Index

• Aarhus Research Center, 136

• Action potentials (APs), 9, 10
  • from DRG neurons, 10, 11f
  • inappropriate repetitive firing of, 15, 16f
  • L858H mutation decreases AP threshold in DRG neurons, 90
• Aging and peripheral neuropathy, 171
• Ahn, Hye-Sook, 160
• Alabama, 25
• Amino acids, 27–28, 31, 57, 206, 248, 249
• Atomic-level structural modeling, 72
  • of the putative activation gene, 73–74
• Autonomic dysfunction, 183
• Axons, 9, 10, 271
  • axotomy of peripheral, 66
  • giant, 11
  • injured, 164, 166, 166f
  • Na_V1.8 and, 139, 150, 200
  • in neuromas, 66, 139
  • neuropathy-associated Na_V1.7 variant I228M impairs integrity of DRG neuron axons, 195–197, 200–202
  • peripheral neuropathy and, 15–16, 17f, 170–171
  • small fiber neuropathy (SFN) and, 202
  • sodium channel blockers and, 171, 190

• Bacteria and sodium channels, 248–249. See also Na_VAb
• Beijing, China, 157–158
• Bennett, Michael, xiii, 156
• Biogen, 289
• Black, Joel A., 14, 136, 166
• Boston City Hospital, xiii
• Burbank, Mahlon, 28
• Butt, Richard, xiii

• Carbamazepine (CBZ), 247, 271–273, 277, 281, 281f, 285–286
  • axons and, 171
  • and brain activity, 279–282, 280f, 281f
  • current thresholds of CBZ-treated DRG neurons expressing S241T or F1449V mutation channels, 257, 259f
  • depolarization and, 76, 254–257, 256f
  • firing frequencies and membrane potentials of CBZ-treated DRG neurons expressing F1449V, 260, 262f
  • firing frequencies and membrane potentials of CBZ-treated DRG neurons expressing S241T, 260, 261f
  • and I228M-induced reduced neurite length, 196–197, 198–199f
  • inherited erythromelalgia (IEM) and, 75, 76, 247–248, 275–277
  • modeling to predict drug actions, 249–250
  • overview, 247, 251
  • pain characteristics and effects of, 278, 279f
  • paroxysmal extreme pain disorder (PEPD) and, 58
  • protects neurites expressing I228M, 196–197, 201
  • S241T and, 249–252, 264, 265, 271, 275, 276, 276b, 278–279, 279f, 284, 285
• CBZ and warmth-induced firing of DRG neurons expressing S241T mutant channels, 282, 283f, 284f
• CBZ depolarizes S241T mutant channel activation, 254–256, 256f
  • SCN9A mutations and, 75
  • V400M mutation and, 75, 76, 248, 249, 251, 252, 255, 260, 264, 265, 276, 284
• Catterall, William, 245
• Cell background, 85
• Channelopathies, inherited sodium, 67
• Channelopathy-associated insensitivity to pain, 58, 176
• Channelopathy-associated SFN, 191
• Cheng, Xiaoyang, xiii, 160, 207
• China, 157–158
• Choi, Jin, 160
• Cingulate cortex, 273
• “Common disease/rare variant” model, 205–206
• Comparative genomic hybridization (CGH), 226
• Complete insensitivity to pain (CIP), 67b, 70–72, 75
• Convergence Pharmaceuticals, 289
• Craner, Matthew, 14
• Crick, Francis, 27
• Crystallography, 245
• Cummins, Ted, xiii, 18, 32
• Current-clamp analysis, 32, 48–49, 51, 209 , 241-242
• Current-clamp recordings
  • transfected DRG neurons and, 46, 99, 178, 257, 258–259f, 267
  • transfected SCG neurons and, 99

