Opioids and Dopamine 251

I. Ventral Tegmental Area Studies 251II. Nucleus Accumbens Studies 253

III. Summary 254D. Conclusions 255References 256

CHAPTER 41

Opioids in Respiration and VomitingJ. FL6REZ and M.A. HURLE 263

A. Opioids in Respiration 263I. Introduction 263

II. The Neural Control of Breathing 263HI. Opioid Peptides and Receptors in Respiration-Related

Nuclei 2661. Opioid Peptides 266

XXII Contents

2. Opioid Receptors ; : 267IV. Respiratory Effects of Opiates 268

1. General Effects in Humans and Other Species 2682. Ventilatory Responses to Hypercapnia and Hypoxia 2693. Sites and Mechanisms of Action 270

V. Opioid Receptors Mediating Respiratory Effects 274VI. Tolerance to the Respiratory Effects 276

VII. Endogenous Opioids and Breathing 2771. Adult Subjects 2782. Prenatal Period 2793. Pathological Breathing Patterns in Children 280

VIII. Antitussive Action of Opiates 280B. Opioids and Vomiting 281

I. The Vomiting Reflex: Mechanisms 281II. The Action of Opiates on the Vomiting Reflex 282

III. Summary 284References 284

CHAPTER 42

Opioid Systems and StressR. PRZEWLOCKI. With 3 Figures 293

A. Introduction 293I. The Concept of Stress 293

II. Multiple Opioid Peptides and Their Receptors 294B. Opioid Neurons in the Neuronal Stress Network 294

I. Opioid Peptide Distribution in Stress Circuits 2941. POMC System 2942. PDYN System 2953. PENK System 295

II. Anatomical Relationships of EOP Systems with CRF- andAVP-Synthesizing Neurons 295

HI. Noradrenergic (NA) System 296IV. Dopaminergic (DA) System 296

C. Biochemical Alterations of Opioid Peptides in Stress 298I. POMC System 298

II. PDYN System 300III. PENK System 300

D. Opioid Receptor Response to Stress 301E. Multiple Neurochemical Consequences of Stress 302

I. Interactions Among EOP and CRF Systems ; 302II. Opioid Control of the AVP System 303

III. EOP and NA System Interactions in Stress 305IV. Stress, EOP, and the Autonomic Nervous System 306

Contents XXIII

V. Opioidergic Modulation of the Brain DA System in Stress 308F . Involvement of Opioids in Some Behavioral and Physiological

Responses to Stress 310I. Stress-Induced Analgesia 310

II. Feeding Behavior 311III. Cardiovascular Responses 312IV. Reproduction 313V. Immune System 313

G. Opioid Control of Stress Response 313References 315

CHAPTER 43

Role of Endogenous Opioid and Opioid Receptors in CentralNervous System InjuryA.I. FADEN 325

A. Introduction 325B. Spinal Cord Injury 325

I. Opioid Receptor Antagonists in Spinal Cord Trauma 325II. Opioid Receptor Antagonists in Spinal Cord Ischemia 327

III. Role of Specific Opioids and Opioid Receptors in SpinalCord Injury 327

C. Head Injury 329D. Brain Ischemia 330

I. Use of Nonselective Antagonists 330II. Role of Specific Opioids and Opioid Receptors in Brain

Ischemia 332III. Opioid Receptor Antagonists in Brain Ischemia: Clinical

Studies 333E. Mechanism of Action of Opioid Receptor Antagonists

in CNS Injury 334F . Conclusions 335References 336

CHAPTER 44

Opioids: Epilepsy and NeuroprotectionF.C. TORTELLA 343

A. Introduction 343B. Proconvulsant Opioids 344

I. Nonspecific Effects 344II. Opioid-Specific Effects 345

1. Behavioral Models 345

XXIV Contents

2. EEG Epileptiform Activity 3463. Disinhibition 346

C. Anticonvulsant Opioids 347I. Receptor Specificity 348

II. Nonopioid Dynorphin System 348D. Endogenous Anticonvulsant System 348

I. Clinical Studies 3491. Postictal Inhibition 3492. Naloxone Studies 3493. PET and Receptor Mechanisms 350

II. Animal Studies 350E. Neuroprotection 351

I. Physiological Studies 351II. Excitatory Amino Acids 352

III. K-Opioids 353F . Summary 354References 355

CHAPTER 45

Opioids in Immunologic ProcessesH.U. BRYANT and J.W. HOLADAY. With 2 Figures 361

A. Introduction 361B. Opioid Receptors in the Immune System 362C. Opioid Availability to the Immune System -... 363D. Effects of Endogenous Opioids on the Immune System 364

