Journal article
Mechanisms Mediating High-Molecular-Weight Hyaluronan-Induced Antihyperalgesia
The Journal of neuroscience, Vol.40(34), pp.6477-6488
08/19/2020
DOI: 10.1523/JNEUROSCI.0166-20.2020
PMID: 32665406
Abstract
We evaluated the mechanism by which high-molecular-weight hyaluronan (HMWH) attenuates nociceptor sensitization, in the setting of inflammation. HMWH attenuated mechanical hyperalgesia induced by the inflammatory mediator prostaglandin E2 (PGE(2)) in male and female rats. Intrathecal administration of an oligodeoxynucleotide antisense (AS-ODN) to mRNA for cluster of differentiation 44 (CD44), the cognate hyaluronan receptor, and intradermal administration of A5G27, a CD44 receptor antagonist, both attenuated antihyperalgesia induced by HMWH. In male rats, HIVIWH also signals via Toll-like receptor 4 (TLR4), and AS-ODN for TLR4 mRNA administered intrathecally, attenuated HMWH-induced antihyperalgesia. Since HMWH signaling is dependent on CD44 clustering in lipid rafts, we pretreated animals with methyl-beta-cyclodextrin (M beta CD), which disrupts lipid rafts. M beta CD markedly attenuated HMWH-induced antihyperalgesia. Inhibitors for components of intra-cellular signaling pathways activated by CD44, including phospholipase C and phosphoinositide 3-kinase (PI3K), also attenuated HMWH-induced antihyperalgesia. Furthermore, in vitro application of HMWH attenuated PGE(2)-induced sensitization of tetrodotoxin-resistant sodium current, in small-diameter dorsal root ganglion neurons, an effect that was attenuated by a PI3K inhibitor. Our results indicate a central role of CD44 signaling in HMWH-induced antihyperalgesia and suggest novel therapeutic targets, downstream of CD44, for the treatment of pain generated by nociceptor sensitization.
Details
- Title: Subtitle
- Mechanisms Mediating High-Molecular-Weight Hyaluronan-Induced Antihyperalgesia
- Creators
- Ivan J. M. Bonet - University of California, San FranciscoDioneia Araldi - University of California, San FranciscoEugen Khomula - University of California, San FranciscoOliver Bogen - University of California, San FranciscoPaul G. Green - University of California, San FranciscoJon D. Levine - University of California, San Francisco
- Resource Type
- Journal article
- Publication Details
- The Journal of neuroscience, Vol.40(34), pp.6477-6488
- DOI
- 10.1523/JNEUROSCI.0166-20.2020
- PMID
- 32665406
- NLM abbreviation
- J Neurosci
- ISSN
- 0270-6474
- eISSN
- 1529-2401
- Publisher
- Soc Neuroscience
- Number of pages
- 12
- Grant note
- R01AR075334 / National Institute of Arthritis and Musculoskeletal and Skin Diseases; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS) AR-075334 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 08/19/2020
- Academic Unit
- Neuroscience and Pharmacology
- Record Identifier
- 9985178662802771
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