• D623N (mutation), 169, 184t, 190
  • electrophysiological analysis of, 185, 187f
  • impaired fast and slow inactivation and DRG neuron hyperexcitability, 185
• Deactivation (sodium channel closing), 32, 37, 37f, 40, 47, 49f, 113, 115f
• Deactivation kinetics, 37, 40, 47
• Delay lines, 10
• Demyelination, 13–14
• Depolarization, 11f, 169, 189f, 207, 207f–209f, 256f, 257. See also specific topics
  • carbamazepine (CBZ) and, 76, 254–257, 256f
  • D623N and, 185
  • DRG neurons and, 16, 74, 86, 90, 91f, 93, 96, 98, 119, 123, 123f–125f, 124, 126, 129, 150, 170, 188, 201, 257, 259, 261f, 262f
  • F1449V and, 47–49, 51, 51f, 52f, 53, 256, 256f, 257, 262f
  • hNa_V1.7 and, 39, 39f, 40
  • I720K and, 183, 185
  • IEM-linked SCN9A mutations and, 68, 68f, 69
  • inherited erythromelalgia (IEM) and, 227, 231f, 235
  • L858H mutations and, 89, 90, 91f, 92f, 93, 94f, 96, 97f, 98, 110, 119, 121, 123, 123f–125f, 124, 126, 129
  • Na_V1.3 and, 139, 149
  • Na_V1.7 and, 41, 48, 63b, 64, 64f, 67b, 68f, 71–72, 74, 86, 87f, 88–90, 106, 113, 119, 121, 127, 129, 139, 149, 175–176, 190, 264
  • Na_V1.8 and, 41, 48, 74, 86–87, 96, 97f, 98, 140, 150
  • Na_V1.9 and, 18t, 170
  • PEPD and, 67–69, 68f
  • S241T and, 254–257, 256f, 261f
  • SCG neurons and, 74, 90, 92f, 93, 96, 98
  • small fiber neuropathy (SFN) and, 71–72, 190
  • TTX-S channels and, 127
• Depolarizing shifts, paroxysmal, 208, 209f
• Diabetic neuropathy, 6, 66, 76, 155, 163. See also Peripheral neuropathy
• Dib-Hajj, Sulayman, xiii, 17, 33, 57, 160, 207, 290
• DNA, 27
• Dorsal root ganglion (DRG) neurons, xi, 14, 15f. See also specific topics
  • defined, xii
  • as generators of pain, 14–16
  • pain-signaling, 14 (see also Nociceptive neurons)
• Dorsal root ganglion (DRG) neuron transfection. See Transfected DRG neurons
• Dravet syndrome, 206
• Drenth, Joost P. H., xiii, 29–30, 33, 157–161
• Dynamic-clamp analysis, 105, 106. See also under Wild-type (WT) Na_V1.7
• Dynamic-clamp recordings, 109, 111, 113, 124f, 126–128, 126f

• Eccles, John, 104, 156
• Einstein, Albert, 25, 209
• Embryonic kidney cells. See HEK (human embryonic kidney) cells
• Enabler study, 218–220
• Epilepsy, 205–207
  • causes and pathophysiology, 11, 66, 89, 205, 206, 208, 209f, 210
  • N1768D mutation and, 206–207, 207f
  • Na_V1.6 and, 206, 207f, 208, 210
  • Na_V1.7 and, 57–58, 63
  • neuronal hyperexcitability and, 11, 57–58, 205
  • neuropathic pain and, 76, 89, 205
  • SCN9A mutations and, 66, 206
• Epilepsy Foundation, 12
• Epileptic encephalopathy, 205
• Erythermalgia. See Erythromelalgia
• Erythromelalgia. See also Familial erythromelalgia; specific topics
  • comorbidity, 26
  • etymology of the term, 25
  • history, 28–30
  • overview and nature of, 45
  • pain of, depicted in art, 4f, 25, 26f
  • prevalence, 25, 135
  • symptoms, xii, 25–26
  • terminology, 26, 28, 53
  • treatment of, 26
• from theory toward therapy, 217–218
• Erythromelagia Association, xiii
• Estacion, Mark, xiii, 160
• Excitatory neurons, 10
• Exon 23 (E23), mutation in, 47
• Exons
  • of SCN9A, 47, 71, 178
  • that produce Na_V1.7 cDNA, 46
• Exon screening, 45–46, 178
• Extracellular signal-regulated kinases 1 and 2 (ERK1/2), 136. See also MAPK1; MAPK3
  • upregulated in painful human neuromas, 66, 136, 140, 144, 147–150, 148f

• F1449V (mutation), 33, 52, 53, 252, 253f, 254, 264
  • depolarization and, 47–49, 51, 51f, 52f, 53, 256, 256f, 257, 262f
  • and inactivation of hNa_V1.7, 48, 49f, 50f
  • in Na_V1.7, 48, 70f, 73, 74, 74f, 89
  • overexpression of, 225
  • V400M and, 231, 237, 253f, 254, 255f, 260
• F1449V mutant channels, 33, 51, 51f, 53, 255f, 256, 267
  • carbamazepine (CBZ) and, 256
  • DRG neurons expressing, 48, 49, 51, 52f, 53, 257,260, 262f
  • steady-state fast inactivation of, 48, 256
  • voltage dependence of activation and steady-state fast inactivation of, 256
• F1449V mutant hNa_V1.7_R channels, 46, 47, 49f
• Faber, Catharina (Karin) G., xiii, 159–161, 163, 164, 165f, 167, 195, 200
• Familial erythromelalgia, 28, 35, 53
  • gain of function mutation in Na_V1.7 in, 45–53
• Familial primary erythromelalgia. See Erythromelalgia
• Familial rectal pain disorder. See Paroxysmal extreme pain disorder
• Families with inherited pain, the search for, 6
• Finlay, Sara Crews, 28
• Finlay, Wayne H., 28–30
• Flaherty, Dundas and Sandra, xiii
• Foster, Robert, 14
• Functional magnetic resonance imaging (fMRI), 272, 273, 276–278, 285

• Geha, Paul, xiii, 271, 273–274
• Genome. See also Whole genome sequencing
  • human, 5, 27, 28, 290
• Genomically based therapeutics. See Pharmacogenomics
• Genomically guided pharmacotherapy, 57, 274, 276, 286. See also Pharmacogenomics
• Gerard, Ralph, 104
• Geshwind, Norman, xiii
• Giant axons, 11, 104
• God’s megaphone, 3
• Grundfest, Harry, 156

