Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 321 (5889): 702-705

Copyright © 2008 by the American Association for the Advancement of Science

The Cell and Molecular Basis of Mechanical, Cold, and Inflammatory Pain

Bjarke Abrahamsen,1 Jing Zhao,1 Curtis O. Asante,2 Cruz Miguel Cendan,1 Steve Marsh,2 Juan Pedro Martinez-Barbera,3 Mohammed A. Nassar,1 Anthony H. Dickenson,2 John N. Wood1*

Abstract: Peripheral pain pathways are activated by a range of stimuli. We used diphtheria toxin to kill all mouse postmitotic sensory neurons expressing the sodium channel Nav1.8. Mice showed normal motor activity and low-threshold mechanical and acute noxious heat responses but did not respond to noxious mechanical pressure or cold. They also showed a loss of enhanced pain responses and spontaneous pain behavior upon treatment with inflammatory insults. In contrast, nerve injury led to heightened pain sensitivity to thermal and mechanical stimuli indistinguishable from that seen with normal littermates. Pain behavior correlates well with central input from sensory neurons measured electrophysiologically in vivo. These data demonstrate that Nav1.8-expressing neurons are essential for mechanical, cold, and inflammatory pain but not for neuropathic pain or heat sensing.

1 Molecular Nociception Group, University College London (UCL), Gower Street, London, WC1E 6BT, UK.
2 Department of Pharmacology, UCL, Gower Street, London, WC1E 6BT, UK.
3 Neural Development Unit, UCL Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK.

