Highlights
- •Involvement of TLR4 in HMWH-induced anti-hyperalgesia is sexually dimorphic.
- •HMWH anti-hyperalgesia is TLR4-dependent only in male rats.
- •TLR4 dependence of HMWH anti-hyperalgesia is MyD88 mediated.
Abstract
High molecular weight hyaluronan (HMWH), a prominent component of the extracellular
matrix binds to and signals via multiple receptors, including cluster of differentiation
44 (CD44) and toll-like receptor 4 (TLR4). We tested the hypothesis that, in the setting
of inflammation, HMWH acts at TLR4 to attenuate hyperalgesia. We found that the attenuation
of prostaglandin E2 (PGE2)-induced hyperalgesia by HMWH was attenuated by a TLR4 antagonist (NBP2-26245), but
only in male and ovariectomized female rats. In this study we sought to evaluated
the role of the TLR4 signaling pathway in anti-hyperalgesia induced by HMWH in male
rats. Decreasing expression of TLR4 in nociceptors, by intrathecal administration
of an oligodeoxynucleotide (ODN) antisense to TLR4 mRNA, also attenuated HMWH-induced
anti-hyperalgesia, in male and ovariectomized female rats. Estrogen replacement in
ovariectomized females reconstituted the gonad-intact phenotype. The administration
of an inhibitor of myeloid differentiation factor 88 (MyD88), a TLR4 second messenger,
attenuated HMWH-induced anti-hyperalgesia, while an inhibitor of the MyD88-independent
TLR4 signaling pathway did not. Since it has previously been shown that HMWH-induced
anti-hyperalgesia is also mediated, in part by CD44 we evaluated the effect of the
combination of ODN antisense to TLR4 and CD44 mRNA. This treatment completely reversed
HMWH-induced anti-hyperalgesia in male rats. Our results demonstrate a sex hormone-dependent,
sexually dimorphic involvement of TLR4 in HMWH-induced anti-hyperalgesia, that is
MyD88 dependent.
Perspective
The role of TLR4 in anti-hyperalgesia induced by HMWH is a sexually dimorphic, TLR4 dependent inhibition of inflammatory hyperalgesia that
provides a novel molecular target for the treatment of inflammatory pain.
Key words
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Article info
Publication history
Published online: April 19, 2021
Accepted:
March 31,
2021
Received:
March 17,
2021
Footnotes
Disclosures: All authors report no financial interests or potential conflicts of interest. This study was funded by National Institutes of Health (NIH) grant AR075334.
The authors have no conflicts of interest to declare.
Identification
Copyright
© 2021 by United States Association for the Study of Pain, Inc.