• Hammer, Michael, 205, 206, 210
• Han, Chongyang, xiii, 157, 158, 160
• Harvard Medical School, xiii
• HEK 293 cells (human embryonic kidney cells 293), 183, 185, 186f, 255, 255f, 256, 256f, 266. See also Transfected HEK 293 cells
  • carbamazepine (CBZ) and, 255, 256, 256f
  • Na_V1.7 and, 31–32, 36f, 39f, 41, 47, 61, 63b, 72, 110, 128, 178
  • β-1 and β-2 subunits and, 36, 41, 178
• Hermann, Howard, xiii
• Heutink, Peter, 30
• hNa_V1.4 channels, 40, 41, 53
• hNa_V1.7
  • F1449V and inactivation of, 48, 49f, 50f
  • HEK 293 cells and, 36, 37f, 39f, 40, 47, 49f
  • I848T and L858H mutations of, 36–42, 37f–39f, 46, 48, 49f, 50f, 51–53
  • wild type (WT), 36, 37f, 39
• hNa_V1.7 channels, 42
  • DIIS4–S5 mutations in, 40
  • transfection of, 36, 46
• hNa_V1.7_R, 46
  • wild type (WT), 36, 46, 47, 265–266
• hNE channel, 18
• Hodgkin, Alan, 11, 12, 104, 222
• Hodgkin–Huxley equations, 11
• Huang, Jianying, 160
• Human embryonic kidney cells. See HEK (human embryonic kidney) cells
• Human Na_V1.7. See hNa_V1.7
• Huang, Jianying, xiii
• Huxley, Andrew, 9, 11, 12, 104, 222
• Hyperexcitability of neurons, 11

• I228M (mutation), 196, 197f
  • carbamazepine protects neurites expressing, 196–197, 201
  • impairment of axon integrity, 195–197, 200–202
• I228M channels do not induce DRG neuron death
• I228M-induced reduced neurite length
  • effect of carbamazepine and KB-R7943 on, 196–197, 198–199f
  • reverse Na-Ca exchange contributes to, 197, 200–202
  • cell viability 3 days after transfection, 196, 198f, 200, 201
• I720K (mutation), 183, 184f, 185, 186f, 196, 197f, 200, 201
  • electrophysiological analysis of, 185, 186f
  • impaired slow inactivation and DRG neuron hyperexcitability, 183, 185
• I848T mutation
  • in hNa_V1.7, 31, 36–41, 37f–39f, 48, 51, 52
  • in IEM, 226t, 228, 231, 233, 233f, 234f, 235, 237, 237f
  • pro-excitatory effect, 32
  • V400M mutation and, 231, 235, 237
• Icagen, 217, 218
• Idiopathic small fiber neuropathy (I-SFN/iSFN), 195. See also Small fiber neuropathy
  • causes, 175
  • diagnosis, 179
  • gain of function Na_V1.7 mutations in, 71–72, 175–179, 179f, 183, 185, 188, 190–191, 200
  • SCN9A mutations and, 176, 179, 191, 225, 238
• IEM (inherited erythromelalgia). See also Familial erythromelalgia; specific topics
  • overview of, 3, 109, 251, 275–276
  • pharmacological reversal of a pain phenotype in patients with, 225–242
  • pharmacotherapy (guided by genomic analysis and functional profiling) , 275–286
• IEM iPSC-SNs. See also iPSCs/iPS cells; iPSC-SNs
  • Na_V1.7 blockers reduce elevated excitability of, 228, 231, 231f–233f
  • selective Na_V1.7 blocker reverses elevated sensitivity to heat in, 231, 234f
• IEM patients
  • clinical phenotype of, 226, 226t
  • differentiating iPSCs from IEM patients into functional sensory neurons, 226–230f
• Immunocytochemistry, 95, 98–99, 136, 137, 139, 141–142, 241
• Immunofluorescence, 143, 147
• Immunolabeling, 148f
  • Na_V1.1, 146f
  • Na_V1.2, 144
  • Na_V1.3, 143, 144f, 149
  • Na_V1.6, 144, 147f
  • Na_V1.7, 143, 145f, 149
  • Na_V1.8, 143, 145f. 149
  • Na_V1.9, 144
  • neuroma, 142
• Impedance, input, 166
• Impedance mismatch, 13
• Induced pluripotent stem cells. See iPSCs/iPS cells
• Inflammatory pain, 14–15
• Inherited erythromelalgia. See IEM
• Inhibitory neurons, 10
• Input impedance, 166
• Intra-axonal recording, 15, 16, 17
• Intracellular microelectrode, 104
• Intraepidermal nerve fiber (IENF), 195, 200. See also Intraepidermal nerve fiber density
  • dynamic plasticity, 195
• Intraepidermal nerve fiber density (IENFD), 159. See also Intraepidermal nerve fiber
  • assessment of, 202
  • reduced, in SFN, 175, 176, 177f, 179, 180–182t, 183, 188, 195, 200
• iPSCs/iPS cells (induced pluripotent stem cells), 220
  • differentiating iPSCs into functional sensory neurons, 226–227, 228–230f, 241
• iPSC-SNs (iPSC-derived sensory neurons), 226. See also IEM iPSC-SNs
  • derived from IEM subjects show elevated excitability, 227–228, 231
  • Na_V1.7 and elevated heat sensitivity of, 231, 233, 235f
  • pharmacological reversal of a pain phenotype in, 225–242
• iPSC technology
  • generation of cells from patients, 226
  • utility for preclinical studies, 238

