Expression of ectopic heat shock protein 90 in male and female primary afferent nociceptors regulates inflammatory pain.


Heat shock protein 90 (Hsp90) is a ubiquitously expressed integral cellular protein essential for regulating proteomic stress. Previous research has shown that Hsp90 regulates critical signaling pathways underlying chronic pain and inflammation. Recent discovery of membrane bound ectopic Hsp90 (eHsp90) on tumor cells has shown that Hsp90 induction to the plasma membrane can stabilize disease-relevant proteins. Here, we characterize eHsp90 expression in a mouse model of inflammation and demonstrate its role in nociception and pain. We found that intraplantar complete Freund adjuvant (CFA) induced robust expression of eHsp90 on the cell membranes of primary afferent nociceptors located in the L3-L5 dorsal root ganglia (DRG), bilaterally, with minimal to no expression in other tissues. Complete Freund adjuvant-induced increases in eHsp90 expression on lumbar DRG were significantly greater in females compared with males. Furthermore, exogenous Hsp90 applied to primary Pirt-GCaMP3 nociceptors induced increases in calcium responses. Responses were estrogen-dependent such that greater activity was observed in female or estrogen-primed male nociceptors compared with unprimed male nociceptors. Treatment of mice with the selective eHsp90 inhibitor HS-131 (10 nmol) significantly reversed CFA-induced mechanical pain, thermal heat pain, and hind paw edema. Notably, a higher dose (20 nmol) of HS-131 was required to achieve analgesic and anti-inflammatory effects in females. Here, we provide the first demonstration that inflammation leads to an upregulation of eHsp90 on DRG nociceptors in a sex-dependent manner and that inhibition of eHsp90 reduces nociceptor activity, pain, and inflammation. Thus, eHsp90 represents a novel therapeutic axis for the development of gender-tailored treatments for inflammatory pain.






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Publication Info

Wang, Yaomin, Scott A Scarneo, Shin Hyung Kim, Xin Zhang, Jiegen Chen, Kelly W Yang, Philip Hughes, Timothy Haystead, et al. (2021). Expression of ectopic heat shock protein 90 in male and female primary afferent nociceptors regulates inflammatory pain. Pain, Publish Ahead of Print. 10.1097/j.pain.0000000000002511 Retrieved from

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Xin Zhang

Adjunct Assistant Professor in the Department of Anesthesiology

Dr. Xin Zhang is an Adjunct Assistant Professor in the Department of Anesthesiology’s Center for Translational Pain Medicine (CTPM) at Duke University and a Professor at Nanjing Medical University in China. With a doctoral degree in the pain field and 20 years of clinical experience, he possesses a unique perspective on translating preclinical research to patient care. During his postdoctoral fellowship in Dr. Andrea Nackley's lab, Xin’s research focused on chronic primary ‘overlapping’ pain syndromes (CPPCs). He demonstrated the involvement of peripheral β2- and β3-adrenergic receptors in driving nociception and persistent pain, and the link between CPPCs and depressive disorders mediated by heightened catecholaminergic tone. Xin continues to collaborate on the development and validation of novel CPPC mouse models for in vivo discovery and screening of novel analgesic therapeutics.


Timothy Arthur James Haystead

Professor of Pharmacology and Cancer Biology

Haystead, Timothy. Using chemical biology approaches to define novel drug targets for the treatment of hypertension, obesity, cancer, inflammatory and infectious disease. 


Research Interests

The major focus of my laboratory is the discovery and development of novel small molecule inhibitors targeting purine-utilizing proteins involved in various aspects of human disease. Specific targets of interest include heat shock protein 90 (Hsp90), heat shock protein 70 (Hsp70), fatty acid synthase, acetyl CoA Carboxylase, DAPK3 (ZIPK), PIM kinases, dengue fever non-structural protein 5 (NS5) and TAK1 ( Hsp90, Hsp70 and fatty acid synthase all have cancer and antiviral therapeutic indications and we are actively developing a series molecules specifically targeting these proteins that were scratch discovered in our laboratory. We have also developed a series of novel imaging molecules based on our Hsp90 inhibitor series that have utility as both diagnostics and potentially curative strategies for a number human cancers and viral infections. Our DAPK(ZIPK) and PIMK inhibitors have shown indications as anti-hypertensive agents as well as having utility in preventing reperfusion injury after stroke. Our TAK1 inhibitor program (discovered with the Derbyshire Laboratory, Department of Chemistry, Duke) has defined a highly potent and selective inhibitor of TAK1 kinase an important protein kinases thought to mediate the actions of proinflammatory cytokines such as TNFa, IL1 and TGFb. The foundations of these programs are based on the development a chemoproteomic strategy utilizing affinity methods combined with in house organic synthetic chemistry.

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