I. Lymphocytes 3641. P-Endorphin 3642. Enkephalin 3663. Other Endogenous Opioid Peptides 367

II. Myeloid Cells 3671. P-Endorphin 3682. Enkephalin 3693. Other Endogenous Opioid Peptides 370

HI! Natural Killer Cells 3701. P-Endorphin 3702. Enkephalin 3713. Other Endogenous Opioid Peptides 372

IV. In Vivo Assessments of Immune Function 3721. P-Endorphin 3722. Enkephalin 372

E. Effects of Opioid Alkaloids on the Immune System 373I. Lymphocytes 374

1. Morphine 374

Contents XXV

2. Other Opioids 376II. Myeloid Cells 377

1. Morphine 3772. Other Opioids 378

III. Natural Killer Cells 3791. Morphine 3792. Other Opioids , 379

IV. In Vivo Assessments of Immune Function 3801. Morphine 3802. Other Opioids 380

F . Effects of Opioid Antagonists on the Immune System 381G. Conclusions 382References 385

CHAPTER 46

Effect of Opioids on the Spontaneous Behavior of AnimalsA. COWAN. With 2 Figures 393

A. Introduction 393B. Effects of Prototype Opioids on Overt Behavior 394

I. Naloxone 394II. P-Endorphin 394

III. Morphine 396IV. DAMGO 397V. U-50,488 399

VI. Dynorphin A . 400VII. DPDPE 402

C. Explosive Motor Behavior 403D. Repetitive Behaviors 404

I. Excessive Grooming 404II. Stereotypies 405

III. Bizarre Excitation 408IV. Body Shaking 411

E. Conclusion 414References 414

CHAPTER 47

Involvement of Opioid Peptides in Learning and MemoryJ.L. MCGAUGH, I.B. INTROINI-COLLISON, and C. CASTELLANO 429

A. Introduction 429B. Effects of Opioid Receptor Agonists and Antagonists on

Acquisition 429

XXVI Contents

C. Effects of Opioid Receptor Agonists and Antagonists onMemory Storage 432

D. Genetic Strain Differences in Opiate Influences on Memory 434E. Involvement of Opioid Peptides in Stress-Induced Effects on

Memory 435F . State Dependency . . : 436G. Involvement of Peripheral and Central Receptors 437H. Interaction of Opioid Peptidergic and Other Neuromodulatory

Systems 439J . Concluding Comments 441References 441

CHAPTER 48

Establishing Correlations Between the Pharmacodynamic Characteristicsof Opioid Agonists and Their Behavioral EffectsA.J. BERTALMIO, C.P. FRANCE, and J.H. WOODS 449

A. Introduction 449B. An Illustration of the Importance of Pharmacodynamic Analysis

for Understanding the Behavioral Effects of Drugs 450C. Areas of Application: Pharmacodynamics in Behavioral Settings . . . 451D. Identification of Opioid Mechanisms of Action Underlying

the Behavioral Effects of Drugs 451I. Selectivity of the Effect 452

1. Nonselective Effects 4522. Specific Effects 4533. Partially Selective Effects 4554. Summary and Conclusions: Effect Selectivity 455

II. Selectivity of the Agonist 456III. Interaction Between Effect Selectivity and Agonist Selectivity 458IV. Antagonist Selectivity 459

