Neuronal hyperpolarization-activated pacemaker channels drive neuropathic pain.

Abstract

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 Abeta and Adelta 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.

• Authors: Sandra R Chaplan, Hong-Qing Guo, Doo Hyun Lee, Lin Luo, Changlu Liu, Chester Kuei, Alexander A Velumian, Matthew P Butler, Sean M Brown, Adrienne E Dubin
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 23 Issue 4 Pg. 1169-78 (Feb 15 2003) ISSN: 1529-2401 [Electronic] United States
• PMID: 12598605 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclic Nucleotide-Gated Cation Channels
• HCN1 protein, human
• HCN3 protein, human
• Hcn1 protein, rat
• Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
• Ion Channels
• Nerve Tissue Proteins
• Potassium Channels
• Pyrimidines
• RNA, Messenger
• ICI D2788

Topics

• Action Potentials
• Animals
• Cell Line
• Cell Membrane (chemistry)
• Cells, Cultured
• Cyclic Nucleotide-Gated Cation Channels
• Electric Conductivity
• Ganglia, Spinal (cytology, drug effects, physiopathology)
• Humans
• Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
• Ion Channels (antagonists & inhibitors, genetics, physiology)
• Kinetics
• Male
• Nerve Tissue Proteins
• Neuralgia (etiology, genetics, physiopathology)
• Neurons (physiology, ultrastructure)
• Potassium Channels (physiology)
• Pyrimidines (pharmacology)
• RNA, Messenger (analysis)
• Rats
• Rats, Sprague-Dawley