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A Spinal Role of Toll-Like Receptors in Mediating Histamine-dependent and Independent Pruritus /


Pruritus is the sensation that induces the desire or act of scratching. Pruritus is of broad clinical significance, but its etiology is poorly understood. Most pruritus is insensitive to traditional antihistamine-treatment, and there is great need of new mechanisms and treatments of itch. Toll-like Receptors are found to play a role in pruritus. In this work I developed a detection system to analyze scratching induced by intradermal injection of 48/ 80 or chloroquine (CQ). Roles of TLR3,4,7, and 9 and their adaptors in scratching produced by 48/80 and CQ were examined. 48/80 and CQ initiated a robust scratching in wild type (WT) mice. 48/80-initiated scratching was significantly reduced by TLR3 deficiency but not TLR4,7,9. Adaptor MyD88-knockout reduced 48/80 scratching, while TRIF and MyD88-TRIF deficiency increased scratching. TLR3, 4,7,9, MyD88,TRIF, or MyD88-TRIF deficiency decreased CQ scratching. Intrathecal TLR4-antagonist LPS-RS did not effect 48/80 scratching, but reduced CQ; 48/80 and CQ significantly increased cFOS expression in ipsilateral, not contralateral, dorsal horn. LPS-RS reduced CQ-induced cFOS, but not 48/80. Dorsal horn GFAP and IBA1 glial- staining revealed no effect of side by 48/80 or CQ. These results support 48/80 and chloroquine acting differentially through several TLRs and adaptors. TLR3,4,7, 9, MyD88 and TRIF play a role in histamine-independent CQ- induced pruritus. Only TLR3 and TRIF were required for histamine-dependent 48/80-induced pruritus. Increased scratching in TRIF KO after 48/80, not CQ, suggests a regulatory feedback system. Spinal TLR4 antagonism emphasize that for chloroquine, but not 48/80, a component mediating the role of TLR4 receptors lies within the neuraxis

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