Pain Genetics

Inna Belfer, MD, PhD, is an Associate Professor of Anesthesiology and Human Genetics and Director of the Molecular Epidemiology of Pain Program at the Department of Anesthesiology, School of Medicine, University of Pittsburgh. Luda Diatchenko, MD, PhD, is a Canada Excellence Research Chair in Human Pain Genetics, Professor, Faculty of Medicine, Department of Anesthesia, and Faculty of Dentistry at McGill University, Alan Edwards Centre for Research on Pain.

Editors’ Biographies xi

Contributors xiii

1 How Do Pain Genes Affect Pain Experience? 1
Marshall Devor

Introduction 2

Heritability of Pain: Historical Roots 2

Why is Pain Genetics Interesting and Potentially Useful? 4

What Are Pain Genes? 8

How Do Pain Genes Affect Pain Experience? 9

Disease Susceptibility Genes Versus Pain Susceptibility Genes 12

Perspective 13

Acknowledgments 13

2 Conservation of Pain Genes Across Evolution 15
Thang Manh Khuong and G. Greg Neely

Introduction 15

Anatomical Organization of Nociception Apparatus in Mammals and Drosophila 16

Acute Heat Pain in Mammals 16

Acute Heat Nociception in Drosophila 18

Mechanical Pain in Mammals 19

Mechanical Nociception in Drosophila 19

Chemical Nociception in Mammals 21

Chemical Nociception in Drosophila 21

Inflammatory Pain in Mammals 22

Persistent Pain in Drosophila 22

Neuropathic Pain in Mammals 25

Structural Reorganizations of Nerve Fibers in Neuropathic Pain 25

Mammalian Neuropathic Pain Genes That Are Conserved in Drosophila 25

Long-Term Potentiation and Long-Term Depression in Neuropathic Pain in Mammals 28

Neuropathic Pain in Drosophila 30

Conclusions 30

3 Defining Human Pain Phenotypes for Genetic Association Studies 37
Christopher Sivert Nielsen

Introduction 37

What is a Pain Phenotype? 38

Pain Scaling 39

Heritability 40

Genotype–Phenotype Matching 41

Reliability and Temporal Stability 41

Clinical Phenotypes 43

Designing Clinical Pain Genetic Studies 43

The Heritability of Specific Clinical Pain Conditions 45

Experimental Phenotypes 45

The Heritability of Experimental Phenotypes 46

Extended Phenotypes 47

Practical Concerns 47

Conclusions 48

Conflict of Interest Statement 48

4 Genetic Contributions to Pain and Analgesia: Interactions with Sex and Stress 51
Roger B. Fillingim and Jeffrey S. Mogil

Introduction 51

Brief Overview of Sex and Gender Differences in Pain and Analgesia 52

Brief Overview of Stress and Pain/Analgesia 52

Sex X Gene Interactions in Pain and Analgesia 53

Summary 57

5 Abnormal Pain Conditions in Humans Related to Genetic Mutations 61
Christopher Geoffrey Woods

Introduction to SCN9A, NTRK1, and NGF and the Roles They Play in Pain 61

Introduction to SCN9A and Its Omnipotent Role in Pain Sensing 62

Introduction to NTRK1 and Its Role in Development and Function in the Pain and Sympathetic Nervous Systems 69

Introduction to NGF, the First Nerve Growth Factor to Be Found and Studied 72

6 Alternative Pre-mRNA Splicing of Mu Opioid Receptor Gene: Molecular Mechanisms Underlying the Complex Actions of Mu Opioids 79
Ying-Xian Pan

Introduction 79

Evolution of OPRM1 Gene 80

OPRM1 Gene: Chromosomal Location and Gene Structure 82

Alternative Promoters 82

Alternative Pre-mRNA Splicing of the OPRM1 Gene 83

Expression and Function of the OPRM1 Splice Variants 90

Conclusion 94

7 Discovering Multilocus Associations with Complex Pain Phenotypes 99
Chia-Ling Kuo, Luda Diatchenko, and Dmitri Zaykin

Introduction 99

Approaches Based on Testing Individual Genetic Variants Within a Region 100

Approaches That Combine Association Signals Across Genetic Variants 101

Methods for Testing Joint Effects of Multiple Genetic Variants 102

Multilocus Analysis of Mu Opioid Receptor Haplotypes 103

Two-Stage Multilocus Association Analysis: Collapsing SNPs with Adjustment for Effect Directions 104

Two-Stage Approach: Simulations 107

Two-Stage Approach: Results 108

Discussion 111

Acknowledgments 113

8 Overlapping Phenotypes: Genetic Contribution to Nausea and Pain 115
Charles C. Horn

Introduction 115

What is the Functional Role of Nausea and Vomiting? 117

Pain Syndromes with Significant Nausea 118

The Neuropharmacology of Nausea and Emesis 119

Emetic and Antiemetic Action of Opioids 121

Preclinical Studies of Nausea and Vomiting 122

Heritability of Nausea and Vomiting Phenotypes 123

Human Genetic Sequence Variants Associated with Nausea and Vomiting 124

Summary and Future Directions 125

9 A Counterpart to Pain: Itch 131
Adam P. Kardon and Sarah E. Ross

Introduction 131

Why Do We Scratch? 132

The Basics of Itch 132

So How is Itch Coded? 133

Measuring Itch in Mice 134

Genetic Models of Itch 135

A Key Role for the Skin in Itch 141

A Shift in the Balance of Pain and Itch 141

Genetic Variation and Itch in Humans – Challenges for the Future 143

Acknowledgments 143

10 Translating Genetic Knowledge into Clinical Practice for Musculoskeletal Pain Conditions 147
Luda Diatchenko, Shad B. Smith, and William Maixner

Introduction 147

Results of Human Association Studies 148

Gene Sequencing 150

Development of New Therapeutics 150

Understanding of Interactions 155

In Summary 156

11 The Human Chronic Pain Phenome: Mapping Nongenetic Modifiers of the Heritable Risk 161
Ze’ev Seltzer, Scott R. Diehl, Hance Clarke, and Joel Katz

The Current Crisis in Pain Medicine 162

The Importance of Estimating Risk of Chronic Neuropathic Pain (CNP) 162

Modification of the Heritable Risk for CNP 163

The Natural History of CNP 165

Modification of Heritable Risk for CNP In Utero 166

Modifications of the Heritable Risk for CNP Across Generations 167

Postnatal Modifications of the Heritable Risk for CNP 168

Modifications of the Heritable Risk for CNP by Childhood Adverse Experiences 168

Modifications of the Heritable Risk for CNP by Prior Chronic Pain Epochs 169

Modification of the Heritable Risk for CNP by Certain Personality Traits 172

Modification of the Heritable Risk for CNP by Social Factors 172

Modification of the Heritable Risk for CNP by Diet, Medications, Smoking, and Alcohol Intake Consumed Preoperatively 174

Modification of the Heritable Risk for CNP by Climate 175

Modification of the Heritable Risk for CNP by Lifestyle 175

Modifications of the Heritable Risk for Chronic Pain by Other Diseases 176

Modifications of the Heritable Risk for CNP by Nongenetic Factors Occurring Just Prior and During the Inciting Event 176

Summary 177

Appendix: List of Abbreviations 183

Index 185

Color insert found between pages 114 and 115