Neural circuits for pain: Recent advances and current views

Pain Mechanisms: A New Theory: A gate control system modulates sensory input from the skin before it evokes pain perception and response.

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Impaired nociception and pain sensation in mice lacking the capsaicin receptor

Caterina, M. J., Leffler, A., Malmberg, A. B., Martin, W. J., Trafton, J., Petersen-Zeitz, K. R., Koltzenburg, M., Basbaum, A. I., & Julius, D. (2000) · Science · doi:10.1126/science.288.5464.306 · Cited by 3,544

Piezo1 and Piezo2 Are Essential Components of Distinct Mechanically Activated Cation Channels

Coste, B., Mathur, J., Schmidt, M., Earley, T. J., Ranade, S., Petrus, M. J., Dubin, A. E., & Patapoutian, A. (2010) · Science · doi:10.1126/science.1193270 · Cited by 3,316

Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencing

Usoskin, D., Furlan, A., Islam, S., Abdo, H., Lönnerberg, P., Lou, D., Hjerling-Leffler, J., Haeggström, J., Kharchenko, O., Kharchenko, P. V., et al. (2015) · Nature Neuroscience · doi:10.1038/nn.3881 · Cited by 2,136

BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain

Coull, J. A. M., Beggs, S., Boudreau, D., Boivin, D., Tsuda, M., Inoue, K., Gravel, C., Salter, M. W., & De Koninck, Y. (2005) · Nature · doi:10.1038/nature04223 · Cited by 1,965

The Sensory Neurons of Touch

Abraira, V. E., & Ginty, D. D. (2013) · Neuron · doi:10.1016/j.neuron.2013.07.051 · Cited by 1,648

Neuronal circuitry for pain processing in the dorsal horn

Todd, A. J. (2010) · Nature Reviews Neuroscience · doi:10.1038/nrn2947 · Cited by 1,475

Different immune cells mediate mechanical pain hypersensitivity in male and female mice

Sorge, R. E., Mapplebeck, J. C. S., Rosen, S., Beggs, S., Taves, S., Alexander, J. K., Martin, L. J., Austin, J.-S., Sotocinal, S. G., Chen, D., et al. (2015) · Nature Neuroscience · doi:10.1038/nn.4053 · Cited by 1,442

Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain

Coull, J. A. M., Boudreau, D., Bachand, K., Prescott, S. A., Nault, F., Sík, A., Koninck, P. D., & Koninck, Y. D. (2003) · Nature · doi:10.1038/nature01868 · Cited by 1,118

Sex differences in pain and pain inhibition: multiple explanations of a controversial phenomenon

Mogil, J. S. (2012) · Nature Reviews Neuroscience · doi:10.1038/nrn3360 · Cited by 1,065

Allodynia and hyperalgesia in neuropathic pain: clinical manifestations and mechanisms

Jensen, T. S., & Finnerup, N. B. (2014) · The Lancet Neurology · doi:10.1016/s1474-4422(14)70102-4 · Cited by 976

Piezo2 is the major transducer of mechanical forces for touch sensation in mice

Ranade, S. S., Woo, S.-H., Dubin, A. E., Moshourab, R. A., Wetzel, C., Petrus, M., Mathur, J., Bégay, V., Coste, B., Mainquist, J., et al. (2014) · Nature · doi:10.1038/nature13980 · Cited by 928

Soft, stretchable, fully implantable miniaturized optoelectronic systems for wireless optogenetics

Park, S. I., Brenner, D. S., Shin, G., Morgan, C. D., Copits, B. A., Chung, H. U., Pullen, M. Y., Noh, K. N., Davidson, S., Oh, S. J., et al. (2015) · Nature Biotechnology · doi:10.1038/nbt.3415 · Cited by 794

The Functional Organization of Cutaneous Low-Threshold Mechanosensory Neurons

Li, L., Rutlin, M., Abraira, V. E., Cassidy, C., Kus, L., Gong, S., Jankowski, M. P., Luo, W., Heintz, N., Koerber, H. R., et al. (2011) · Cell · doi:10.1016/j.cell.2011.11.027 · Cited by 774

Distinct subsets of unmyelinated primary sensory fibers mediate behavioral responses to noxious thermal and mechanical stimuli

Cavanaugh, D. J., Lee, H., Lo, L., Shields, S. D., Zylka, M. J., Basbaum, A. I., & Anderson, D. J. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0901507106 · Cited by 707

Nociceptor-specific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain

Nassar, M. A., Stirling, L. C., Forlani, G., Baker, M. D., Matthews, E. A., Dickenson, A. H., & Wood, J. N. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0404915101 · Cited by 681

