Expression of ectopic heat shock protein 90 in male and female primary afferent nociceptors regulates inflammatory pain.
Journal
Pain
ISSN: 1872-6623
Titre abrégé: Pain
Pays: United States
ID NLM: 7508686
Informations de publication
Date de publication:
01 06 2022
01 06 2022
Historique:
received:
06
04
2021
accepted:
24
09
2021
pubmed:
8
1
2022
medline:
18
5
2022
entrez:
7
1
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34995041
doi: 10.1097/j.pain.0000000000002511
pii: 00006396-202206000-00014
pmc: PMC9001751
mid: NIHMS1746438
doi:
Substances chimiques
Estrogens
0
HSP90 Heat-Shock Proteins
0
Freund's Adjuvant
9007-81-2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1091-1101Subventions
Organisme : NINDS NIH HHS
ID : R01 NS109541
Pays : United States
Informations de copyright
Copyright © 2021 International Association for the Study of Pain.
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