Journal article
PI3Kγ/AKT Signaling in High Molecular Weight Hyaluronan (HMWH)-Induced Anti-Hyperalgesia and Reversal of Nociceptor Sensitization
The Journal of neuroscience, Vol.41(40), pp.8414-8426
10/06/2021
DOI: 10.1523/JNEUROSCI.1189-21.2021
PMID: 34417329
Abstract
High molecular weight hyaluronan (HMWH), a well-established treatment for osteoarthritis pain, is anti-hyperalgesic in preclinical models of inflammatory and neuropathic pain. HMWH-induced anti-hyperalgesia is mediated by its action at cluster of differentiation 44 (CD44), the cognate hyaluronan receptor, which can signal via phosphoinositide 3-kinase (PI3K), a large family of kinases involved in diverse cell functions. We demonstrate that intrathecal administration of an oligodeoxynucleotide (ODN) antisense to mRNA for PI3Kγ (a Class I PI3K isoform) expressed in dorsal root ganglia (DRGs), and intradermal administration of a PI3Kγ-selective inhibitor (AS605240), markedly attenuates HMWH-induced anti-prostaglandin E
(PGE
) hyperalgesia, in male and female rats. Intradermal administration of inhibitors of mammalian target of rapamycin (mTOR; rapamycin) and protein kinase B (AKT; AKT Inhibitor IV), signaling molecules downstream of PI3Kγ, also attenuates HMWH-induced anti-hyperalgesia.
patch-clamp electrophysiology experiments on cultured nociceptors from male rats demonstrate that some HMWH-induced changes in generation of action potentials (APs) in nociceptors sensitized by PGE
are PI3Kγ dependent (reduction in AP firing rate, increase in latency to first AP and increase in slope of current ramp required to induce AP) and some are PI3Kγ independent [reduction in recovery rate of AP afterhyperpolarization (AHP)]. Our demonstration of a role of PI3Kγ in HMWH-induced anti-hyperalgesia and reversal of nociceptor sensitization opens a novel line of research into molecular targets for the treatment of diverse pain syndromes.
We have previously demonstrated that high molecular weight hyaluronan (HMWH) attenuates inflammatory hyperalgesia, an effect mediated by its action at cluster of differentiation 44 (CD44), the cognate hyaluronan receptor, and activation of its downstream signaling pathway, in nociceptors. In the present study, we demonstrate that phosphoinositide 3-kinase (PI3K)γ and downstream signaling pathway, protein kinase B (AKT) and mammalian target of rapamycin (mTOR), are crucial for HMWH to induce anti-hyperalgesia.
Details
- Title: Subtitle
- PI3Kγ/AKT Signaling in High Molecular Weight Hyaluronan (HMWH)-Induced Anti-Hyperalgesia and Reversal of Nociceptor Sensitization
- Creators
- Ivan J M Bonet - University of California, San FranciscoEugen V Khomula - University of California, San FranciscoDionéia Araldi - 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.41(40), pp.8414-8426
- DOI
- 10.1523/JNEUROSCI.1189-21.2021
- PMID
- 34417329
- NLM abbreviation
- J Neurosci
- ISSN
- 0270-6474
- eISSN
- 1529-2401
- Grant note
- R01 AR075334 / NIAMS NIH HHS
- Language
- English
- Date published
- 10/06/2021
- Academic Unit
- Neuroscience and Pharmacology
- Record Identifier
- 9985177943402771
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