Membrane protein sequestering by ionic protein–lipid interactions

van den Bogaart, G., Meyenberg, K., Risselada, H. J., Amin, H., Willig, K. I., Hubrich, B. E., Dier, M., Hell, S. W., Grubmüller, H., Diederichsen, U., et al. (2011) · Nature · doi:10.1038/nature10545 · Cited by 617

The gentle touch receptors of mammalian skin

Zimmerman, A., Bai, L., & Ginty, D. D. (2014) · Science · doi:10.1126/science.1254229 · Cited by 617

Epidermal Merkel cells are mechanosensory cells that tune mammalian touch receptors

Maksimovic, S., Nakatani, M., Baba, Y., Nelson, A. M., Marshall, K. L., Wellnitz, S. A., Firozi, P., Woo, S.-H., Ranade, S., Patapoutian, A., et al. (2014) · Nature · doi:10.1038/nature13250 · Cited by 597

TRPM3 Is a Nociceptor Channel Involved in the Detection of Noxious Heat

Vriens, J., Owsianik, G., Hofmann, T., Philipp, S. E., Stab, J., Chen, X., Benoit, M., Xue, F., Janssens, A., Kerselaers, S., et al. (2011) · Neuron · doi:10.1016/j.neuron.2011.02.051 · Cited by 583

Identification of Spinal Circuits Transmitting and Gating Mechanical Pain

Duan, B., Cheng, L., Bourane, S., Britz, O., Padilla, C., Garcia-Campmany, L., Krashes, M., Knowlton, W., Velasquez, T., Ren, X., et al. (2014) · Cell · doi:10.1016/j.cell.2014.11.003 · Cited by 582

Injured sensory neuron–derived CSF1 induces microglial proliferation and DAP12-dependent pain

Guan, Z., Kuhn, J. A., Wang, X., Colquitt, B., Solorzano, C., Vaman, S., Guan, A. K., Evans-Reinsch, Z., Braz, J., Devor, M., et al. (2016) · Nature Neuroscience · doi:10.1038/nn.4189 · Cited by 557

Injury-induced mechanical hypersensitivity requires C-low threshold mechanoreceptors

Seal, R. P., Wang, X., Guan, Y., Raja, S. N., Woodbury, C. J., Basbaum, A. I., & Edwards, R. H. (2009) · Nature · doi:10.1038/nature08505 · Cited by 466

Somatosensory neuron types identified by high-coverage single-cell RNA-sequencing and functional heterogeneity

Li, C.-L., Li, K.-C., Wu, D., Chen, Y., Luo, H., Zhao, J.-R., Wang, S.-S., Sun, M.-M., Lu, Y.-J., Zhong, Y.-Q., et al. (2016) · Cell Research · doi:10.1038/cr.2015.149 · Cited by 460

Transmitting Pain and Itch Messages: A Contemporary View of the Spinal Cord Circuits that Generate Gate Control

Braz, J., Solorzano, C., Wang, X., & Basbaum, A. I. (2014) · Neuron · doi:10.1016/j.neuron.2014.01.018 · Cited by 447

Disinhibition Opens the Gate to Pathological Pain Signaling in Superficial Neurokinin 1 Receptor-Expressing Neurons in Rat Spinal Cord

Torsney, C., & MacDermott, A. B. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.4584-05.2006 · Cited by 407

Black mamba venom peptides target acid-sensing ion channels to abolish pain

Diochot, S., Baron, A., Salinas, M., Douguet, D., Scarzello, S., Dabert-Gay, A.-S., Debayle, D., Friend, V., Alloui, A., Lazdunski, M., et al. (2012) · Nature · doi:10.1038/nature11494 · Cited by 402

The calcium-activated chloride channel anoctamin 1 acts as a heat sensor in nociceptive neurons

Cho, H., Yang, Y. D., Lee, J., Lee, B., Kim, T., Jang, Y., Back, S. K., Na, H. S., Harfe, B. D., Wang, F., et al. (2012) · Nature Neuroscience · doi:10.1038/nn.3111 · Cited by 371

Fast Synaptic Inhibition in Spinal Sensory Processing and Pain Control

Zeilhofer, H. U., Wildner, H., & Yévenes, G. E. (2012) · Physiological Reviews · doi:10.1152/physrev.00043.2010 · Cited by 371

Presynaptic and Postsynaptic Amplifications of Neuropathic Pain in the Anterior Cingulate Cortex

Xu, H., Wu, L.-J., Wang, H., Zhang, X., Vadakkan, K. I., Kim, S. S., Steenland, H. W., & Zhuo, M. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.1812-08.2008 · Cited by 370

