 |
||||
|
||||
|
||||
|
||||
Previous Article | Next Article
The Journal of Neuroscience, February 15, 2003, 23(4):1169
Neuronal Hyperpolarization-Activated Pacemaker Channels Drive Neuropathic Pain
Sandra R. Chaplan, Hong-Qing Guo, Doo Hyun Lee, Lin Luo, Changlu Liu, Chester Kuei, Alexander A. Velumian, Matthew P. Butler, Sean M. Brown, and Adrienne E. Dubin Neuroscience, Johnson & Johnson Pharmaceutical Research and Development, San Diego, California 92121
Neuropathic pain is a common and often incapacitating clinical problem for which little useful therapy is presently available. Painful peripheral neuropathies can have many etiologies, among which are trauma, viral infections, exposure to radiation or chemotherapy, and metabolic or autoimmune diseases. Sufferers generally experience both pain at rest and exaggerated, painful sensitivity to light touch. Spontaneous firing of injured nerves is believed to play a critical role in the induction and maintenance of neuropathic pain syndromes. Using a well characterized nerve ligation model in the rat, we demonstrate that hyperpolarization-activated, cyclic nucleotide-modulated (HCN) "pacemaker" channels play a previously unrecognized role in both touch-related pain and spontaneous neuronal discharge originating in the damaged dorsal root ganglion. HCN channels, particularly HCN1, are abundantly expressed in rat primary afferent somata. Nerve injury markedly increases pacemaker currents in large-diameter dorsal root ganglion neurons and results in pacemaker-driven spontaneous action potentials in the ligated nerve. Pharmacological blockade of HCN activity using the specific inhibitor ZD7288 reverses abnormal hypersensitivity to light touch and decreases the firing frequency of ectopic discharges originating in A
and A
fibers by 90 and 40%, respectively, without conduction blockade. These findings suggest novel insights into the molecular basis of pain and the possibility of new, specific, effective pharmacological therapies.
Key words: neuropathic pain; ectopic discharge; dorsal root ganglion; HCN channel; pacemaker channel; spinal nerve ligation; Ih
Copyright © 2003 Society for Neuroscience 0270-6474/03/2341169-10$05.00/0
This article has been cited by other articles:
K. A. Alier, J. A. Endicott, P. L. Stemkowski, N. Cenac, L. Cellars, K. Chapman, P. Andrade-Gordon, N. Vergnolle, and P. A. Smith
Intrathecal Administration of Proteinase-Activated Receptor-2 Agonists Produces Hyperalgesia by Exciting the Cell Bodies of Primary Sensory Neurons
J. Pharmacol. Exp. Ther., January 1, 2008; 324(1): 224 - 233.
[Abstract] [Full Text] [PDF]
F. W. Hopf, M. Martin, B. T. Chen, M. S. Bowers, M. M. Mohamedi, and A. Bonci
Withdrawal From Intermittent Ethanol Exposure Increases Probability of Burst Firing in VTA Neurons In Vitro
J Neurophysiol, October 1, 2007; 98(4): 2297 - 2310.
[Abstract] [Full Text] [PDF]
S.-W. Ying, F. Jia, S. Y. Abbas, F. Hofmann, A. Ludwig, and P. A. Goldstein
Dendritic HCN2 Channels Constrain Glutamate-Driven Excitability in Reticular Thalamic Neurons
J. Neurosci., August 8, 2007; 27(32): 8719 - 8732.
[Abstract] [Full Text] [PDF]
D. V. Vasilyev, Q. Shan, Y. Lee, S. C. Mayer, M. R. Bowlby, B. W. Strassle, E. J. Kaftan, K. E. Rogers, and J. Dunlop
Direct Inhibition of Ih by Analgesic Loperamide in Rat DRG Neurons
J Neurophysiol, May 1, 2007; 97(5): 3713 - 3721.
[Abstract] [Full Text] [PDF]
K. J. Fogle, A. K. Lyashchenko, H. K. Turbendian, and G. R. Tibbs
HCN Pacemaker Channel Activation Is Controlled by Acidic Lipids Downstream of Diacylglycerol Kinase and Phospholipase A2
J. Neurosci., March 14, 2007; 27(11): 2802 - 2814.
[Abstract] [Full Text] [PDF]
W. Xie, J. A. Strong, H. Li, and J.-M. Zhang
Sympathetic Sprouting Near Sensory Neurons After Nerve Injury Occurs Preferentially on Spontaneously Active Cells and Is Reduced by Early Nerve Block
J Neurophysiol, January 1, 2007; 97(1): 492 - 502.
[Abstract] [Full Text] [PDF]
N. P. Poolos, J. B. Bullis, and M. K. Roth
Modulation of h-channels in hippocampal pyramidal neurons by p38 mitogen-activated protein kinase.
J. Neurosci., July 26, 2006; 26(30): 7995 - 8003.
[Abstract] [Full Text] [PDF]
T. Okamoto, M. T. Harnett, and H. Morikawa
Hyperpolarization-Activated Cation Current (Ih) Is an Ethanol Target in Midbrain Dopamine Neurons of Mice
J Neurophysiol, February 1, 2006; 95(2): 619 - 626.
[Abstract] [Full Text] [PDF]
P. Mistrik, R. Mader, S. Michalakis, M. Weidinger, A. Pfeifer, and M. Biel
The Murine HCN3 Gene Encodes a Hyperpolarization-activated Cation Channel with Slow Kinetics and Unique Response to Cyclic Nucleotides
J. Biol. Chem., July 22, 2005; 280(29): 27056 - 27061.
[Abstract] [Full Text] [PDF]
B. Santoro, B. J. Wainger, and S. A. Siegelbaum
Regulation of HCN Channel Surface Expression by a Novel C-Terminal Protein-Protein Interaction
J. Neurosci., November 24, 2004; 24(47): 10750 - 10762.
[Abstract] [Full Text] [PDF]
M. R. Watters, P. W. Poff, B. T. Shiramizu, P. S. Holck, K. M.S. Fast, C. M. Shikuma, and V. G. Valcour
Symptomatic distal sensory polyneuropathy in HIV after age 50
Neurology, April 27, 2004; 62(8): 1378 - 1383.
[Abstract] [Full Text] [PDF]
V. Macri and E. A. Accili
Structural Elements of Instantaneous and Slow Gating in Hyperpolarization-activated Cyclic Nucleotide-gated Channels
J. Biol. Chem., April 16, 2004; 279(16): 16832 - 16846.
[Abstract] [Full Text] [PDF]
Y. Komagiri and N. Kitamura
Effect of Intracellular Dialysis of ATP on the Hyperpolarization-Activated Cation Current in Rat Dorsal Root Ganglion Neurons
J Neurophysiol, October 1, 2003; 90(4): 2115 - 2122.
[Abstract] [Full Text] [PDF]
|
|
|
|
 |
|