Hedging against Neuropathic Pain: Role of Hedgehog Signaling in Pathological Nerve Healing

Abstract

The peripheral nervous system has important regenerative capacities that regulate and restore peripheral nerve homeostasis. Following peripheral nerve injury, the nerve undergoes a highly regulated degeneration and regeneration process called Wallerian degeneration, where numerous cell populations interact to allow proper nerve healing. Recent studies have evidenced the prominent role of morphogenetic Hedgehog signaling pathway and its main effectors, Sonic Hedgehog (SHH) and Desert Hedgehog (DHH) in the regenerative drive following nerve injury. Furthermore, dysfunctional regeneration and/or dysfunctional Hedgehog signaling participate in the development of chronic neuropathic pain that sometimes accompanies nerve healing in the clinical context. Understanding the implications of this key signaling pathway could provide exciting new perspectives for future research on peripheral nerve healing.

Keywords: desert hedgehog; nerve healing; neuropathic pain; peripheral nerve injury; sonic hedgehog.

Figure 1

Hedgehog signaling during peripheral nerve healing and homeostasis. HH = Hedgehog; DHH = Desert Hedgehog; SC = Schwann cell; SHH = Sonic Hedgehog; putative roles are featured with a question mark.

Figure 2

Comparison of Hedgehog signaling and Sonic Hedgehog localizations following nerve transection (a) or nerve crush (b). Relative quantities of Sonic Hedgehog and Gli-1 protein/mRNA are represented at the time of highest expression in each nerve injury model (based on data from Yamada et al. 2018 [17] and Hashimoto et al. 2008 [15], respectively). Noteworthy: the SHH gradient in the nerve crush model (b) and lack of said gradient in the transection model (a), which has more focalized accumulations of SHH protein. Gli-1 = glioma-associated oncogene homolog-1; SHH = Sonic Hedgehog.

Figure 3

Chronic constriction injury (CCI) of the sciatic nerve induces early and prolonged downregulation of Smoothened receptor mRNA. Changes over time of Smoothened (SMO) mRNA levels were assessed in the sciatic nerve of sham or CCI-injured rats using semiquantitative reverse transcription polymerase chain reaction analyses. Data are presented as relative quantification (R.Q.) in arbitrary units (A.U.) corresponding to the ratio of specific mRNA over RPS18 mRNA. Each bar corresponds to the mean ±SEM of n = 6–8 animals for each time post-injury; * p < 0.05. One-way analysis of variance followed by Bonferroni post hoc test was used.

Figure 4

Vascular morphological changes observed using confocal microscopy in axial slices of infra-orbital nerves (IoN) subjected to chronic constriction injury (IoN-CCI) at 24 h post-injury (upper left panel) or sham surgery (upper right panel) or perineural injections of cyclopamine at 6 h post-injection (lower left panel) or vehicle (lower right panel) using Reca-1 and sodium fluorescein (NaFlu) for vessel immunolabeling, respectively. Chronic constriction injury and perineural injections were performed according to previously described methodologies (see Moreau et al. 2016 [18], 2017 [19] for methodological details).