Expression of ectopic heat shock protein 90 in male and female primary afferent nociceptors regulates inflammatory pain.
Abstract
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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https://hdl.handle.net/10161/24314Published Version (Please cite this version)
10.1097/j.pain.0000000000002511Publication Info
Wang, Yaomin; Scarneo, Scott A; Kim, Shin Hyung; Zhang, Xin; Chen, Jiegen; Yang, Kelly
W; ... Nackley, Andrea G (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 https://hdl.handle.net/10161/24314.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
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.
&
Andrea Gail Nackley
Associate Professor in Anesthesiology
Pain is a multidimensional sensory and emotional experience that is important for
our survival, but once pain becomes chronic it is no longer beneficial and, instead,
becomes a disorder in and of itself. Chronic pain remains one of our nation’s most
significant healthcare problems due to a limited understanding of the underlying genetic
and environmental factors. There are three main objectives of our lab’s research in
this area:
To determine
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 ‘ove
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