Coexistence of Two Forms of LTP in ACC Provides a Synaptic Mechanism for the Interactions between Anxiety and Chronic Pain

Koga, K., Descalzi, G., Chen, T., Ko, H.-G., Lu, J., Li, S., Son, J., Kim, T., Kwak, C., Huganir, R. L., et al. (2015) · Neuron · doi:10.1016/j.neuron.2014.12.021 · Cited by 364

P2X4R+ microglia drive neuropathic pain

Beggs, S., Trang, T., & Salter, M. W. (2012) · Nature Neuroscience · doi:10.1038/nn.3155 · Cited by 360

Painful and painless channelopathies

Bennett, D. L. H., & Woods, C. G. (2014) · The Lancet Neurology · doi:10.1016/s1474-4422(14)70024-9 · Cited by 348

Inhibition of mechanical allodynia in neuropathic pain by TLR5-mediated A-fiber blockade

Xu, Z.-Z., Kim, Y. H., Bang, S., Zhang, Y., Berta, T., Wang, F., Oh, S. B., & Ji, R.-R. (2015) · Nature Medicine · doi:10.1038/nm.3978 · Cited by 343

A heteromeric Texas coral snake toxin targets acid-sensing ion channels to produce pain

Bohlen, C. J., Chesler, A. T., Sharif-Naeini, R., Medzihradszky, K. F., Zhou, S., King, D., Sánchez, E. E., Burlingame, A. L., Basbaum, A. I., & Julius, D. (2011) · Nature · doi:10.1038/nature10607 · Cited by 336

Dorsal Horn Circuits for Persistent Mechanical Pain

Peirs, C., Williams, S.-P. G., Zhao, X., Walsh, C. E., Gedeon, J. Y., Cagle, N. E., Goldring, A. C., Hioki, H., Liu, Z., Marell, P. S., et al. (2015) · Neuron · doi:10.1016/j.neuron.2015.07.029 · Cited by 327

Dorsal Horn Parvalbumin Neurons Are Gate-Keepers of Touch-Evoked Pain after Nerve Injury

Petitjean, H., Pawlowski, S. A., Fraine, S. L., Sharif, B., Hamad, D., Fatima, T., Berg, J., Brown, C. M., Jan, L.-Y., Ribeiro-da-Silva, A., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.09.080 · Cited by 326

A feed-forward spinal cord glycinergic neural circuit gates mechanical allodynia

Lu, Y., Dong, H., Gao, Y., Gong, Y., Ren, Y., Gu, N., Zhou, S., Xia, N., Sun, Y.-Y., Ji, R.-R., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci70026 · Cited by 286

Decreased motivation during chronic pain requires long-term depression in the nucleus accumbens

Schwartz, N., Temkin, P., Jurado, S., Lim, B. K., Heifets, B. D., Polepalli, J. S., & Malenka, R. C. (2014) · Science · doi:10.1126/science.1253994 · Cited by 278

A Sensory-Labeled Line for Cold: TRPM8-Expressing Sensory Neurons Define the Cellular Basis for Cold, Cold Pain, and Cooling-Mediated Analgesia

Knowlton, W. M., Palkar, R., Lippoldt, E. K., McCoy, D. D., Baluch, F., Chen, J., & McKemy, D. D. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.1943-12.2013 · Cited by 271

Peptidergic CGRPα Primary Sensory Neurons Encode Heat and Itch and Tonically Suppress Sensitivity to Cold

McCoy, E. S., Taylor-Blake, B., Street, S. E., Pribisko, A. L., Zheng, J., & Zylka, M. J. (2013) · Neuron · doi:10.1016/j.neuron.2013.01.030 · Cited by 263

Transcriptional profiling at whole population and single cell levels reveals somatosensory neuron molecular diversity

Chiu, I. M., Barrett, L. B., Williams, E. K., Strochlic, D. E., Lee, S., Weyer, A. D., Lou, S., Bryman, G. S., Roberson, D. P., Ghasemlou, N., et al. (2014) · eLife · doi:10.7554/elife.04660 · Cited by 240

Somatic and vicarious pain are represented by dissociable multivariate brain patterns

Krishnan, A., Woo, C.-W., Chang, L. J., Ruzic, L., Gu, X., López-Solà, M., Jackson, P. L., Pujol, J., Fan, J., & Wager, T. D. (2016) · eLife · doi:10.7554/elife.15166 · Cited by 234

A role for Piezo2 in EPAC1-dependent mechanical allodynia

Eijkelkamp, N., Linley, J. E., Torres, J. M., Bee, L., Dickenson, A. H., Gringhuis, M., Minett, M. S., Hong, G. S., Lee, E., Oh, U., et al. (2013) · Nature Communications · doi:10.1038/ncomms2673 · Cited by 231

Pain imaging in health and disease — how far have we come?

