Pain Genetics: Basic to Translational Science -- Copyright -- Contents -- Editors' Biographies -- Contributors -- 1 How Do Pain Genes Affect Pain Experience? -- Introduction -- Variability in Pain Experience -- Heritability of Pain: Historical Roots -- Why is Pain Genetics Interesting and Potentially Useful? -- What Are Pain Genes? -- How Many Pain Genes Are There? -- How Do Pain Genes Affect Pain Experience? -- Direct Effects of Allelic Variation on Pain Mechanisms -- Indirect Effects of Allelic Variation on Pain Mechanisms -- Disease Susceptibility Genes Versus Pain Susceptibility Genes -- Perspective -- Acknowledgments -- References -- 2 Conservation of Pain Genes Across Evolution -- Introduction -- Anatomical Organization of Nociception Apparatus in Mammals and Drosophila -- Acute Heat Pain in Mammals -- Acute Heat Nociception in Drosophila -- Mechanical Pain in Mammals -- Mechanical Nociception in Drosophila -- Chemical Nociception in Mammals -- Chemical Nociception in Drosophila -- Inflammatory Pain in Mammals -- Persistent Pain in Drosophila -- Neuropathic Pain in Mammals -- Structural Reorganizations of Nerve Fibers in Neuropathic Pain -- Mammalian Neuropathic Pain Genes That Are Conserved in Drosophila -- Long-Term Potentiation and Long-Term Depression in Neuropathic Pain in Mammals -- Neuropathic Pain in Drosophila -- Conclusions -- References -- 3 Defining Human Pain Phenotypes for Genetic Association Studies -- Introduction -- What is a Pain Phenotype? -- Pain Scaling -- Heritability -- Genotype-Phenotype Matching -- Reliability and Temporal Stability -- Clinical Phenotypes -- Designing Clinical Pain Genetic Studies -- The Heritability of Specific Clinical Pain Conditions -- Experimental Phenotypes -- The Heritability of Experimental Phenotypes -- Extended Phenotypes -- Practical Concerns -- Conclusions.

Conflict of Interest Statement -- References -- 4 Genetic Contributions to Pain and Analgesia: Interactions with Sex and Stress -- Introduction -- Brief Overview of Sex and Gender Differences in Pain and Analgesia -- Brief Overview of Stress and Pain/Analgesia -- Sex X Gene Interactions in Pain and Analgesia -- Sex Chromosome-Linked Genes -- Genes Related to Hormone Function -- Sex-Dependent Mechanisms: Qualitative Versus Quantitative Differences -- Preclinical Findings -- Human Findings -- Translational Findings -- Summary -- References -- 5 Abnormal Pain Conditions in Humans Related to Genetic Mutations -- Introduction to SCN9A, NTRK1, and NGF and the Roles They Play in Pain -- Introduction to SCN9A and Its Omnipotent Role in Pain Sensing -- Phenotypes Caused by SCN9A Mutations -- SCN9A Gene -- Pathogenic SCN9A Mutations -- Nav1.7 Protein -- The Role of SCN9A/Nav1.7 in Pain -- Future Development of Nav1.7 Antagonists -- Introduction to NTRK1 and Its Role in Development and Function in the Pain and Sympathetic Nervous Systems -- Phenotype Caused by NTRK1 Gene Mutations (OMIM 256800) -- NTRK1 Gene -- Pathogenic NTRK1 Mutations -- TRKA Protein -- Role of NTRK1/TRKA and NGF in Pain and the HSAN Phenotype -- Future Drug Developments -- Introduction to NGF, the First Nerve Growth Factor to Be Found and Studied -- Phenotypes Caused by Gene Mutations -- Gene -- Pathogenic NGF Mutations -- Nerve Growth Factor Protein -- Role of NGF in Pain -- Future Drug Developments -- References -- 6 Alternative Pre-mRNA Splicing of Mu Opioid Receptor Gene: Molecular Mechanisms Underlying the Complex Actions of Mu Opioids -- Introduction -- Evolution of OPRM1 Gene -- OPRM1 Gene: Chromosomal Location and Gene Structure -- Alternative Promoters -- Exon 1 Promoter -- Alternative Pre-mRNA Splicing of the OPRM1 Gene.

