Sexually Dimorphic Role of Toll-like Receptor 4 (TLR4) in High Molecular Weight Hyaluronan (HMWH)-induced Anti-hyperalgesia

Autor: Dionéia Araldi, Ivan José Magayewski Bonet, Jon D. Levine, Paul G. Green
Rok vydání: 2021
Předmět:
Male
high molecular weight hyaluronan
toll-like receptor 4
Medical and Health Sciences
0302 clinical medicine
030202 anesthesiology
Immunologic
Anesthesiology
Prostaglandin E2
Hyaluronic Acid
Receptor
Sex Characteristics
Pain Research
anti-hyperalgesia
Neurology
Hyperalgesia
Second messenger system
Ovariectomized rat
lipids (amino acids
peptides
and proteins)
Female
medicine.symptom
medicine.drug
Signal Transduction
medicine.medical_specialty
Ovariectomy
Inflammation
Article
Dinoprostone
prostaglandin E(2) (PGE(2))
hyaluronan
03 medical and health sciences
Adjuvants
Immunologic
Internal medicine
medicine
Animals
Adjuvants
prostaglandin E-2 (PGE(2))
business.industry
Animal
Psychology and Cognitive Sciences
Estrogen
Rats
Toll-Like Receptor 4
Molecular Weight
Disease Models
Animal
Anesthesiology and Pain Medicine
Endocrinology
Disease Models
Myeloid Differentiation Factor 88
TLR4
Neurology (clinical)
business
030217 neurology & neurosurgery
Zdroj: The journal of pain, vol 22, iss 10
J Pain
Popis: 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.
Databáze: OpenAIRE
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