Translational Pain Research

One of the Most Rapidly Advancing Fields in Modern Neuroscience

The success of molecular biology and the new tools derived from molecular genetics have revolutionized pain research and its translation to therapeutic effectiveness. Bringing together recent advances in modern neuroscience regarding genetic and genomic studies in mice and humans and the practicality of clinical trials, Translational Pain Research: From Mouse to Man effectively bridges the gap between basic research and patient care by humanely examining rodent models for pain associated with bone cancer, osteoarthritis, and cardiac episodes.

Distinguished Team of International Contributors

In addition to addressing the groundbreaking technical advances in tract tracing, endocannabinoids, cannabis, gene therapy, siRNA gene studies, and the role of glia, cytokines, P2X receptors, and ATP, this book also presents cutting-edge information on

• Nociceptor sensitization
• Visceral afferents in disease
• Innovative rodent model for bone cancer pain
• Highly specific receptor cloning
• Modular molecular mechanisms relevant to painful neuropathies

This sharply focused work also discusses unexpected discoveries derived from brain imaging studies related to thalamic pain. Translational Pain Research covers the progress made toward bringing laboratory science (much of it at the molecular level) to our understanding of pain phenomena in humans, with the ultimate goal of reducing the suffering that often accompanies pain and its indirect consequences.