E. Intrinsic Activity 463F . Conclusions 465References 467

Section F: Neuroendocrinology

CHAPTER 49

Opioid Peptides in the Regulation of Anterior Pituitary HormonesS.G. CELLA, V. LOCATELLI, and E.E. MULLER. With 1 Figure 473

A. Introduction 473B. Growth Hormone 474

Contents XXVII

C. Gonadotropins 476D. Adrenocorticotropic Hormone 479E. Thyrotropin 481F . Prolactin 483References 486

CHAPTER 50

Opioids and the Neuroendocrine Control of ReproductionO.F.X. ALMEIDA 497

A. Introduction 497B. Reproductive Neuroendocrinology: A Primer 497C. Acute Opioid Administration to Mature Animals 498

I. Opioid Agonists 498II. Opioid Antagonists 500

D. Chronic Opioid Administration to Mature Animals 501I. Opioid Agonists: Physiological Effects 501

II. Opioid Antagonists: Physiological Effects 501III. Pharmacological Effects Related to Sensitivity, Tolerance

and Dependence 5021. Acute Tolerance to Naloxone 5022. Naloxone-Induced Sensitivity to Opioids 5033. Tolerance and Dependence 504

E. Sites and Mechanisms of Action and Receptors Involved 506I. Opioid Peptide and Receptor Distribution 506

II. Central vs Pituitary Sites of Action 506III. Opioid Receptor Types Involved 507IV. Neurotransmitter Interactions 508

F . Bidirectional Opioid-Steroid Interactions 509G. Opioids and LH Secretion in Some Physiological States 511

I. Reproductive Development 511II. Seasonal Reproduction 512

III. The Ovarian Cycle 513IV. Stress 514

H. Autoregulation of Opioid Release: A Mechanism forGenerating GnRH/LH Pulses? 515

J . Conclusions 515References 516

XXVIII Contents

CHAPTER 51

Opioids in the Neurohypophysial SystemR.J. BICKNELL. With 1 Figure 525

A. Introduction 525B. Physiological Opioid Regulation of Neurohypophysial Secretion . . . 526

I. Circulating Oxytocin Concentrations 526II. Circulating Vasopressin Concentrations 527

C. Opioid Peptides Intrinsic to the Neurohypophysial System 530I. Coexpression of Pro-Dynorphin 530

II. Source of Neurohypophysial Enkephalins 530D. Opioid Binding Sites in the Neurohypophysial System 532

I. Hypothalamic Magnocellular Nuclei 532II. Neurohypophysial Opioid Binding Sites 532

III. Cellular Localisation of Neurohypophysial Opioid Receptors . . 532E. Sites of Opioid Actions on Neurohypophysial Neurones 533

I. Electrophysiological Actions of Opioids 533II. Neurohypophysial Actions of Opioids 534

1. Oxytocin Secretion 5342. Vasopressin Secretion 5353. Mode of Action of Opioids in the Neurohypophysis 536

III. Cell Body Versus Nerve Terminal Opioid Actions 5381. Osmotic Stimuli 5382. Other Stimuli 5393. Pregnancy and Parturition 539

F . Opiate Tolerance and Dependence in Oxytocin Neurones 541References 542

CHAPTER 52

Opioids Peptide Expression in Peripheral Tissuesand Its Functional ImplicationsD.L. KlLPATRICK 551

A. Introduction 551B. Opioid Expression Within the Reproductive System 551

I. Testis 5511. Cellular Localization 5512. Regulatory and Functional Considerations 552

II. Male Reproductive Tract 5551. Pro-Opiomelanocortin 5552. Proenkephalin 5553. Prodynorphin 5564. Functional Aspects 556

III. Female Reproductive Organs 557

Contents XXIX

1. Cellular Localization and Regulation 5572. Possible Functions in Female Reproductive Tissues 559

C. Opioid Expression in Other Peripheral Cells and Organs 560I. Heart 560

1. Nature and Cellular Localization 5602. Regulation and Possible Functions of Cardiac Opioids 561

II. Opioid Expression by Cells of the Immune System 562III. Transient Expression of PENK in Developing

Peripheral Tissues 562D. Additional Functional Considerations 564References 565

Section G: Reinforcement - Tolerance/Dependence

CHAPTER 53

Opioid Tolerance and Physical Dependence and Their RelationshipE.L. WAY 573

A. Introduction 573B. Types of Tolerance 573C. Assessment of Tolerance 574D. Physical Dependence Characteristics 575E. Assessment of Physical Dependence 577F . Relationship Between Tolerance and Physical Dependence '. 579G. Approaches Towards Demonstrating a Relationship Between