• Jensen, Troels, 136

• Katz, Bernard, 104
• KB-R7943
  • effect on I228M-induced reduced neurite length, 196–197, 198–199f
  • effect on WT-transfected neurons with no mutant channels, 200
• Kidney cells. See HEK (human embryonic kidney) cells
• Kocsis, Jeffrey D., xiii, 14, 15, 16f, 17f
• Krafte, Doug, xiii
• Kroner, Karsten, 136
• Kuffler, Stephen, 156

• L858H channels, 36-38, 90, 92f, 93, 94f, 96, 97f, 109, 110, 111, 119, 121, 124, 126, 129
  • and biophysical properties of hNa_V1.7, 36–39, 37f–39f
  • WT-to-L858H conductance exchange, 123, 124, 126, 126f
• L858H mutation 30–33, 36–41, 37f–39f, 48, 51, 52, 74. See also under Depolarization; hNa_V1.7; specific topics
  • attenuates repetitive firing in SCG neurons, 93, 94f
  • and biophysical properties of hNa_V1.7, 36–41, 37f–39f
  • increases Na⁺ influx during subthreshold membrane depolarizations and interspike intervals, 124, 124f–126f, 126–129
  • enhances repetitive firing in DRG neurons, 93, 94f
  • lowers current threshold and enhances AP firing probability of DRG neurons, 121, 122f
  • depolarizes RMP and decreases AP threshold in DRG neurons, 90, 91f
  • depolarizes RMP but increases AP threshold in SCG neurons, 90, 92f
  • selective presence of NaV1.8 within DRG (but not SCG) neurons contributes to opposing effects of, 95–96, 97f, 98
  • WT Na_V1.7 and, 91f, 93, 94f, 98, 99, 109, 120f, 123f
• L858H mutant model predicts enhanced channel activity during repetitive DRG neuron firing, 119, 120f, 121, 122f, 123, 123f
• Labeled line theory, 10
• Layzer, R. B., 35
• Lettvin, Jerry, xiii
• Lewis, C. S., 3
• Linkage analysis, 29, 30, 33

• M932L/V991L, 184t
  • increased resurgent currents and DRG neuron hyperexcitability, 185, 188, 189f
• M932L/V991L (mutation), electrophysiological analysis of, 185, 188, 189f
• Mandel, Gail, 17
• Maastricht University, 159–161
• “Man on fire” syndrome. See Erythromelalgia
• MAPKs (mitogen-activated protein kinases), 66, 136, 140, 147, 150. See also P38
  • accumulating in neuromas, 66, 136, 140, 147, 148f, 150
• MAPK signaling pathways, 140, 144, 147, 148
• Marine Biological Laboratory, Woods Hole, Massachusetts, 155–156
• McCulloch, Warren, 9
• McDonnell, Aoibhinn, xiii
• McKernan, Ruth, xiii, 222
• Medications, new
  • challenge of, 215–217
  • from theory toward therapy, 217–218
• Meisler, Miriam, 205–207
• Merkies, Ingemar S. J., xiii, 159, 160, 163, 167
• Michiels, Jan, 29, 30
• Missense mutation, 30
• Mitchell, Silas Weir, 25, 135
• Mitchell’s disease. See Erythromelalgia
• Mitogen-activated protein kinases. See MAPKs
• Molecular target, 216
• Moore, John, xiii
• Morrisett, Valerie, xiii
• Morse code in the brain, 10–11
• Multiple sclerosis (MS), 12–14, 26
  • as “model disease
  • pathophysiology, 12–14, 207
  • remissions, 13, 14
• Mutant cycle analysis, 254, 264
• Mutations. See also specific mutations
  • definition and nature of, 6
  • Myelin, 13