Contents

• Series Preface
• Preface
• The Editors
• Contributors
• 1. Painful Multi-Symptom Disorders: A Systems Perspective
  C. Richard Chapman.
  • 1.1. COMPLEX SYSTEMS FRAMEWORK
  • 1.2. FEATURES OF COMPLEX ADAPTIVE SYSTEMS
  • 1.3. THE NERVOUS-ENDOCRINE-IMMUNE SUPERSYSTEM
  • 1.4. STRESS RESPONSE, SICKNESS, AND DEPRESSION
  • 1.5. DISTURBED INTERSUBSYSTEM COORDINATION
  • 1.6. INDEXES OF DYSREGULATION
  • 1.7. STRESS, DYSFUNCTION, AND CHRONIC DISORDERS
  • REFERENCES
• 2. Neurotrophic Factors and Nociceptor Sensitization
  Michael P. Jankowski and H. Richard Koerber.
  • 2.1. NEUROTROPHIC FACTORS CAN SENSITIZE SPECIFIC POPULATIONS OF SENSORY NEURONS
  • 2.2. PERIPHERAL INJURY CAUSES SENSITIZATION OF NOCICEPTORS
  • 2.3. CLINICAL RELEVANCE
  • 2.4. FUTURE TREATMENTS FOR NEUROTROPHIC FACTOR-INDUCED NOCICEPTOR SENSITIZATION
  • REFERENCES
• 3. The Role of Visceral Afferents in Disease
  Julie A. Christianson and Brian M. Davis.
  • 3.1. INTRODUCTION
  • 3.2. ANATOMICAL CHARACTERIZATION OF VISCERAL AFFERENTS
  • 3.3. ROLE OF SPECIFIC CHANNELS IN VISCERAL SENSATION AND PERSISTENT VISCERAL PAIN
  • 3.4. ROLE OF VISCERAL AFFERENTS IN DISEASE
  • 3.5. SUMMARY
  • REFERENCES
• 4. Cancer Pain: From the Development of Mouse Models to Human Clinical Trials
  Juan Miguel Jimenez Andrade and Patrick Mantyh.
  • 4.1. INTRODUCTION
  • 4.2. DEVELOPMENT OF A MURINE MODEL OF BONE CANCER: TUMOR GROWTH, SKELETAL REMODELING, AND PAIN BEHAVIORS
  • 4.3. MECHANISMS UNDERLYING BONE CANCER PAIN
  • 4.4. CONCLUSIONS
  • REFERENCES
• 5. Therapeutic Targeting of Peripheral Cannabinoid Receptors in Inflammatory and Neuropathic Pain States
  Igor Spigelman.
  • 5.1. INTRODUCTION
  • 5.2. CANNABINOID RECEPTORS
  • 5.3. ENDOCANNABINOIDS AND THEIR METABOLISM
  • 5.4. ENDOCANNABINOIDS AND SYNAPTIC PLASTICITY
  • 5.5. ANTINOCICEPTIVE ACTIONS OF CANNABINOIDS
  • 5.6. CANNABINOID ACTIONS ON MOTOR CONTROL AND COGNITION
  • 5.7. ENDOCANNABINOID SYSTEM ALTERATIONS IN INFLAMMATORY AND NEUROPATHIC PAIN STATES
  • 5.8. HOMEOSTATIC ROLE OF THE ENDOCANNABINOID SYSTEM
  • 5.9. ACTIONS AT NON-CANNABINOID RECEPTORS
  • 5.10. DISSOCIATING EFFECTS OF PERIPHERAL AND CENTRAL CANNABINOID RECEPTOR ACTIVATION
  • 5.11. STRATEGIES FOR PERIPHERAL CANNABINOID RECEPTOR TARGETING
  • 5.12. FUTURE PROSPECTS
  • ACKNOWLEDGMENT
  • REFERENCES
• 6. Molecular Strategies for Therapeutic Targeting of Primary Sensory Neurons in Chronic Pain Syndromes
  Ichiro Nishimura, Devang Thakor, Audrey Lin, Supanigar Ruangsri, and Igor Spigelman.
  • 6.1. INTRODUCTION
  • 6.2. CHALLENGES ASSOCIATED WITH GENE TRANSFER TO NEURONAL CELLS IN VITRO
  • 6.3. ADMINISTRATION ROUTES FOR IN VIVO GENE TRANSFER TO PRIMARY SENSORY NEURONS
  • 6.4. “LOSS- OR GAIN-OF-FUNCTION” EXPERIMENTS IN PERIPHERAL NEUROPATHY ANIMAL MODELS
  • 6.5. CONCLUSIONS
  • ACKNOWLEDGMENTS
  • REFERENCES
• 7. Transgenic Mouse Models for the Tracing of “Pain” Pathways
  Allan I. Basbaum and João M. Bráz.
  • 7.1. INTRODUCTION
  • 7.2. TRADITIONAL ANATOMICAL TRACING APPROACHES
  • 7.3. GENETIC TRACING WITH TRANSNEURONAL TRACERS
  • 7.4. A GENETIC APPROACH TO THE ANATOMICAL MAPPING OF COMPLEX CIRCUITS: THE ZW MOUSE