* To whom correspondence should be addressed. E-mail: j.wood{at}

Spontaneous hair cell regeneration in the neonatal mouse cochlea in vivo.
B. C. Cox, R. Chai, A. Lenoir, Z. Liu, L. Zhang, D.-H. Nguyen, K. Chalasani, K. A. Steigelman, J. Fang, A. G. Cheng, et al. (2014)
Development 141, 816-829
   Abstract »    Full Text »    PDF »
Remote Optogenetic Activation and Sensitization of Pain Pathways in Freely Moving Mice.
I. Daou, A. H. Tuttle, G. Longo, J. S. Wieskopf, R. P. Bonin, A. R. Ase, J. N. Wood, Y. De Koninck, A. Ribeiro-da-Silva, J. S. Mogil, et al. (2013)
J. Neurosci. 33, 18631-18640
   Abstract »    Full Text »    PDF »
Genome-wide identification and functional analyses of microRNA signatures associated with cancer pain.
K. K. Bali, D. Selvaraj, V. P. Satagopam, J. Lu, R. Schneider, and R. Kuner (2013)
EMBO Mol Med. 5, 1740-1758
   Abstract »    Full Text »    PDF »
Cellular and Molecular Mechanisms of Dental Nociception.
G. Chung, S. J. Jung, and S. B. Oh (2013)
Journal of Dental Research 92, 948-955
   Abstract »    Full Text »    PDF »
Neuronal prostaglandin E2 receptor subtype EP3 mediates antinociception during inflammation.
G. Natura, K.-J. Bar, A. Eitner, M. K. Boettger, F. Richter, S. Hensellek, A. Ebersberger, J. Leuchtweis, T. Maruyama, G. O. Hofmann, et al. (2013)
PNAS 110, 13648-13653
   Abstract »    Full Text »    PDF »
Spinal {mu} and {delta} Opioids Inhibit Both Thermal and Mechanical Pain in Rats.
A. Normandin, P. Luccarini, J.-L. Molat, L. Gendron, and R. Dallel (2013)
J. Neurosci. 33, 11703-11714
   Abstract »    Full Text »    PDF »
A Sensory-Labeled Line for Cold: TRPM8-Expressing Sensory Neurons Define the Cellular Basis for Cold, Cold Pain, and Cooling-Mediated Analgesia.
W. M. Knowlton, R. Palkar, E. K. Lippoldt, D. D. McCoy, F. Baluch, J. Chen, and D. D. McKemy (2013)
J. Neurosci. 33, 2837-2848
   Abstract »    Full Text »    PDF »
Selective Ablation of Pillar and Deiters' Cells Severely Affects Cochlear Postnatal Development and Hearing in Mice.
M. M. Mellado Lagarde, B. C. Cox, J. Fang, R. Taylor, A. Forge, and J. Zuo (2013)
J. Neurosci. 33, 1564-1576
   Abstract »    Full Text »    PDF »
Runx1 Controls Terminal Morphology and Mechanosensitivity of VGLUT3-expressing C-Mechanoreceptors.
S. Lou, B. Duan, L. Vong, B. B. Lowell, and Q. Ma (2013)
J. Neurosci. 33, 870-882
   Abstract »    Full Text »    PDF »
Phenotyping the Function of TRPV1-Expressing Sensory Neurons by Targeted Axonal Silencing.
C. Brenneis, K. Kistner, M. Puopolo, D. Segal, D. Roberson, M. Sisignano, S. Labocha, N. Ferreiros, A. Strominger, E. J. Cobos, et al. (2013)
J. Neurosci. 33, 315-326
   Abstract »    Full Text »    PDF »
Gain-of-function Nav1.8 mutations in painful neuropathy.
C. G. Faber, G. Lauria, I. S. J. Merkies, X. Cheng, C. Han, H.-S. Ahn, A.-K. Persson, J. G. J. Hoeijmakers, M. M. Gerrits, T. Pierro, et al. (2012)
PNAS 109, 19444-19449
   Abstract »    Full Text »    PDF »
Ciguatoxins activate specific cold pain pathways to elicit burning pain from cooling.
I. Vetter, F. Touska, A. Hess, R. Hinsbey, S. Sattler, A. Lampert, M. Sergejeva, A. Sharov, L. S. Collins, M. Eberhardt, et al. (2012)
EMBO J. 31, 3795-3808
   Abstract »    Full Text »    PDF »
Neurological perspectives on voltage-gated sodium channels.
N. Eijkelkamp, J. E. Linley, M. D. Baker, M. S. Minett, R. Cregg, R. Werdehausen, F. Rugiero, and J. N. Wood (2012)
Brain 135, 2585-2612
   Abstract »    Full Text »    PDF »
Projection of Non-peptidergic Afferents to Mouse Tooth Pulp.
