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.

Dendritic HCN2 Channels Constrain Glutamate-Driven Excitability in Reticular Thalamic Neurons

“…The influence of I h on overall cellular excitability is dependent on at least two major factors, channel isoform and subcellular distribution (Chaplan et al, 2003;Strauss et al, 2004;Fan et al, 2005). This study focused on identifying the major HCN channel isoform underlying the generation of I h and regulation of excitability in mouse RTN neurons.…”

Governing role of primary afferent drive in increased excitation of spinal nociceptive neurons in a model of sciatic neuropathy

“…These can be at multiple sites along the axons, including distal terminals. Evidence from earlier studies has implicated multiple sites in the generation of ectopic activity, including peripheral nerve terminals (Albrecht et al, 2006;Kauppila et al, 2002;Pare et al, 2007), at the site of nerve injury (Bird et al, 2007;Coward et al, 2000;Devor et al, 1993;Novakovic et al, 1998;Omana-Zapata et al, 1997a,b;Tal and Eliav, 1996), along the nerve (Amir et al, 2005;Gold et al, 2003;Pertin et al, 2005), adjacent nerves (Sotgiu et al, 2006), and in the dorsal root ganglia (Amir et al, 1999;Chaplan et al, 2003;Craner et al, 2002;Liu et al, 2000bLiu et al, , 2002Michaelis et al, 2000;Na et al, 2000;Novakovic et al, 1998;Omana-Zapata et al, 1997a,b;Study and Kral, 1996;Xie et al, 1995).…”

HCN3 Contributes to the Ventricular Action Potential Waveform in the Murine Heart

“…So far, only three groups succeeded in expressing HCN3 in heterologous systems. [21][22][23] Moreover, unlike for HCN1, HCN2, and HCN4, a murine knockout model is not yet available for this channel. We became interested in HCN3 because our previous work indicated that this channel is present in murine ventricle, suggesting that it may also be relevant for cardiac function.…”