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.
Subscribe

Logo for

Science 333 (6048): 1462-1466

Copyright © 2011 by the American Association for the Advancement of Science

HCN2 Ion Channels Play a Central Role in Inflammatory and Neuropathic Pain

Edward C. Emery,1,* Gareth T. Young,1,* Esther M. Berrocoso,1,2 Lubin Chen,1 Peter A. McNaughton1,{dagger}

Abstract: The rate of action potential firing in nociceptors is a major determinant of the intensity of pain. Possible modulators of action potential firing include the HCN ion channels, which generate an inward current, Ih, after hyperpolarization of the membrane. We found that genetic deletion of HCN2 removed the cyclic adenosine monophosphate (cAMP)–sensitive component of Ih and abolished action potential firing caused by an elevation of cAMP in nociceptors. Mice in which HCN2 was specifically deleted in nociceptors expressing NaV1.8 had normal pain thresholds, but inflammation did not cause hyperalgesia to heat stimuli. After a nerve lesion, these mice showed no neuropathic pain in response to thermal or mechanical stimuli. Neuropathic pain is therefore initiated by HCN2-driven action potential firing in NaV1.8-expressing nociceptors.

1 Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK.
2 Department of Neuroscience, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), School of Medicine, University of Cádiz, 11003 Cádiz, Spain.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: pam42{at}cam.ac.uk

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
HCN1 Channels as Targets for Anesthetic and Nonanesthetic Propofol Analogs in the Amelioration of Mechanical and Thermal Hyperalgesia in a Mouse Model of Neuropathic Pain.
G. R. Tibbs, T. J. Rowley, R. L. Sanford, K. F. Herold, A. Proekt, H. C. Hemmings Jr., O. S. Andersen, P. A. Goldstein, and P. D. Flood (2013)
J. Pharmacol. Exp. Ther. 345, 363-373
   Abstract »    Full Text »    PDF »
New Therapeutic Targets in Cardiology: Heart Failure and Arrhythmia: HCN Channels.
F. Roubille and J.-C. Tardif (2013)
Circulation 127, 1986-1996
   Full Text »    PDF »
HCN channels: Function and clinical implications.
E. E. Benarroch (2013)
Neurology 80, 304-310
   Abstract »    Full Text »    PDF »
Role of Ih in the firing pattern of mammalian cold thermoreceptor endings.
P. Orio, A. Parra, R. Madrid, O. Gonzalez, C. Belmonte, and F. Viana (2012)
J Neurophysiol 108, 3009-3023
   Abstract »    Full Text »    PDF »
Sensory Neuron Downregulation of the Kv9.1 Potassium Channel Subunit Mediates Neuropathic Pain following Nerve Injury.
C. Tsantoulas, L. Zhu, Y. Shaifta, J. Grist, J. P. T. Ward, R. Raouf, G. J. Michael, and S. B. McMahon (2012)
J. Neurosci. 32, 17502-17513
   Abstract »    Full Text »    PDF »
HCN1 and HCN2 Proteins Are Expressed in Cochlear Hair Cells: HCN1 CAN FORM A TERNARY COMPLEX WITH PROTOCADHERIN 15 CD3 AND F-ACTIN-BINDING FILAMIN A OR CAN INTERACT WITH HCN2.
N. A. Ramakrishnan, M. J. Drescher, K. M. Khan, J. S. Hatfield, and D. G. Drescher (2012)
J. Biol. Chem. 287, 37628-37646
   Abstract »    Full Text »    PDF »
Sensory and Signaling Mechanisms of Bradykinin, Eicosanoids, Platelet-Activating Factor, and Nitric Oxide in Peripheral Nociceptors.
G. Petho and P. W. Reeh (2012)
Physiol Rev 92, 1699-1775
   Abstract »    Full Text »    PDF »
Expression and properties of hyperpolarization-activated current in rat dorsal root ganglion neurons with known sensory function.
L. L. Gao, S. McMullan, L. Djouhri, C. Acosta, A. A. Harper, and S. N. Lawson (2012)
J. Physiol. 590, 4691-4705
   Abstract »    Full Text »    PDF »
Chronic pain as a manifestation of potassium channel-complex autoimmunity.
C. J. Klein, V. A. Lennon, P. A. Aston, A. McKeon, and S. J. Pittock (2012)
Neurology 79, 1136-1144
   Abstract »    Full Text »    PDF »
Spike Resonance Properties in Hippocampal O-LM Cells Are Dependent on Refractory Dynamics.
T. J. Kispersky, F. R. Fernandez, M. N. Economo, and J. A. White (2012)
J. Neurosci. 32, 3637-3651
   Abstract »    Full Text »    PDF »
M channel enhancers and physiological M channel block.
J. E. Linley, L. Pettinger, D. Huang, and N. Gamper (2012)
J. Physiol. 590, 793-807
   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