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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.

SUBMITTER: Chaplan SR 

PROVIDER: S-EPMC6742242 | biostudies-literature | 2003 Feb

REPOSITORIES: biostudies-literature

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Neuronal hyperpolarization-activated pacemaker channels drive neuropathic pain.

Chaplan Sandra R SR   Guo Hong-Qing HQ   Lee Doo Hyun DH   Luo Lin L   Liu Changlu C   Kuei Chester C   Velumian Alexander A AA   Butler Matthew P MP   Brown Sean M SM   Dubin Adrienne E AE  

The Journal of neuroscience : the official journal of the Society for Neuroscience 20030201 4


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  ...[more]

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