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Roles of A-type Potassium Channels in Primary Sensory Neurons for Bone Cancer Pain and Diclofenac Therapy in Rats

Author: DuanZuoZuo
Tutor: ZhangYuQiu
School: Fudan University
Course: Neurobiology
Keywords: A-type voltage-gated potassium channels diclofenac dorsal root ganglion (DRG) bone cancer pain
CLC: R738
Type: PhD thesis
Year: 2011
Downloads: 110
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Abstract


Roles of A-type potassium channels in primary sensory neurons for bone cancer pain and diclofenac therapy in ratsMillions of individuals will be diagnosed with cancer every year, and between 75 and 90% of patients with metastatic or advanced-stage cancer will experience significant cancer-induced pain. As such, cancer pain not only causes significant suffering but contributes to a decreased quality of life, and greatly increases health care utilization. Bone cancer pain is one of the most severe and common of the chronic pains that accompany breast, prostate, and lung cancers, and remains a clinically challenging problem to treat rapidly and effectively.In the past decade there has been progress in understanding some of the mechanisms that drive cancer pain. One largely unexplored possible mechanism that could drive cancer pain is the ion channel pathology. A-type voltage-gated K+ channels, activated transiently and inactivated rapidly, play a key role in the control of electrical properties and excitability of neurons. Recently, they are wildly implicated in pain plasticity and pathological pain. Here, we first report that the A-type K’channels in primary sensory neurons involve the neuropathy of bone cancer pain in rats, and are demonstrated to be a new target of diclofenac, a non-steroidal anti-inflammatory drug (NSAID), therapy for this distinct chronic pain.There are dynamically functional changes of the A-type K+ channels during bone cancer pain. The A-type K+ currents, mainly expressing in IB.,-positive neurons, are significantly increased on post-tumor day 14 (PTD 14), and then faded but still sustained a higher level on PTD 21. There are dynamically expressing changes of the A-type K+ channels in the dorsal root ganglion (DRG) neurons after bone cancer pain. The Kv1.4 is significantly up-regulated on PTD 14, and then down-regulated to the normal level on PTD 21. The Kv4.3 shows a sustained up-regulation, while the Kv3.4 shows a delayed down-regulation at PTD 21. The A-type K+ currents can be transiently enhanced by diclofenac in a dose-dependent manner. The evoked action potential firing in small DRG neurons is greatly increased after bone cancer, and it can be decreased significantly by diclofenac. The analgesic effect of diclofenac on bone cancer pain is reversed by peripheral administration with the A-type K’channel blockers 4-AP, pandinotoxin-Kα, and by pretreatment with Kvl.4 or Kv4.3 siRNA. Sustained diclofenac not only enhances the Kvl.4 expression in DRG neurons, but also attenuates the swelling soft tissue and tibial bone destruction. These results indicate that the A-type K+ channel modulators may provide a novel mechanism-based therapeutic strategy for bone cancer pain.

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