Abstract
The microtubule, a major constituent of cytoskeletons, was shown to bind and interact with transient receptor potential vanilloid subfamily member 1 (TRPV1), and serves a pivotal role to produce thermal hyperalgesia in inflammatory pain. Nogo-A is a modulator of microtubule assembly and plays a key role in maintaining the function of TRPV1 in inflammatory heat pain. However, whether the microtubule dynamics modulated by Nogo-A in dorsal root ganglion (DRG) neurons participate in the inflammatory pain is not elucidated. Here we reported that the polymerization of microtubules in the DRG neurons, as indicated by the acetylated α-tubulin, tubulin polymerization-promoting protein 3 (TPPP3), and microtubule numbers, was significantly elevated in the complete Freund’s adjuvant (CFA) induced inflammatory pain. Consistent with our previous results, knock-out (KO) of Nogo-A protein significantly attenuated the heat hyperalgesia 72 h after CFA injection and decreased the microtubule polymerization via up-regulation of phosphorylation of collapsin response mediator protein 2 (CRMP2) in DRG. The colocalization of acetylated α-tubulin and TRPV1 in DRG neurons was also reduced dramatically in Nogo-A KO rats under inflammatory pain. Moreover, the down-regulation of TRPV1 in DRG of Nogo-A KO rats after injection of CFA was reversed by intrathecal injection of paclitaxel, a microtubule stabilizer. Furthermore, intrathecal injection of nocodazole (a microtubule disruptor) attenuated significantly the CFA-induced inflammatory heat hyperalgesia and the mechanical pain in a rat model of spared nerve injury (SNI). In these SNI cases, the Nogo-A and acetylated α-tubulin in DRG were also significantly up-regulated. We conclude that the polymerization of microtubules promoted by Nogo-A in DRG contributes to the development of inflammatory heat hyperalgesia mediated by TRPV1.
Highlights
Inflammatory factors from damaged tissues lower the threshold of nociceptors on nerve fibers and cause inflammatory pain [1]. This pain sensation is exuberated in inflammatory thermal hyperalgesia, which is largely mediated by the transient receptor potential vanilloid subfamily member 1 (TRPV1) in primary sensory neurons [2,3]
Taking together that Nogo-A in dorsal root ganglion (DRG) neurons contributes to the inflammatory pain via maintaining the function of TRPV1 [5], it is hypothesized that the Nogo-A/collapsin response mediator protein 2 (CRMP2)/tubulin pathway is involved in pain modulation
The Nogo-A protein in DRG neurons was dramatically elevated after complete Freund’s adjuvant (CFA) administration (Supplementary Figure S1A,B)
Summary
Inflammatory factors from damaged tissues lower the threshold of nociceptors on nerve fibers and cause inflammatory pain [1]. Our previous study demonstrated that Nogo-A, a cytoskeleton modulator, promotes inflammatory heat hyperalgesia via maintaining the function of TRPV1 in DRG neurons [5]. It remains to be determined whether Nogo-A works as an upstream modulator of microtubules to develop inflammatory pain. Phosphorylation of CRMP2 decreases the active form of CRMP-2, and so impairs neuronal polarity by suppressing axon elongation [31] These findings suggest that Nogo-A is an important upstream modulator of the CRMP2/tubulin pathway. Taking together that Nogo-A in DRG neurons contributes to the inflammatory pain via maintaining the function of TRPV1 [5], it is hypothesized that the Nogo-A/CRMP2/tubulin pathway is involved in pain modulation. The polymerization of tubulin prompted by Nogo-A is necessary to maintain the expression of TRPV1 and to develop the CFA-induced inflammatory heat hyperalgesia
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