The BDNF/TrkB Signaling Pathway Is Involved in Heat Hyperalgesia Mediated by Cdk5 in Rats

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From: PLoS ONE(Vol. 9, Issue 1)
Publisher: Public Library of Science
Document Type: Article
Length: 5,061 words
Lexile Measure: 1610L

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Author(s): Hong-Hai Zhang 1,2, Xiao-Qin Zhang 1, Qing-Sheng Xue 1, Yan-Luo 1, Jin-Lu Huang 3, Su Zhang 1, Hai-Jun Shao 1, Han Lu 1, Wen-Yuan Wang 1, Bu-Wei Yu 1,*

Introduction

Cyclin-dependent kinase 5 (Cdk5), one of the cyclin-dependent kinases (Cdks), plays a key role in heat hyperalgesia induced by inflammation [1]-[8]. Cdk5 was shown to mediate carrageenan-induced heat hyperalgesia by phosphorylating vanilloid receptor 1 (VR1) of dorsal root ganglion (DRG) in mice [2], [3]. Recent evidence demonstrated that Cdk5 was involved in CFA-induced heat hyperalgesia by controlling TRPV1 (transient receptor potential channel) membrane trafficking in rats [4]. We previously found that increased synaptophysin protein, an important presynaptic vesicle membrane protein that functions in the release of neurotransmitters, was involved in CFA-induced heat hyperalgesia mediated by Cdk5 in rats, suggesting that Cdk5 may control heat hyperalgesia induced by inflammation via regulating the release of neurotransmitters [7]. However, the mechanism by which Cdk5 mediates inflammation-induced heat hyperalgesia has not been explored in detail [8].

A growing body of evidence has indicated that the BDNF-TrkB signaling pathway plays a critical role in heat hyperalgesia of inflammatory pain [9], [10]. BDNF is synthesized in the primary sensory neurons and transported to the central terminals of the primary afferents in the spinal dorsal horn, where it is involved in modulating pain sensitization caused by different pain stimuli [11]. BDNF synthesis is significantly increased in different populations of DRG neurons during inflammatory and neuropathic pain, and TrkB protein levels were also remarkably increased during these processes [12], [13]. Furthermore, spinal intrathecal administration of BDNF-scavenging protein TrkB-IgG or K252a significantly attenuates nociceptive behavioral responses induced by inflammation [13], [14]. However, increased TrkB protein level in the spinal dorsal horn only persisted for several days post-inflammation treatment, indicating that the BDNF-TrkB pathway may function during the early phase of inflammatory pain [15].

Recent studies demonstrated that Cdk5 and its activator p35 is involved in the development of hippocampal neurons of mice by close interactions with TrkB [16]. Namely, in vitro administration of roscovitine significantly abolished the increase in surface TrkB protein level induced by glycine stimulation. TrkB surface recruitment was remarkably abrogated in hippocampal neurons in Cdk5 or p35 knockdown mice. Another study showed that activated Cdk5 increased the percentage of TrkB on the surface of hippocampal neurons in mice [17]. Given the accumulating evidence, we hypothesize that the BDNF-TrkB signaling cascade may be involved in the inflammation-induced heat hyperalgesia mediated by Cdk5 in the spinal cord in rats. Here we examine the effects of administration of the Cdk5 inhibitor roscovitine on heat hyperalgesia induced by CFA in regards to BDNF synthesis and transport, and TrkB protein expression.

Materials and Methods

Animals and experimental design

A total of 141 adult male Sprague-Dawley rats (200-250 g) were used in this study. All procedures were approved by the Committee of Animal Use for Research and Education of Shanghai JiaoTong University School of Medicine, and were in accordance with the guidelines established by the Ethical Issues of the International Association...

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Gale Document Number: GALE|A478855429