Tolerance and Physical Dependence 580H. Basic Processes Related to the Development of Tolerance

and Physical Dependence 583J . Transducing Proteins and Effector Systems 585K. Calcium Disposition and Opioid Action 588L. Concluding Remarks 591References 592

CHAPTER 54

Opioid Tolerance/Dependence in Isolated OrgansR. SCHULZ. With 2 Figures 597

A. Introduction 597B. Neuroanatomical Arrangements and Pharmacology of the Mouse

Vas Deferens and Guinea Pig Ileum 597I. Mouse Vas Deferens 598

II. Longitudinal Muscle-Myenteric Plexus Preparationof the Guinea Pig Ileum ' 598

XXX Contents

III. Isolated Preparations from Animals Chronically Exposedto an Opioid 599

C. Adaptations Caused by Chronic Opioid Actions 601I. Opioid Receptor Level 601

II. Second Messengers 602D. Guanine Nucleotide-Binding Proteins (G Proteins) 602

I. Cholera Toxin 603II. Pertussis Toxin 603

III. Concentrations of G Protein Subunits in the Guinea Pig Ileum 604E. Conclusions 605References 606

CHAPTER 55

Opioid Abuse Liability Assessment in Rhesus MonkeysJ.H. WOODS, C.P. FRANCE, G. WINGER, A.J. BERTALMIO,

and K. SCHWARZ-STEVENS. With 1 Figure 609

A. Introduction 609B. Reinforcing Stimulus Effects of Opioids 612C. Physical Dependence (Observational Studies) 618D. Discriminative Stimulus Effects 621

I. Drug Discrimination in Rhesus Monkeys 621II. Discrimination in Morphine-Treated Monkeys 623

E. Relations Among Behavioral Effects 625I. Detecting and Analyzing Compounds That May Differ

in Efficacy at Opioid Receptors 628II. Detecting Compounds with Novel Spectra

of Behavioral Effects 629F . Conclusions 629References 630

CHAPTER 56

Motivational Effects of OpioidsT.S. SHIPPENBERG 633

A. Introduction 633B. Theoretical Perspectives 633C. Opioids as Reinforcers . . : 635

I. Opiates 635II. Opioid Peptides 635

D. Conditioned Reinforcing Effects of Opioid Antagonists: Existenceof an Endogenous Opioid Reward Pathway 637

Contents XXXI

E. Factors Influencing the Reinforcing and Aversive Effectsof Opioids 638

I. Drug Exposure 638II. Genetics 639

III. Prior Experience 639F . Neuroanatomical Substrates Mediating the Motivational

Effects of Opioids 639I. CNS vs. Peripheral Sites of Action 639

II. Microinjection and Lesion Studies 640G. Neurochemical Substrates Mediating the Motivational Effects

of Opioids 642H. Conclusions 645References 646

Section H: Clinical Aspects

CHAPTER 57

CSF Opioids in PathophysiologyF. NYBERG , 653

A. Introduction 653B. Basic Aspects 653

I. The CSF Compartment 654II. Opioid Peptides in CSF ; 655

C. Measurements of CSF Opioids 656I. Radioreceptor Assays 657

II. Radioimmunoassays 657D. CSF Opioids Under Pathophysiological Conditions 658

I. Pain •. 658II. Psychiatric Disorders 659

1. Schizophrenia and Depressive Disorders 6602. Postpartum Psychosis 661

III. Childhood Diseases 6621. Infantile Autism 6622. Rett Syndrome 6623. Gilles de la Tourette's Syndrome 6634. Respiratory Disorders 6635. Anorexia Nervosa 664