Schweinhardt, P., & Bushnell, M. C. (2010) · Journal of Clinical Investigation · doi:10.1172/jci43498 · Cited by 222

Virally mediated optogenetic excitation and inhibition of pain in freely moving nontransgenic mice

Iyer, S. M., Montgomery, K. L., Towne, C., Lee, S. Y., Ramakrishnan, C., Deisseroth, K., & Delp, S. L. (2014) · Nature Biotechnology · doi:10.1038/nbt.2834 · Cited by 218

Forebrain GABAergic Neuron Precursors Integrate into Adult Spinal Cord and Reduce Injury-Induced Neuropathic Pain

Bráz, J. M., Sharif-Naeini, R., Vogt, D., Kriegstein, A., Alvarez-Buylla, A., Rubenstein, J. L., & Basbaum, A. I. (2012) · Neuron · doi:10.1016/j.neuron.2012.02.033 · Cited by 215

Glycine Inhibitory Dysfunction Turns Touch into Pain through PKCgamma Interneurons

Miraucourt, L. S., Dallel, R., & Voisin, D. L. (2007) · PLoS ONE · doi:10.1371/journal.pone.0001116 · Cited by 208

Keratinocytes can modulate and directly initiate nociceptive responses

Baumbauer, K. M., DeBerry, J. J., Adelman, P. C., Miller, R. H., Hachisuka, J., Lee, K. H., Ross, S. E., Koerber, H. R., Davis, B. M., & Albers, K. M. (2015) · eLife · doi:10.7554/elife.09674 · Cited by 188

Touch sense: Functional organization and molecular determinants of mechanosensitive receptors

Roudaut, Y., Lonigro, A., Coste, B., Hao, J., Delmas, P., & Crest, M. (2012) · Channels · doi:10.4161/chan.22213 · Cited by 187

Discovery of a selective Na V 1.7 inhibitor from centipede venom with analgesic efficacy exceeding morphine in rodent pain models

Yang, S., Xiao, Y., Kang, D., Liu, J., Li, Y., Undheim, E. A. B., Klint, J. K., Rong, M., Lai, R., & King, G. F. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1306285110 · Cited by 177

Pain without Nociceptors? Nav1.7-Independent Pain Mechanisms

Minett, M. S., Falk, S., Santana-Varela, S., Bogdanov, Y. D., Nassar, M. A., Heegaard, A.-M., & Wood, J. N. (2014) · Cell Reports · doi:10.1016/j.celrep.2013.12.033 · Cited by 176

The “pain matrix” in pain-free individuals

Salomons, T. V., Iannetti, G. D., Liang, M., & Wood, J. N. (2016) · JAMA Neurology · doi:10.1001/jamaneurol.2016.0653 · Cited by 170

TAFA4, a Chemokine-like Protein, Modulates Injury-Induced Mechanical and Chemical Pain Hypersensitivity in Mice

Delfini, M.-C., Mantilleri, A., Gaillard, S., Hao, J., Reynders, A., Malapert, P., Alonso, S., François, A., Barrere, C., Seal, R., et al. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.09.013 · Cited by 160

Morphological, neurochemical and electrophysiological features of parvalbumin‐expressing cells: a likely source of axo‐axonic inputs in the mouse spinal dorsal horn

Hughes, D. I., Sikander, S., Kinnon, C. M., Boyle, K. A., Watanabe, M., Callister, R. J., & Graham, B. A. (2012) · The Journal of Physiology · doi:10.1113/jphysiol.2012.235655 · Cited by 151

Selective keratinocyte stimulation is sufficient to evoke nociception in mice

Pang, Z., Sakamoto, T., Tiwari, V., Kim, Y., Yang, F., Dong, X., Güler, A. D., Guan, Y., & Caterina, M. J. (2015) · Pain · doi:10.1097/j.pain.0000000000000092 · Cited by 137

CGRPα-Expressing Sensory Neurons Respond to Stimuli that Evoke Sensations of Pain and Itch

McCoy, E. S., Taylor‐Blake, B., & Zylka, M. J. (2012) · PLoS ONE · doi:10.1371/journal.pone.0036355 · Cited by 130

miR-7a alleviates the maintenance of neuropathic pain through regulation of neuronal excitability

Sakai, A., Saitow, F., Miyake, N., Miyake, K., Shimada, T., & Suzuki, H. (2013) · Brain · doi:10.1093/brain/awt191 · Cited by 129

