• Yutaka Matsuoka, Ayahiro Yamashita, Megumi Matsuda, Kenshiro Kawai, Teiji Sawa, and Fumimasa Amaya.
• Department of Anesthesiology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
• Pain. 2019 Sep 1; 160 (9): 2149-2160.

AbstractInflammatory pain hypersensitivity is associated with activation of primary afferent neurons. This study investigated the existence of the inflammasome in dorsal root ganglion (DRG) and the functional significance in the development of inflammatory pain hypersensitivity. Tissue inflammation was induced in male C57BL/6 mice with complete Freund's adjuvant (CFA) or ceramide injection into the hind paw. Behavioral testing was performed to investigate inflammation-induced pain hypersensitivity. Ipsilateral L5 DRGs were obtained for analysis. Expression of nucleotide oligomerization domain-like receptors (NLRs) was analyzed with real-time PCR. Cleaved interleukin (IL)-1β and NLRP2 expression was investigated with immunohistochemistry and western blotting. Caspase 1 activity was also measured. A caspase 1 inhibitor and NLRP2 siRNA were intrathecally administered to inhibit NLRP2 inflammasome signaling in DRG. Cleaved IL-1β expression was significantly increased after CFA injection in small-sized DRG neurons. The amount of cleaved IL-1β and caspase 1 activity were also increased. Among several NLRs, NLRP2 mRNA was significantly increased in DRG after CFA injection. NLRP2 was expressed in small-sized DRG neurons. Intrathecal injection of a caspase 1 inhibitor or NLRP2 siRNA reduced CFA-induced pain hypersensitivity and cleaved IL-1β expression in DRG. Induction of cleaved IL-1β and NLRP2 in DRG neurons was similarly observed after ceramide injection. NLRP2 siRNA inhibited ceramide-induced pain hypersensitivity. These results confirmed the existence of NLRP2 inflammasome in DRG neurons. Activation of the NLRP2 inflammasome leads to activation of DRG neurons and subsequent development of pain hypersensitivity in various types of tissue inflammation.

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