• N1768D (mutation) in Nav1.6 206f
• N1768D mutant NaV1.6 channels, transmembrane currents produced by, 208f
  • effect on hippocampal neurons, 209f
• Na⁺/Ca²⁺ exchanger. See Sodium–calcium exchanger
• NaN (Na-nociceptive) sodium channel. See Na_V1.9
• Na_V1.1, 48f, 61, 86, 93, 95f
  • SCN1A mutations and, 206
• Na_V1.1 immunolabeling, 146f
• Na_V1.2, 48f, 61, 76, 95f
  • carbamazepine (CBZ) and, 264
  • PF-05089771 and, 217
• Na_V1.3, 48f, 61
  • producing changes in Na⁺ currents in spinal sensory neurons contributing to neuropathic pain, 35
  • upregulated in human painful neuromas, 140, 143, 144f
• Na_V1.3 immunolabeling, 143, 144f, 149
• Na_V1.4, 40, 41, 48f, 61, 71, 76, 96, 264
• Na_V1.4 mutations, 40, 41, 53, 96
• Na_V1.6, 48f, 61, 66, 142, 205
  • DRG neurons and, 74, 86, 93, 95f, 200
  • epilepsy and, 206–208, 207f
  • immunoreactivity, 144, 147f
  • intraepidermal nerve fibers (IENF) and, 195, 200
  • MAPK and, 140, 147
  • SCG neurons and, 93, 95f, 98
  • SCN8A and, 208
  • wild-type (WT), 207f, 209f
• Na_V1.6 mutations, 205–208, 207f, 208f, 210
• Na_V1.7, 17, 18, 48f, 61, 168f. See also specific topics
  • atomic-level model of, 18, 19f
  • depolarization, 247
  • domain structure, 62f
  • epilepsy and, 57–58, 63
  • function, 18t
  • immunoreactivity, 143, 145f, 149
  • nociceptors and, 63
  • as threshold channel, 53, 64, 65, 68, 72, 116, 117f, 118f, 122f
  • upregulated in human painful neuromas, 143, 145f
• Na_V1.7 blockers, 75, 170, 221, 225, 233, 235, 289. See also PF-05089771; PF-05153462
  • reduce elevated excitability of IEM iPSC-SNs, 228, 231, 233f
  • reversal of elevated sensitivity to heat in IEM iPSC-SNs, 231, 234f
  • reversed elevated heat sensitivity of IEM iPSC-derived sensory neurons, 231, 234f
  • rheobase and, 237
  • selective, 191, 217, 218
  • state-dependent blockers, 75–76
  • subtype-specific, 170, 217, 220
• Na_V1.7 cDNA, exons that produce, 46
• Na_V1.7 channel, structural modeling , 252, 253f
• Na_V1.7 conductance. See also Wild-type (WT)
  • regulates current threshold for AP generation in a linear manner, 113, 115f, 116, 117f, 118f, 119
• Na_V1.7 immunolabeling, 149
• Na_V1.7 mutant channel, structural modeling and mutant cycle analysis, 251–267
• Na_V1.7 mutations
  • electrophysiological properties of mutant Na_V1.7 in an inherited neuropathy, 35–42
  • functional characterization of, 183
  • gain of function, 45–53
• Na_V1.7-related pain disorders, location for characterized mutations in, 62f
• Na_V1.8, 17, 18, 41, 48f, 61, 99, 139, 168f, 289
  • axons and, 139, 150, 200
  • discovery, 17
  • DRG neurons and, 18, 20, 35, 48, 53, 66, 74, 86–87, 89, 93, 95, 95f, 96, 98, 128, 140, 150, 170, 289
  • function, 18t
  • and high-frequency firing, 289
  • IENF and, 195, 200
  • immunoreactivity, 143, 145f, 149
  • L858H Nav1.7 mutation and, 96, 97f, 98
  • MAPK and, 140
  • Na_V1.7 and, 87, 137
  • Na_V1.9 and, 170
  • neuromas and, 136, 137, 139, 140, 143, 145f, 147–150
  • nociceptors and, 41, 63
  • phosphorylation by activated p38, 150
  • SCG neurons express Na_V1.7 but not, 89, 93, 95–96, 95f, 98
  • selective presence within DRG (but not SCG) neurons, 95–96, 97f, 98
  • tetrodotoxin (TTX) and, 110, 111, 128
• Na_V1.8 blockers, 137, 170, 290
• Na_V1.8 mutations
  • gain-of-function, 170, 289
  • Na_V1.7 mutations and, 170
  • neuropathy and, 170
• Na_V1.9, 17, 18, 48f, 61, 290
  • function, 18t
  • immunoreactivity, 144
• Na_V1.9 blockers, 170
• Na_VAb (bacterial voltage-gated sodium channel), 73. See also Bacteria and sodium channels
  • (crystal) structure, 73, 251–252, 263, 263f
• alignment of Na_V1.7 structural model with Na_VAb structure, 263, 263f
• NCX (Na⁺/Ca²⁺ exchanger). See Sodium–calcium exchanger
• Neher, Erwin, 104
• Nerve impulse. See Action potential
• Nerve injury, 135. See also specific topics
• Neuralgia
  • postherpetic, 3, 77, 163
  • trigeminal, 247, 251, 289
• Neurite length, reduction in, 196–197, 198–199f, 200–202
• Neurites expressing I228M, CBZ and, 196–197, 201
• Neuromas, 135–137, 143f, 148–150
  • axons in, 139
  • axotomy of peripheral axons and, 66
  • human, 136
• activated p38 upregulated in painful, 144, 147
• ERK1/2 upregulated in painful, 66, 136, 140, 144, 147–150, 148f
• sodium channel isoforms and mitogen-activated protein kinases in, 139–150
  • MAPKs accumulating in, 66, 136, 140, 147, 148f
  • Na_V1.3 upregulated in human painful, 140, 143, 144f
  • Na_V1.7 and, 66, 128, 137, 140
  • Na_V1.7 upregulated in human painful, 143, 145f
  • Na_V1.8 and, 136, 137, 139, 140, 143, 145f, 147–150
  • and neuropathic pain, 139, 140, 142, 149
  • surgical removal, 137
  • symptoms, 139
• Neurons. See also specific topics
  • communication between neurons 10–11
  • as “threshold logic units
  • types of, 10
• Neuropathic pain, 15–16, 61. See also specific topics
  • causes, 135
  • defined, 3, 14, 15
  • descriptions of the experience of, 5
  • ectopic spontaneous action potential discharges in
  • impact and burden of, 3, 5
  • neuronal hyperexcitability and, 205
  • prevalence, 135
  • role for Na⁺ channels and MAPK pathways in 148
• Neuropathic Pain Scale (NPS), 178
• Nijmegen, The Netherlands, 158
• Nikolajsen, Lone, 136
• Nirenberg, Marshall, 27
• Nociceptive neurons (nociceptors), 14, 41, 63, 65, 66. See also DRG neurons: pain-signaling
• Nucleus accumbens, 273
• “Null” mutations, 58