M.- K. Chung, S. S. Jue, and X. Dong (2012)
Journal of Dental Research 91, 777-782
   Abstract »    PDF »
In Vivo Proliferative Regeneration of Balance Hair Cells in Newborn Mice.
J. C. Burns, B. C. Cox, B. R. Thiede, J. Zuo, and J. T. Corwin (2012)
J. Neurosci. 32, 6570-6577
   Abstract »    Full Text »    PDF »
Repetitive activity slows axonal conduction velocity and concomitantly increases mechanical activation threshold in single axons of the rat cranial dura.
R. De Col, K. Messlinger, and R. W. Carr (2012)
J. Physiol. 590, 725-736
   Abstract »    Full Text »    PDF »
Fast Synaptic Inhibition in Spinal Sensory Processing and Pain Control.
H. U. Zeilhofer, H. Wildner, and G. E. Yevenes (2012)
Physiol Rev 92, 193-235
   Abstract »    Full Text »    PDF »
Hypermorphic mutation of the voltage-gated sodium channel encoding gene Scn10a causes a dramatic stimulus-dependent neurobehavioral phenotype.
A. L. Blasius, A. E. Dubin, M. J. Petrus, B.-K. Lim, A. Narezkina, J. R. Criado, D. N. Wills, Y. Xia, E. M. Y. Moresco, C. Ehlers, et al. (2011)
PNAS 108, 19413-19418
   Abstract »    Full Text »    PDF »
Presynaptic {alpha}2-GABAA Receptors in Primary Afferent Depolarization and Spinal Pain Control.
R. Witschi, P. Punnakkal, J. Paul, J.-S. Walczak, F. Cervero, J.-M. Fritschy, R. Kuner, R. Keist, U. Rudolph, and H. U. Zeilhofer (2011)
J. Neurosci. 31, 8134-8142
   Abstract »    Full Text »    PDF »
Scraping through the ice: uncovering the role of TRPM8 in cold transduction.
D. D. McCoy, W. M. Knowlton, and D. D. McKemy (2011)
Am J Physiol Regulatory Integrative Comp Physiol 300, R1278-R1287
   Abstract »    Full Text »    PDF »
Oxaliplatin-induced cold hypersensitivity is due to remodelling of ion channel expression in nociceptors.
J. Descoeur, V. Pereira, A. Pizzoccaro, A. Francois, B. Ling, V. Maffre, B. Couette, J. Busserolles, C. Courteix, J. Noel, et al. (2011)
EMBO Mol Med. 3, 266-278
   Abstract »    Full Text »    PDF »
A sensory subpopulation depends on vesicular glutamate transporter 2 for mechanical pain, and together with substance P, inflammatory pain.
M. C. Lagerstrom, K. Rogoz, B. Abrahamsen, A.-L. Lind, C. Olund, C. Smith, J. A. Mendez, A. Wallen-Mackenzie, J. N. Wood, and K. Kullander (2011)
PNAS 108, 5789-5794
   Abstract »    Full Text »    PDF »
Inflammatory Pain Unmasks Heterosynaptic Facilitation in Lamina I Neurokinin 1 Receptor-Expressing Neurons in Rat Spinal Cord.
C. Torsney (2011)
J. Neurosci. 31, 5158-5168
   Abstract »    Full Text »    PDF »
A spicy family tree: TRPV1 and its thermoceptive and nociceptive lineage.
D. D. McKemy (2011)
EMBO J. 30, 453-455
   Abstract »    Full Text »    PDF »
TRPV1-lineage neurons are required for thermal sensation.
S. K. Mishra, S. M. Tisel, P. Orestes, S. K. Bhangoo, and M. A. Hoon (2011)
EMBO J. 30, 582-593
   Abstract »    Full Text »    PDF »
Serotonin Receptor 5-HT2B Mediates Serotonin-Induced Mechanical Hyperalgesia.
S.-Y. Lin, W.-J. Chang, C.-S. Lin, C.-Y. Huang, H.-F. Wang, and W.-H. Sun (2011)
J. Neurosci. 31, 1410-1418
   Abstract »    Full Text »    PDF »
VGLUT2 expression in primary afferent neurons is essential for normal acute pain and injury-induced heat hypersensitivity.
G. Scherrer, S. A. Low, X. Wang, J. Zhang, H. Yamanaka, R. Urban, C. Solorzano, B. Harper, T. S. Hnasko, R. H. Edwards, et al. (2010)
PNAS 107, 22296-22301
   Abstract »    Full Text »    PDF »
Low Nociceptor GRK2 Prolongs Prostaglandin E2 Hyperalgesia via Biased cAMP Signaling to Epac/Rap1, Protein Kinase C{varepsilon}, and MEK/ERK.