C-terminal Full-Length Splice Variants Generated Through 3′ Splicing -- Truncated Splice Variants with 6 TMs Generated Through 5′ Splicing (Figure  6.3) -- N-Terminal Full-Length Splice Variants Through Alternative 5′ and 3′ Splicing -- Truncated Splice Variants with Single TM Generated Through Exon Skipping and Insertion -- Expression and Function of the OPRM1 Splice Variants -- Region-Specific Expression of mRNAs and Proteins -- Functions of C-Terminal Splice Variants -- Functions of Exon 11-Associated Truncated 6-TM Variants -- Conclusion -- References -- 7 Discovering Multilocus Associations with Complex Pain Phenotypes -- Introduction -- Approaches Based on Testing Individual Genetic Variants Within a Region -- Approaches That Combine Association Signals Across Genetic Variants -- Methods for Testing Joint Effects of Multiple Genetic Variants -- Multilocus Analysis of Mu Opioid Receptor Haplotypes -- Two-Stage Multilocus Association Analysis: Collapsing SNPs with Adjustment for Effect Directions -- Two-Stage Approach: Simulations -- Two-Stage Approach: Results -- Discussion -- Acknowledgments -- References -- 8 Overlapping Phenotypes: Genetic Contribution to Nausea and Pain -- Introduction -- What is the Functional Role of Nausea and Vomiting? -- Pain Syndromes with Significant Nausea -- The Neuropharmacology of Nausea and Emesis -- Emetic and Antiemetic Action of Opioids -- Preclinical Studies of Nausea and Vomiting -- Heritability of Nausea and Vomiting Phenotypes -- Human Genetic Sequence Variants Associated with Nausea and Vomiting -- Summary and Future Directions -- References -- 9 A Counterpart to Pain: Itch -- Introduction -- Why Do We Scratch? -- The Basics of Itch -- Pruritogen Receptors Couple to Trp Channels -- Noxious Chemicals Are Not Specific to Pain or Itch -- So How is Itch Coded? -- Measuring Itch in Mice.

Genetic Models of Itch -- NGF Signaling is Required for the Survival of Pruritoceptors -- Particular Itch Receptors are Required for Specific Types of Itch -- Key Signaling Molecules Are Also Required for Itch -- The Pruritogenic Soup -- A Key Role for the Skin in Itch -- A Shift in the Balance of Pain and Itch -- Genetic Variation and Itch in Humans - Challenges for the Future -- Acknowledgments -- References -- 10 Translating Genetic Knowledge into Clinical Practice for Musculoskeletal Pain Conditions -- Introduction -- Results of Human Association Studies -- Gene Sequencing -- Development of New Therapeutics -- Understanding of Interactions -- In Summary -- References -- 11 The Human Chronic Pain Phenome: Mapping Nongenetic Modifiers of the Heritable Risk -- The Current Crisis in Pain Medicine -- The Importance of Estimating Risk of Chronic Neuropathic Pain (CNP) -- Modification of the Heritable Risk for CNP -- The Natural History of CNP -- Modification of Heritable Risk for CNP In Utero -- Modifications of the Heritable Risk for CNP Across Generations -- Postnatal Modifications of the Heritable Risk for CNP -- Modifications of the Heritable Risk for CNP by Childhood Adverse Experiences -- Modifications of the Heritable Risk for CNP by Prior Chronic Pain Epochs -- Modification of the Heritable Risk for CNP by Certain Personality Traits -- Modification of the Heritable Risk for CNP by Social Factors -- Modification of the Heritable Risk for CNP by Diet, Medications, Smoking, and Alcohol Intake Consumed Preoperatively -- Modification of the Heritable Risk for CNP by Climate -- Modification of the Heritable Risk for CNP by Lifestyle -- Modifications of the Heritable Risk for Chronic Pain by Other Diseases -- Modifications of the Heritable Risk for CNP by Nongenetic Factors Occurring Just Prior and During the Inciting Event -- Summary -- References.

Appendix: List of Abbreviations -- Index -- Supplementary Images.