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Cognitive impairment in a rat model of neuropathic pain

role of hippocampal microtubule stability

You, Zeronga; Zhang, Shuzhuob; Shen, Shiqiana; Yang, Jinshenga; Ding, Weihuaa,c; Yang, Liuyuea; Lim, Grewoa; Doheny, Jason T.a; Tate, Samuela; Chen, Lucya; Mao, Jianrena,*

doi: 10.1097/j.pain.0000000000001233
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Clinical evidence indicates that cognitive impairment is a common comorbid condition of chronic pain. However, the cellular basis for chronic pain–mediated cognitive impairment remains unclear. We report here that rats exhibited memory deficits after spared nerve injury (SNI). We found that levels of stable microtubule (MT) were increased in the hippocampus of the rats with memory deficits. This increase in stable MT is marked by α-tubulin hyperacetylation. Paclitaxel, a pharmacological MT stabilizer, increased the level of stable MT in the hippocampus and induced learning and memory deficits in normal rats. Furthermore, paclitaxel reduced long-term potentiation in hippocampal slices and increased stable MT (evidenced by α-tubulin hyperacetylation) levels in hippocampal neuronal cells. Intracerebroventricular infusion of nocodazole, an MT destabilizer, ameliorated memory deficits in rats with SNI-induced nociceptive behavior. Expression of HDAC6, an α-tubulin deacetylase, was reduced in the hippocampus in rats with cognitive impairment. These findings indicate that peripheral nerve injury (eg, SNI) affects the MT dynamic equilibrium, which is critical to neuronal structure and synaptic plasticity.

Peripheral nerve injury affects hippocampal microtubule dynamic equilibrium, which is critical to neuronal structure and synaptic plasticity.

aDepartment of Anesthesia, Critical Care and Pain Medicine, MGH Center for Translational Pain Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States

bBeijing Institute of Pharmacology and Toxicology, Beijing, China

cThe First Affiliated Hospital of Zhejiang University, Hangzhou, China

Corresponding author. Address: Department of Anesthesia, Critical Care and Pain Medicine, MGH Center for Translational Pain Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States. Tel.: 617-726-2338; fax: 617-724-2719. E-mail address: jmao@mgh.harvard.edu (J. Mao).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.painjournalonline.com).

Z. You, S. Zhang, and S. Shen contributed equally to this work.

Received October 02, 2017

Received in revised form February 11, 2018

Accepted February 20, 2018

© 2018 International Association for the Study of Pain
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