• Obama, Barack, 271
• Ochoa, Severo, 27
• Olfactory sensory neurons (OSNs), 63, 63b, 65

• P38, activated, 140, 147–150, 148f
• Pain. See also specific topics
  • nature of, 3
  • prevalence of chronic, xi, 5
  • types of, 14–15
• Pain gene, x, 3, 6–7. See also specific topics
  • defined, xi
  • Na_V1.7 and, 18, 215, 289
  • SCN9A gene and, 215, 289 (see also SCN9A)
  • search for a, ix, xi–xiv, 10, 30, 155, 215, 289–291
• beginnings of the, 25
• Pain medications. See Medications; specific medications
• Pappas, George D., xii
• Paralyzed Veterans of America, xiii, 18
• Paroxysmal depolarizing shifts, 208, 209f
• Paroxysmal extreme pain disorder (PEPD), 58, 67–70, 183, 188, 190
  • depolarization and, 67–69, 68f
  • gain-of-function mutations in, 58, 62f, 176
  • Na_V1.7 mutations in, 58, 62f, 68–70, 77, 149–150, 163, 176, 183, 190, 226
  • overview, 58
  • SCN9A mutations and, 62f, 67–69, 68f, 75, 176, 188, 225, 238
  • treatment, 75
• Pascual, Juan M., 12, 274
• Patch clamp, 104
• Payandeh, Jian, 249
• Peking University First Hospital, 157
• Peripheral nerves, 163
• Peripheral neuropathy, 155, 159, 163, 171. See also Familial erythromelalgia; Small fiber neuropathy; specific neuropathies
  • axons and, 15, 17f, 170–171
• microelectrode recording from single axons, 15–16, 17f
  • causes, 3, 6, 163, 170–171
  • ectopic spontaneous action potential discharges in humans with, 149
  • epidemiology, 171
  • Na_V1.7 mutations and, 161, 164, 167, 169, 170
  • Na_V1.8 mutations and, 170, 289–290
  • Na_V1.9 mutations and, 170, 290
  • SCN9A and, 39
  • similarities to inherited erythromelalgia, 164
• Peripheral sodium channel, 16
• Personalized medicine, 207, see also precision medicine
• Persson, Anna-Karin, 166
• PF-05089771, 217, 227, 242
  • inherited erythromelalgia (IEM) and, 226, 228, 233f, 235, 237, 237f, 238
  • iPSC-SNs and, 227, 228, 233f
  • Na_V1.7 and, 217
• PF-05153462, 227, 228, 228f, 231, 233f–235f, 237
• Pfizer, 217–219, 221–222
  • Clinical Research Unit in New Haven, 218, 220
  • induced pluripotent stem cells (iPSCs) and, 221
  • Na_V1.7 blockers and, 217
  • pain research program, 218
• Phantom limb, 135, 136
• Phantom pain, 71, 135, 136, 140–141, 141t, 142t
• Pharmacogenomics, xii, 75, 247, 248, 250, 251, 271, 274, 276b. See also Genomically guided pharmacotherapy
  • pharmacotherapy guided by genomic analysis and functional profiling, 275–286
• Pitts, Walter, 9
• Plasmids, 36, 46, 196, 265–266
• Pluripotent stem cells (PSC). See iPSCs/iPS cells
• PN1 channel, 18
• Polymorphism, 29
• Postherpetic neuralgia, 3, 77, 163
• Postsynaptic neurons, 103
• Precision Medicine Initiative, 271
• Precision medicine/personalized medicine, 207, 247, 250, 271, 274. See also Pharmacogenomics
• Primary erythermalgia. See Erythromelalgia
• Primary erythromelalgia. See Erythromelalgia
• Proband, 247
• Purpura, Dominick P., xiii