  • 7.5. GENETIC TRACING OF ASCENDING “PAIN” PATHWAYS: SELECTIVE INDUCTION OF A TRANSNEURONAL TRACER IN PRIMARY AFFERENT NOCICEPTORS
  • 7.6. NERVE INJURY-INDUCED EXPRESSION OF WGA: A WINDOW INTO THE STUDY OF CIRCUIT PLASTICITY
  • 7.7. GENETIC TRACING OF DESCENDING “MODULATORY” CIRCUITS: SELECTIVE INDUCTION OF WGA IN SEROTONERGIC NETWORKS
  • 7.9. CONCLUSIONS
  • ACKNOWLEDGMENTS
  • REFERENCES
• 8. Cytokines in Pain
  Veronica I. Shubayev, Kinshi Kato, and Robert R. Myers.
  • 8.1. INTRODUCTION
  • 8.2. CYTOKINES
  • 8.3. NOCICEPTION AND NEUROPATHIC PAIN
  • 8.4. CYTOKINES IN CENTRAL NEUROINFLAMMATION AND GLIAL ACTIVATION
  • 8.5. AXONAL TRANSPORT OF CYTOKINES
  • 8.6. CYTOKINES AND PAIN SIGNALING
  • 8.7. CYTOKINE-RELATED THERAPEUTICS
  • REFERENCES
• 9. Glial Modulation in Pain States: Translation into Humans
  Ryan J. Horvath, Edgar Alfonso Romero-Sandoval, and Joyce A. De Leo.
  • 9.1. OPIOIDS: THE ROLE OF GLIA IN INCREASED USE AND ABUSE
  • 9.2. CANNABINOIDS/ENDOCANNABINOIDS FOR ANALGESIA: PROBLEMS AND PROMISES
  • 9.3. POTENTIAL FOR DIRECT TRANSLATION: TREATMENT AND DIAGNOSIS
  • 9.4. CONCLUSIONS: LOOK TO THE FUTURE
  • REFERENCES
• 10. On the Role of ATP-Gated P2X Receptors in Acute, Inflammatory and Neuropathic Pain
  Estelle Toulme, Makoto Tsuda, Baljit S. Khakh, and Kazuhide Inoue.
  • 10.1. INTRODUCTION
  • 10.2. P2X3 RECEPTORS AND ACUTE PAIN
  • 10.3. P2X4 RECEPTORS AND NEUROPATHIC PAIN
  • 10.4. P2X7 RECEPTORS AND INFLAMMATORY PAIN
  • 10.5. SUMMARY
  • REFERENCES
• 11. Myalgia and Fatigue: Translation from Mouse Sensory Neurons to Fibromyalgia and Chronic Fatigue Syndromes
  Alan R. Light, Charles J. Vierck, and Kathleen C. Light.
  • 11.1. INTRODUCTION
  • 11.2. DO SKELETAL MUSCLES HAVE TWO UNIQUE TYPES OF SENSORY RECEPTORS THAT DETECT METABOLITES: ONE TYPE NOCICEPTIVE (CAPABLE OF SIGNALING PAIN), THE OTHER ERGORECEPTIVE (CAPABLE OF DETECTING MUSCLE WORK)?
  • 11.3. MOLECULAR RECEPTORS THAT ARE ACTIVATED BY METABOLITES PRODUCED BY MUSCLE CONTRACTION
  • 11.4. THE NEED FOR TRANSLATIONAL BRIDGES TO FIBROMYALGIA AND CHRONIC FATIGUE SYNDROME
  • 11.5. ARE THESE MOLECULAR RECEPTORS RESPONSIBLE FOR SENSORY MUSCLE FATIGUE AND MUSCLE PAIN?
  • 11.6. TRANSLATION FROM MOUSE TO HUMAN
  • 11.7. MOLECULAR RECEPTORS INVOLVED IN CHRONIC FATIGUE SYNDROME
  • 11.8. DYSREGULATED MRNAS MAY ALSO EXPLAIN COMMON CO-MORBIDITIES OF CFS
  • 11.9. CAN ACUTE FATIGUE LEAD TO CHRONIC FATIGUE?
  • 11.10. COMMON CAUSES OF ACUTE FATIGUE MIGHT CAUSE UP-REGULATION OF THE mRNA FOR THE MOLECULAR RECEPTORS SUGGESTED TO MEDIATE SENSORY MUSCLE FATIGUE AND PAIN
  • 11.11. MENTAL FATIGUE
  • 11.12. SYMPATHETIC DYSREGULATION CONTRIBUTES TO ENHANCED SENSORY FATIGUE
  • 11.13. ADRENERGIC RECEPTORS ON SENSORY NEURONS?
  • 11.14. BACK TO THE MOUSE TO FIGURE OUT HOW ADRENERGIC RECEPTORS COULD INCREASE MUSCLE PAIN AND FATIGUE
  • 11.15. FUTURE RESEARCH DIRECTIONS
  • ACKNOWLEDGMENTS
  • REFERENCES
• 12. Reflex Autonomic Responses Evoked by Group III and IV Muscle Afferents
  Jennifer L. McCord and Marc P. Kaufman.
  • 12.1. INTRODUCTION
  • 12.2. MUSCLE AFFERENTS
