title: Sensory neuron downregulation of the Kv9.1 potassium channel subunit mediates neuropathic pain following nerve injury.
abstract: Chronic neuropathic pain affects millions of individuals worldwide, is typically long-lasting, and remains poorly treated with existing therapies. Neuropathic pain arising from peripheral nerve lesions is known to be dependent on the emergence of spontaneous and evoked hyperexcitability in damaged nerves. Here, we report that the potassium channel subunit Kv9.1 is expressed in myelinated sensory neurons, but is absent from small unmyelinated neurons. Kv9.1 expression was strongly and rapidly downregulated following axotomy, with a time course that matches the development of spontaneous activity and pain hypersensitivity in animal models. Interestingly, siRNA-mediated knock-down of Kv9.1 in naive rats led to neuropathic pain behaviors. Diminished Kv9.1 function also augmented myelinated sensory neuron excitability, manifested as spontaneous firing, hyper-responsiveness to stimulation, and persistent after-discharge. Intracellular recordings from ex vivo dorsal root ganglion preparations revealed that Kv9.1 knock-down was linked to lowered firing thresholds and increased firing rates under physiologically relevant conditions of extracellular potassium accumulation during prolonged activity. Similar neurophysiological changes were detected in animals subjected to traumatic nerve injury and provide an explanation for neuropathic pain symptoms, including poorly understood conditions such as hyperpathia and paresthesias. In summary, our results demonstrate that Kv9.1 dysfunction leads to spontaneous and evoked neuronal hyperexcitability in myelinated fibers, coupled with development of neuropathic pain behaviors.
authors.affiliation: Neurorestoration Group, Wolfson Centre for Age-Related Diseases, King's College London, SE1 1UL London, United Kingdom.
authors.forename: Christoforos
authors.initials: C
authors.lastname: Tsantoulas
authors.forename: Lan
authors.initials: L
authors.lastname: Zhu
authors.forename: Yasin
authors.initials: Y
authors.lastname: Shaifta
authors.forename: John
authors.initials: J
authors.lastname: Grist
authors.forename: Jeremy P T
authors.initials: JP
authors.lastname: Ward
authors.forename: Ramin
authors.initials: R
authors.lastname: Raouf
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Michael
authors.forename: Stephen B
authors.initials: SB
authors.lastname: McMahon
mesh_terms: D000818:Animals; D019771:Axotomy; D001522:Behavior, Animal / Q000502:physiology; D015536:Down-Regulation; D006930:Hyperalgesia / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D009413:Nerve Fibers, Myelinated / Q000378:metabolism; D009437:Neuralgia / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D010147:Pain Measurement; D059348:Peripheral Nerve Injuries / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D051381:Rats; D017208:Rats, Wistar; D011984:Sensory Receptor Cells / Q000378:metabolism*
chemical_list: C503465:Kcns1 protein, rat; D024642:Potassium Channels, Voltage-Gated; D034741:RNA, Small Interfering