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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Wang, Y; Scarneo, SA; Kim, SH; Zhang, X; Chen, J; Yang, KW; Hughes, P; Haystead, T; Nackley, AG

Published Date

  • June 1, 2022

Published In

Volume / Issue

  • 163 / 6

Start / End Page

  • 1091 - 1101

PubMed ID

  • 34995041

Pubmed Central ID

  • PMC9001751

Electronic International Standard Serial Number (EISSN)

  • 1872-6623

Digital Object Identifier (DOI)

  • 10.1097/j.pain.0000000000002511

Language

  • eng

Conference Location

  • United States