IV. Degenerative CNS Disorders 6641. Alzheimer's Disease 6642. Parkinson's Disease 665

V. CSF Opioids in Opioid Dependence 666E. Concluding Remarks 667References 667

XXXII Contents

CHAPTER 58

Circulating Opioids in ManL. MCLOUGHLIN, S. MEDBAK, and A.B. GROSSMAN. With 5 Figures . . . . 673

A. Introduction 673B. Pro-Opiomelanocortin-Derived Peptides 673

I. Radioimmunoassays for P-Endorphin 674II. Peptide Levels in Normal Subjects and in Diseases

of the Hypothalamo-Pituitary-Adrenal (HPA) Axis 674III. p-Endorphin Levels in Acute and Chronic Stress 677IV. Physiological Role of Circulating P-Endorphin 679V. P-Endorphin and the Immune System 679

C. Prodynorphin-Derived Peptides 680D. Proenkephalin-Derived Peptides 682

I. Plasma Met-Enkephalin Radioimmunoassay 683II. Gel Filtration Chromatography 683

III. Met-Enkephalin in Plasma 684IV. Enkephalin and Stress 684

1. Hypoglycaemia 6842. Acute Hypo- and Hypertension 6853. Hyper- and Hypocapnia 6854. Met-Enkephalin and Other Forms of Stress 686

V. Enkephalins and Alcohol 686VI. Enkephalins and Liver Disease 687

VII. Enkephalins and Tumours 688VIII. Pathophysiology of Circulating Met-Enkephalin-Like

Immunoreactivity 688IX. Molecular Forms of Circulating Met-Enkephalin 689X. Origin of the Circulating Met-Enkephalin 690

E. Summary 691References 691

CHAPTER 59

Opioid Analgesics in Clinical Pain ManagementK.M. FOLEY. With 6 Figures 697

A. Introduction 697B. Types of Opioid Analgesic 697C. Types of Pain and Choice of Opioid Drug 698D. Concept of Relative Analgesic Potency 700E. Clinical Pharmacology of the Commonly Used Opioid Analgesics .. 703

I. Agonist Drugs 7031. Morphine and Its Congeners 7032. Meperidine and Its Congeners 707

Contents XXXIII

3. Methadone and Its Congeners 7084. Fentanyl 709

II. Mixed Agonist/Antagonist Drugs 7091. Pentazocine 7092. Nalbuphine 7103. Butorphanol 711

III. Partial Agonist Drugs 7111. Buprenorphine 711

IV. Pure Antagonist Drugs 7121. Naloxone Hydrochloride 712

F . Pharmacodynamic and Pharamacokinetic Studiesof Opioid Analgesics 713

I. Pharmacodynamic and Pharmacokinetic Models 713II. Opioid Pharmacokinetics Altered by Disease, Other Drugs

and Age 7191. Influence of Disease 7192. Influence of Other Drugs 7213. Influence of Age 721

G. Routes of Drug Administration 721I. Oral Route 721

II. Intranasal Route 722III. Sublingual Route 722IV. Buccal Route 723V. Transmucosal Route 723

VI. Rectal Route 723VII. Transdermal Route , 724

VIII. Parenteral Route 7241. Intravenous Route 7242. Epidural and Intrathecal Infusions 7263. Intraventricular Route 728

H. Methods of Drug Administration 728I. On Demand (PRN) and Fixed Time Interval 728

II. Patient-Controlled Analgesia 729J. Side-Effects of Opioid Analgesics 730

I. Respiratory Depression 730II. Sedation 731

HI. Nausea and Vomiting 732IV. Constipation 732V. Multifocal Myoclonus and Seizures 732

K. Clinical Aspects of Tolerance, Physical Depandenceand Psychological Dependence 733

I. Tolerance , . . . 733II. Physical Dependence 734 •

III. Psychological Dependence 734L. Guidelines for Opioid Use in Clinical Pain Management 735References 737

XXXIV Contents

CHAPTER 60

Opioids in Operative AnesthesiaP.L. BAILEY. With 1 Figure 745

A. Introduction 745B . Mechanisms of Action 745C . Neurophysiologic Actions 746D. Cardiovascular Actions 747E . Respiratory Actions 748F . Endocrine Effects 749G. Other Organ and Systemic Effects 750H. Anesthetic Techniques 751