• Radboud University Medical Center, 159
• Ramp current, 63–64
• Repriming, 63
• Resting membrane potential (RMP) of DRG neurons, 11f, 89, 257
• Rheobase, 231, 237
• Ritchie, J. Murdoch, 13
• Robertson, J. D., xiii, 10
• Rothman, James E., x
• Rush, Tony, xiii

• S241 and V400 show atomic proximity in human Na_V1.7 channel, 252, 253f
• S241T (mutation). See also under Carbamazepine
  • depolarization and, 254–257, 256f, 261f
  • DRG neurons expressing, 250
  • V400M mutation and, 249–250, 252, 253f, 254, 260, 264, 265, 284
• energetic coupling during activation, 250, 254, 255, 260, 264, 276, 284
• S241T mutant channel activation, carbamazepine depolarized, 254–256
• S241T mutant channels, 252, 260
  • CBZ effect on steady-state fast inactivation of, 256
  • CBZ normalizes excitability of DRG neurons expressing, 257, 260
  • voltage dependence of activation and steady-state fast inactivation of, 254, 255f, 256
• S241T Na_V1.7 mutations, 253f, 254, 255f
• Sakmann, Bert, 104
• Schulman, Betsy, xiii
• SCN1A, 206, 241
• SCN8A, 208, 241
  • epilepsy and, 208
  • mutations, 206, 208
  • Na_V1.6 and, 208
• SCN9A, 30. See also Na_V1.7
  • exons of, 47, 71, 178
  • genomic sequence, 46
  • iPSC lines expressing, 227
  • Na_V1.7 and, 238, 289
  • pain gene and, 215, 289
  • role in inherited erythromelalgia (IEM), 225, 226, 226t, 227, 233, 238, 275
  • variants, 248
• Scn9a, knockout of, 65, 67b
• SCN9A alleles, 70, 71
• SCN9A mutations, 31, 32, 35–36, 39, 65, 67, 71, 226, 226t, 233
  • carbamazepine (CBZ) and, 75
  • clinical description of, and small fiber neuropathy (SFN), 179, 180t
  • and insensitivity to pain (CIP), 67, 70, 71, 77
  • gain-of-function, 61, 62f, 65, 66, 71, 225, 238
  • and inherited erythromelalgia (IEM), 62f, 67–69, 68f
  • loss-of-function, 67, 225
  • and paroxysmal extreme pain disorder (PEPD), 62f, 67–69, 68f, 75, 176, 188
  • in primary erythromelalgia, 45
  • recessively inherited SCN9A nonsense or splicing-defective mutations, 70
  • and reports of epilepsy, 66, 206
  • and small fiber neuropathy (SFN), 62f
• SCN9A novel mutations, SFN-SIQ findings in patients with, 183, 184t
• SCN10A, 18t, 241
• SCN11A, 18t, 241
• Sensory neurons. See also Dorsal root ganglion neurons; Olfactory sensory neurons
  • gain of function mutation in Na_V1.7 in familial erythromelalgia induces bursting of, 45–53
• Sensory neuron specific (SNS) sodium channel. See Na_V1.8
• SFN Symptom Inventory Questionnaire (SNF-SIQ), 177–178, 183
• Sherrington, Charles S., 9
• Single-nucleotide polymorphisms (SNPs), 29, 30
• Small fiber nerves. See also Small nerve fiber
  • measures of the health (status) of, 164
• Small fiber neuropathy (SFN), 160, 164, 167, 190. See also Idiopathic small fiber neuropathy
  • autonomic dysfunction in, 190
  • axons and, 202
  • causes, 167
  • channelopathy-associated, 191
  • clinical description of SCN9A mutations and, 179, 180t
  • depolarization and, 71–72
  • diagnosis of, 164, 165f, 167, 188
  • inherited erythromelalgia (IEM) and, 188, 190
  • Na_V1.7 and, 66, 77, 160, 164
  • overview 163, 175, 195
  • pathophysiology, 163, 167, 195
  • prevalence, 163
  • reduced intraepidermal nerve fiber density (IENFD) in, 175, 176, 177f, 179, 180–182t, 183, 188, 195, 200
  • schematic showingNa_V1.7 mutations in idiopathic, 179, 179f
  • and seizures, 66
  • symptoms, 163–164, 188, 190
• Small nerve fiber. See also Small fiber nerves
  • patch-clamp recording from a, 166, 168f
• Small nerve fiber neuropathy. See Small fiber neuropathy
• SNS sodium channel. See Na_V1.8
• SNS2 sodium channel. See Na_V1.9
• SNS (sensory neuron specific) sodium channel. See Na_V1.8
• Sodium–calcium exchange
  • blockers of, 171, 201, 202
  • reverse (calcium-importing), 171, 190, 195, 196
• contribution to reduced neurite length of 1228M-transfected neurons, 197, 200
• Sodium–calcium exchanger (Na⁺/Ca²⁺ exchanger/NCX), 164, 166, 166f, 167f, 171, 190–191, 195–197, 200–202
  • Na-Ca exchanger-2 (NCX2), 191, 195, 201
• Sodium channel blockers, 16, 53, 75, 76, 149, 150, 170. See also Carbamazepine
  • axons and, 171, 190
  • binding to pore of voltage-gated sodium channels
  • small fiber neuropathy (SFN) and, 202
  • subtype-specific, 150
  • use-dependent, 195–196
• Sodium channels
  • as molecular batteries, 11–14
  • peripheral, 17, 18t
• as holy grail, 16–18, 19f, 20
• Squid giant axon, 11, 104
• Stys, Peter, 164
• Superior cervical ganglion (SCG) neurons, 74. See also under L858H mutation; Na_V1.8
  • coexpression of L858H and Na_V1.8 channels rescues electrogenic properties in, 97f
  • depolarization and, 74, 90, 92f, 93, 96, 98
  • expressing WT Na_V1.7, 90, 93, 94f, 96, 98, 99
• Sutton, Willie, 155
• Sympathetic ganglia, 85
• Synaptic transmission, 103

