Neuronal hyperpolarization-activated pacemaker channels drive neuropathic pain

被引:269
作者
Chaplan, SR [1 ]
Guo, HQ [1 ]
Lee, DH [1 ]
Luo, L [1 ]
Liu, CL [1 ]
Kuei, C [1 ]
Velumian, AA [1 ]
Butler, MP [1 ]
Brown, SM [1 ]
Dubin, AE [1 ]
机构
[1] Johnson & Johnson Pharmaceut Res & Dev, Neusci, San Diego, CA 92121 USA
关键词
neuropathic pain; ectopic discharge; dorsal root ganglion; HCN channel; pacemaker channel; spinal nerve ligation; I-h;
D O I
10.1523/JNEUROSCI.23-04-01169.2003
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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.
引用
收藏
页码:1169 / 1178
页数:10
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