N. Eijkelkamp, H. Wang, A. Garza-Carbajal, H. L. D. M. Willemen, F. J. Zwartkruis, J. N. Wood, R. Dantzer, K. W. Kelley, C. J. Heijnen, and A. Kavelaars (2010)
J. Neurosci. 30, 12806-12815
   Abstract »    Full Text »    PDF »
Small RNAs Control Sodium Channel Expression, Nociceptor Excitability, and Pain Thresholds.
J. Zhao, M.-C. Lee, A. Momin, C.-M. Cendan, S. T. Shepherd, M. D. Baker, C. Asante, L. Bee, A. Bethry, J. R. Perkins, et al. (2010)
J. Neurosci. 30, 10860-10871
   Abstract »    Full Text »    PDF »
Pain channelopathies.
R. Cregg, A. Momin, F. Rugiero, J. N. Wood, and J. Zhao (2010)
J. Physiol. 588, 1897-1904
   Abstract »    Full Text »    PDF »
Tethered-toxin debut gets cold reception.
M. D. Baker and H. Wen (2010)
J. Physiol. 588, 1663
   Full Text »    PDF »
Epigenetic Gene Silencing Underlies C-Fiber Dysfunctions in Neuropathic Pain.
H. Uchida, L. Ma, and H. Ueda (2010)
J. Neurosci. 30, 4806-4814
   Abstract »    Full Text »    PDF »
RET Signaling Is Required for Survival and Normal Function of Nonpeptidergic Nociceptors.
J. P. Golden, M. Hoshi, M. A. Nassar, H. Enomoto, J. N. Wood, J. Milbrandt, R. W. Gereau IV, E. M. Johnson Jr, and S. Jain (2010)
J. Neurosci. 30, 3983-3994
   Abstract »    Full Text »    PDF »
Aquaporin-1 Tunes Pain Perception by Interaction with Nav1.8 Na+ Channels in Dorsal Root Ganglion Neurons.
H. Zhang and A. S. Verkman (2010)
J. Biol. Chem. 285, 5896-5906
   Abstract »    Full Text »    PDF »
GRK2: A Novel Cell-Specific Regulator of Severity and Duration of Inflammatory Pain.
N. Eijkelkamp, C. J. Heijnen, H. L. D. M. Willemen, R. Deumens, E. A. J. Joosten, W. Kleibeuker, I. J. M. den Hartog, C. T. J. van Velthoven, C. Nijboer, M. A. Nassar, et al. (2010)
J. Neurosci. 30, 2138-2149
   Abstract »    Full Text »    PDF »
Excitability parameters and sensitivity to anemone toxin ATX-II in rat small diameter primary sensory neurones discriminated by Griffonia simplicifolia isolectin IB4.
A. Snape, J. F. Pittaway, and M. D. Baker (2010)
J. Physiol. 588, 125-137
   Abstract »    Full Text »    PDF »
Fat location defines sensation.
U. Oh and J. N. Wood (2009)
PNAS 106, 18435-18436
   Full Text »    PDF »
Sensory Axon-Derived Neuregulin-1 Is Required for Axoglial Signaling and Normal Sensory Function But Not for Long-Term Axon Maintenance.
F. R. Fricker, N. Zhu, C. Tsantoulas, B. Abrahamsen, M. A. Nassar, M. Thakur, A. N. Garratt, C. Birchmeier, S. B. McMahon, J. N. Wood, et al. (2009)
J. Neurosci. 29, 7667-7678
   Abstract »    Full Text »    PDF »
Distinct subsets of unmyelinated primary sensory fibers mediate behavioral responses to noxious thermal and mechanical stimuli.
D. J. Cavanaugh, H. Lee, L. Lo, S. D. Shields, M. J. Zylka, A. I. Basbaum, and D. J. Anderson (2009)
PNAS 106, 9075-9080
   Abstract »    Full Text »    PDF »
The mechano-activated K+ channels TRAAK and TREK-1 control both warm and cold perception.
J. Noel, K. Zimmermann, J. Busserolles, E. Deval, A. Alloui, S. Diochot, N. Guy, M. Borsotto, P. Reeh, A. Eschalier, et al. (2009)
EMBO J. 28, 1308-1318
   Abstract »    Full Text »    PDF »
Structural Determinants of Drugs Acting on the Nav1.8 Channel.
L. E. Browne, F. E. Blaney, S. P. Yusaf, J. J. Clare, and D. Wray (2009)
J. Biol. Chem. 284, 10523-10536
   Abstract »    Full Text »    PDF »
TRPA1 acts as a cold sensor in vitro and in vivo.
Y. Karashima, K. Talavera, W. Everaerts, A. Janssens, K. Y. Kwan, R. Vennekens, B. Nilius, and T. Voets (2009)
PNAS 106, 1273-1278
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882