• Target, molecular, 216
• Tate, Simon, xiii, 17
• Tetrodotoxin (TTX), 66
• Tetrodotoxin resistant (TTX-R) currents, 128
• Tetrodotoxin resistant (TTX-R) human Na_V1.7 (hNa_V1.7r), 36, 99, 265–266
• Tetrodotoxin sensitive (TTX-S) channels, 110, 111, 113, 127, 128, 225
• Tetrodotoxin sensitive (TTX-S) current in small DRG neurons, Na_V1.7 contribution to, 35, 110–111, 113, 115f, 116, 128
• Tetrodotoxin sensitive (TTX-S) currents, 63
• Tetrodotoxin sensitivity (TTX-S), 35, 36
• Thermodynamic mutant cycle analysis, 254, 264
• Threshold channel, Na_V1.7 as a, 53, 64, 65, 68, 72, 116, 117f, 118f, 122f
• Transfection, 36, 94f, 104–105. See also HEK 293 cell transfection
  • effect of KB-R7943 on WT-transfected neurons with no mutant channels, 200
  • of hNa_V1.7 channels, 36, 46
  • with I228M variant Na_V1.7 channels, 171
  • with mutant N1768D channels, 209f
  • with Na_V1.7 channels, 171, 257
  • with S241T mutant channels, 250
  • of SCG neurons, 99
  • with WT channels, 200, 257
• Translational research, 160, 215
• Trigeminal neuralgia, 247, 251, 289
• TTX-resistant human Na_V1.7 cDNA. See hNa_V1.7_R
• Tuesday Night Fights, 160

• University of Aarhus, 136
• University College London, xiii
• University of Maastricht, 159

• V400 and S241 show atomic proximity in Na_V1.7 channel, 252, 253f
• V400M (mutation), 248
  • carbamazepine (CBZ) and, 75, 76, 248, 249, 251, 252, 255, 260, 264, 265, 276, 284
  • IEM and, 75, 76, 226t, 228, 231, 231f, 233f, 235, 237, 237f, 251, 264, 276, 284
  • iPSC-SNs and, 228, 231, 231f, 233f
  • S241T mutation and, 231, 249–250, 252, 253f, 254, 260, 264, 265, 284
• are energetically coupled during activation, 250, 254, 255, 260, 264, 276, 284
  • V991L. See M932L/V991L
  • Vasylyev, Dymtro, xiii, 166
  • Visual Analogue Pain Scale (VAS), 178
  • Voltage clamp, 32, 46, 47, 110–112, 128, 178, 183, 185, 241, 266

• Wall, Patrick, xiii, 12
• “War Room,” 155–157, 160, 169
• Watson, James D., 27
• Whole genome sequencing, 206, 210
• Wild-type (WT) Na_V1.7, 32, 71, 258f
  • DRG neurons expressing, 49, 70f, 90, 91f, 93, 94f, 98, 99, 109, 110, 120f, 123f, 178
  • dynamic-clamp analysis of WT Na_V1.7 and erythromelalgia mutant channel L858H, 109–129
  • F1449V and, 49, 51, 52f
  • kinetic model of WT Na_V1.7, 112–115f
  • L858H and, 91f, 93, 94f, 98, 99, 109
  • SCG neurons expressing, 90, 93, 94f, 96, 98, 99
• Wild-type (WT) Na_V1.7 channel model, 112
• Wilkens, Maurice, 27
• Window current, 41, 52, 86, 96, 119, 170, 201
• Wood, John, xiii, 17, 289
• Woods Hole, Massachusetts, 155–156

• Yang, Yang, xiii, 19f, 75, 248–250, 271, 273, 276
• Yang, Yong, 30, 31, 35–36, 39, 157, 158, 160, 161
• Young, J. Z., xiii, 10

• “Zebras,” as a term to describe rare diseases, 163