Nogo‐A promotes inflammatory heat hyperalgesia by maintaining TRPV‐1 function in the rat dorsal root ganglion neuron

Abstract

Nogo-A is a key inhibitory molecule of axon regeneration in oligodendrocytes. However, little is known about its role in adult neurons. In this study, we showed an important function of Nogo-A on regulation of inflammatory pain in dorsal root ganglion (DRG) neurons. In adult rats with complete Freund's adjuvant (CFA) hind paw inflammation, DRG neurons showed a significant increase in Nogo-A expression. Disruption of Nogo-A signaling with Nogo-66 receptor antagonist peptide, Nogo-A blocking antibody, Nogo-A short hairpin RNA, or Nogo-A gene knockout attenuated CFA-induced inflammatory heat hyperalgesia. Moreover, disruption of Nogo-A signaling suppressed the function and expression in DRG neurons of the transient receptor potential vanilloid subfamily member (TRPV)-1 channel, which is known to be the endogenous transducer of noxious heat during inflammation. These effects were accompanied with a reduction in LIM domain kinase (LIMK)/cofilin phosphorylation and actin polymerization. Similar disruption of actin filament architecture by direct action of Latrunculin A reduced the TRPV-1 activity and up-regulation of TRPV-1 protein caused by CFA. We conclude that Nogo-A plays an essential role in the development of inflammatory heat hyperalgesia, partly through maintaining TRPV-1 function via activation of the LIMK/cofilin pathway, which regulates actin filament dynamics. These findings support a therapeutic potential of modulating Nogo-A signaling in pain management.-Hu, F., Liu, H.-C., Su, D.-Q., Chen, H.-J., Chan, S.-O., Wang, Y., Wang, J. Nogo-A promotes inflammatory heat hyperalgesia by maintaining TRPV-1 function in the rat dorsal root ganglion neuron.

Electroacupuncture Alleviates Experimental Chronic Inflammatory Pain by Inhibiting Calcium Voltage‐Gated Channel‐Mediated Inflammation

“…Some studies have reported that apoptosis is involved in neurotoxicity or pain [28][29][30], which coincides with our findings of significant enrichment of the negative regulation of the neuron apoptotic process (GO:0043524, p value � 1.212e − 02) and negative regulation of the apoptotic process (GO:0043066, p value � 1.628e − 02). Moreover, the FoxO signaling pathway (rno04068, p value � 4.735e − 02) and MAPK signaling pathway (rno04010, p value � 4.672e − 02) were also significantly enriched.…”

Identification of a new functional domain of Nogo‐A that promotes inflammatory pain and inhibits neurite growth through binding to NgR1

“…A purified rabbit polyclonal antibody (IgG) of Nogo‐A aa 846‐861 was made using immunoaffinity purification by AbMax Biotechnology Co., LTD (Beijing, China). Nogo‐A antibody or normal rabbit IgG (sc‐2028, Santa Cruz Biotechnology, CA, USA) (prepared in a concentration of 0.2 μg/μL) was injected intrathecally in a volume of 3 μL 27 . Half hour after the injection of peptide or antibody, 25% of CFA was injected.…”

“…Nogo-A antibody or normal rabbit IgG (sc-2028, Santa Cruz Biotechnology, CA, USA) (prepared in a concentration of 0.2 μg/μL) was injected intrathecally in a volume of 3 μL. 27 Half hour after the injection of peptide or antibody, 25% of CFA was injected. Nociceptive responses were measured 1, 2, 6, and 24 hours after CFA administration.…”

“…These two potential sequences, together with Nogo-Δ20, share the potential as functional domains in Nogo-A-specific region that may work with Nogo-66 in modulating inflammatory heat hyperalgesia induced by CFA, as suggested in our earlier study. 27 To investigate whether the Nogo-A aa 415-430 and Nogo-A aa 846-861 contribute to the induction of pain hypersensitivity, two corresponding antagonist peptides and scramble peptides (846-861 PE and scramble 1; 415-430 KP and scramble 2) were synthesized and intrathecally infused at different concentrations 30 minutes before injection of CFA ( Figure 1A). Paw withdrawal latency (PWL) in response to radiant heat was measured during the 24 hours period after CFA injection.…”

“…LIMK/cofilin is the classical signal pathway downstream of Nogo-A that regulates actin cytoskeleton, 23,35 which has been shown to be activated by Nogo-A/NgR1 in the CFA-induced inflammatory heat hyperalgesia. 27 To investigate the downstream signaling pathway of Nogo-A aa 846-861, we examined the changes of phosphorylated LIMK, phosphorylated cofilin and ratio of polymeric F-actin to monomeric G-actin (indicating the actin filament polymerization) in DRG of rats after CFA injection.…”