I. Balanced Anesthesia 751II. Neuroleptanalgesia-Anesthesia 752

III. Continuous Infusions of Opioids in Anesthesia : . . . . 753IV. High-Dose Anesthesia 754

J. Agonist-Antagonist Opioids 755K. Opioid Antagonists 756L . Pharmacokinetics 756M. Conclusion 758References 758

CHAPTER 61

p-Endorphin in Human ReproductionF. PETRAGLIA, G. COMITINI, and A.R. GENAZZANI. With 7 Figures 763

A. Introduction 763B. P-Endorphin as a Circulating Hormone 763

I. Neuroendocrine Control • 764II. Puberty 765

III. Menstrual Cycle and Ovarian Source 766IV. Climacteric Syndrome and Postmenopausal Findings 768V. Pregnancy and Lactation 769

C. P-Endorphin as a Neuromodulator of Hormonal Secretions 769I. Pubertal Maturation and Pubertal Disorders 770

II. Ovulation and Menstrual Disorders 771III. Postmenopausal Findings and Hormone

Replacement Therapy 773References 775

Contents XXXV

CHAPTER 62

Opioids in the Etiology and Treatment of Psychiatric DisordersD. NABER 781

A. Introduction 781B. Schizophrenia 782

I. Measurement of Endogenous Opioids in Body Fluids 782II. Effect of Neuroleptics on Endogenous Opioid Levels 783

III. Opioid Measurements in Postmortem Brain Tissue 784IV. Effect of Dialysis 784V. Opiate Receptor Binding 784

VI. Treatment with Opioids 785VII. Treatment with Opioid Antagonists 786

C. Manic-Depressive Illness 786I. Measurement of Endogenous Opioids in Body Fluids 786

II. The Effect of Antidepressants and ElectroconvulsiveTreatment 787

III. Premenstrual Syndrome and Postpartum Psychosis 787IV. Measurement of Endogenous Opioids in Postmortem

Brain Tissue 788V. Treatment with Opioid Agonists 788

VI. Neuroendocrine Tests to Measure Opioidergic Regulation . . . . 789D. Other Psychiatric Disorders 790

I. Eating Disorders 790II. Obsessive-Compulsive Disorder 790

III. Autism 791IV. Self-Mutilation 791V. Anxiety 791

VI. Dementia 792VII. Physical Activity and Well-Being 792

E. Conclusions 792References 793

CHAPTER 63

Opioid AddictionC.P. O'BRIEN 803

A. Definitions of Dependence 803I. Personality Disorder 803

II. Substance Dependence Disorder 803III. Pharmacological Tolerance and Dependence 804

B. Pharmacological Dependence 805I. Preclinical Studies 805

II. Plasma and CSF in Opiate-Dependent Humans 806

XXXVI Contents

III. Animal Models of Clinically Important Aspects of Addiction 809IV. Protracted Opiate Abstinence 809V. Possible Role of Endogenous Opioids in Alcohol

Dependence 809C. Variations in Levels of Endogenous Opioids 810

I. Individual Variation 810II. Stress-Induced Changes in Endogenous Opioids 811

III. Therapeutic Maneuvers to Increase Endogenous Opioids 812D. Treatment of Opioid Dependence 813

I. Detoxification 8131. Unassisted Detoxification 8132. Substitution 8133. Nonopioid Detoxification: Clonidine 814

II. Agonist Maintenance 8151. Methadone . . 8152. /-a-Acetylmethadol 816

III. Opioid Antagonist Treatment: Naltrexone 817IV. Mixed Agonist/Antagonist: Buprenorphine 818V. Nonpharmacological Approaches 819

1. Therapeutic Community 8192. Combinations of Psychotherapy and Pharmacotherapy 819

References 820

Subject Index 825