  • 12.3. DISCHARGE PROPERTIES OF GROUP III AND IV AFFERENTS
  • 12.4. METABOLITES RELEASED DURING MUSCULAR CONTRACTION AND PAIN
  • 12.5. AFFERENT PATHWAY
  • 12.6. SYMPATHETIC ACTIVATION
  • 12.7. TRANSLATION TO HEART FAILURE
  • REFERENCES
• 13. Central Pain as a Thalamocortical Dysrhythmia: A Thalamic Efference Disconnection?
  Kerry D. Walton and Rodolfo R. Llinás.
  • 13.1. INTRODUCTION
  • 13.2. DEAFFERENTATION PAIN SYNDROMES
  • 13.3. PERIPHERAL PAIN SYNDROMES
  • 13.4. COMPLEX REGIONAL PAIN SYNDROME
  • 13.5. HUMAN ELECTRICAL RECORDINGS
  • 13.6. ANIMAL STUDIES
  • 13.7. THE THALAMOCORTICAL CIRCUIT
  • 13.8. COMMENTS ON TREATMENT
  • 13.9. PAIN, ITS LOCALIZATION, AND SENSORY BINDING
  • REFERENCES
• 14. What Can Neuroimaging Tell Us about Central Pain?
  D.S. Veldhuijzen, F.A. Lenz, S.C. LaGraize, and J.D. Greenspan.
  • 14.1. INTRODUCTION
  • 14.2. THE NATURE OF SENSORY ABNORMALITIES IN CENTRAL PAIN
  • 14.3. IDENTIFYING COLD ALLODYNIA
  • 14.4. CENTRAL PAIN MECHANISMS: ONGOING PAIN
  • 14.5. CEREBRAL MECHANISMS OF COLD ALLODYNIA IN CENTRAL PAIN
  • 14.6. CEREBRAL MECHANISMS OF TACTILE ALLODYNIA IN CENTRAL PAIN
  • 14.7. CONCLUSIONS
  • ACKNOWLEDGMENT
  • REFERENCES
• 15. Human Brain Imaging Studies of Chronic Pain: Translational Opportunities
  A. Vania Apkarian.
  • 15.1. PSYCHOLOGICAL, COGNITIVE, AND SENSORY ABNORMALITIES
  • 15.2. BRAIN METABOLITES
  • 15.3. SPONTANEOUS PAIN
  • 15.4. BRAIN ACTIVITY DURING CHRONIC PAIN
  • 15.5. BRAIN ACTIVITY FOR THERAPIES FOR CHRONIC PAIN
  • 15.6. BRAIN MORPHOLOGICAL CHANGES WITH CHRONIC PAIN
  • 15.7. PUTTING ALL THE HUMAN OBSERVATIONS TOGETHER
  • 15.8. ANIMAL MODELS AND CORRELATES FOR HUMAN CHRONIC PAIN
  • 15.9. NOVEL PHARMACOTHERAPY BASED ON THE ROLE OF THE CORTEX IN CHRONIC PAIN
  • 15.10. TOWARD A NEW THEORY OF CHRONIC PAIN
  • REFERENCES
• 16. Consideration of Pharmacokinetic Pharmacodynamic Relationships in the Discovery of New Pain Drugs
  Garth T. Whiteside and Jeffrey D. Kennedy.
  • 16.1. INTRODUCTION
  • 16.2. STAGES OF DRUG DISCOVERY
  • 16.3. ROLE OF SMALL ANIMAL MODELS IN PAIN DRUG DISCOVERY
  • 16.4. WHICH PK PARAMETERS TO CONSIDER
  • 16.5. BRAIN AND SPINAL CORD PENETRATION
  • 16.6. PK/PD MODELING
  • 16.7. CONCLUDING REMARKS
  • REFERENCES
• 17. Large Animal Models for Pain Therapeutic Development
  Darrell A. Henze and Mark O. Urban.
  • 17.1. THE IMPORTANCE OF PREDICTIVE ANIMAL MODELS FOR DRUG DISCOVERY AND DEVELOPMENT
  • 17.2. THE POTENTIAL VALUE OF LARGE ANIMAL MODELS
  • 17.3. MODELS OF ACUTE NOCICEPTION
  • 17.4. MODELS OF ACUTE INFLAMMATORY PAIN
  • 17.5. MODELS OF CHRONIC INFLAMMATORY PAIN
  • 17.6. MODELS OF CHRONIC NEUROPATHIC PAIN
  • 17.7. ALGOGENIC/PHARMACODYNAMIC MODELS
  • 17.8. SUMMARY
  • REFERENCES
• 18. Drug Discovery and Development for Pain
  Sandra R. Chaplan, William A. Eckert III, and Nicholas I. Carruthers.
  • 18.1. INTRODUCTION
  • 18.2. OVERVIEW OF THE PROCESS OF DRUG DISCOVERY
  • 18.3. TARGET SELECTION/TARGET IDENTIFICATION
  • 18.4. TARGET VALIDATION
  • 18.5. LEAD IDENTIFICATION
  • 18.6. CANDIDATE SELECTION
  • 18.7. NDA
  • 18.8. CONCLUSION
  • REFERENCES