Optogenetic Silencing of Nav1.8-Positive Afferents Alleviates Inflammatory and Neuropathic Pain

Daou, I., Beaudry, H., Ase, A. R., Wieskopf, J. S., Ribeiro‐da‐Silva, A., Mogil, J. S., & Séguéla, P. (2016) · eNeuro · doi:10.1523/eneuro.0140-15.2016 · Cited by 127

Virus-mediated shRNA Knockdown of Nav1.3 in Rat Dorsal Root Ganglion Attenuates Nerve Injury-induced Neuropathic Pain

Samad, O. A., Tan, A. M., Cheng, X., Foster, E., Dib‐Hajj, S. D., & Waxman, S. G. (2012) · Molecular Therapy · doi:10.1038/mt.2012.169 · Cited by 117

A novel NGF mutation clarifies the molecular mechanism and extends the phenotypic spectrum of the HSAN5 neuropathy

Carvalho, O. P., Thornton, G., Hertecant, J., Houlden, H., Nicholas, A. K., Cox, J. J., Rielly, M., Al‐Gazali, L., & Woods, C. G. (2010) · Journal of Medical Genetics · doi:10.1136/jmg.2010.081455 · Cited by 100

Chloride Homeostasis Critically Regulates Synaptic NMDA Receptor Activity in Neuropathic Pain

Li, L., Chen, S.-R., Chen, H., Wen, L., Hittelman, W. N., Xie, J.-D., & Pan, H. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.04.039 · Cited by 100

Phenotyping the Function of TRPV1-Expressing Sensory Neurons by Targeted Axonal Silencing

Brenneis, C., Kistner, K., Puopolo, M., Segal, D., Roberson, D. P., Sisignano, M., Labocha, S., Ferreirós, N., Strominger, A., Cobos, E. J., et al. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.2804-12.2013 · Cited by 97

Pain treatment: a historical overview

Sabatowski, R., Schafer, D., Kasper, S., Brunsch, H., & Radbruch, L. (2004) · Current Pharmaceutical Design · doi:10.2174/1381612043452974 · Cited by 83

Nociceptive Local Field Potentials Recorded from the Human Insula Are Not Specific for Nociception

Liberati, G., Klöcker, A., Safronova, M. M., Santos, S. F., Vaz, J.-G. R., Raftopoulos, C., & Mouraux, A. (2016) · PLoS Biology · doi:10.1371/journal.pbio.1002345 · Cited by 74

A Putative Relay Circuit Providing Low-Threshold Mechanoreceptive Input to Lamina I Projection Neurons via Vertical Cells in Lamina II of the Rat Dorsal Horn

Yasaka, T., Tiong, S. Y., Polgár, E., Watanabe, M., Kumamoto, E., Riddell, J. S., & Todd, A. J. (2014) · Molecular Pain · doi:10.1186/1744-8069-10-3 · Cited by 60

Inhibition of the kinase WNK1/HSN2 ameliorates neuropathic pain by restoring GABA inhibition

Kahle, K. T., Schmouth, J.-F., Lavastre, V., Latrémolière, A., Zhang, J., Andrews, N., Omura, T., Laganière, J., Rochefort, D. L., Hince, P., et al. (2016) · Science Signaling · doi:10.1126/scisignal.aad0163 · Cited by 54

Transition from acute to chronic pain after surgery

Glare, P., Aubrey, K. R., & Myles, P. S. (2019) · The Lancet · doi:10.1016/s0140-6736(19)30352-6 · Cited by 914

Microglia in neuropathic pain: cellular and molecular mechanisms and therapeutic potential

Inoue, K., & Tsuda, M. (2018) · Nature Reviews Neuroscience · doi:10.1038/nrn.2018.2 · Cited by 908

Neuronal atlas of the dorsal horn defines its architecture and links sensory input to transcriptional cell types

Häring, M., Zeisel, A., Hochgerner, H., Rinwa, P., Jakobsson, J. E. T., Lönnerberg, P., La Manno, G., Sharma, N., Borgius, L., Kiehn, O., et al. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0141-1 · Cited by 470

A TRP channel trio mediates acute noxious heat sensing

Vandewauw, I., De Clercq, K., Mulier, M., Held, K., Pinto, S., Van Ranst, N., Segal, A., Voet, T., Vennekens, R., Zimmermann, K., et al. (2018) · Nature · doi:10.1038/nature26137 · Cited by 470

Paroxysmal sympathetic hyperactivity: the storm after acute brain injury

Meyfroidt, G., Baguley, I. J., & Menon, D. K. (2017) · The Lancet Neurology · doi:10.1016/s1474-4422(17)30259-4 · Cited by 336