Neurotrophin selectivity in organizing topographic regeneration of nociceptive afferents

Abstract

Neurotrophins represent some of the best candidates to enhance regeneration. In the current study, we investigated the effects of artemin, a member of the glial derived neurotrophic factor (GDNF) family, on sensory axon regeneration following a lumbar dorsal root injury and compared these effects with that observed after either NGF or GDNF expression in the rat spinal cord. Unlike previously published data, artemin failed to induce regeneration of large-diameter myelinated sensory afferents when expressed within either the spinal cord or DRG. However, artemin or NGF induced regeneration of calcitonin gene related peptide positive (CGRP+) axons only when expressed within the spinal cord. Accordingly, artemin or NGF enhanced recovery of only nociceptive behavior and showed a cFos distribution similar to the topography of regenerating axons. Artemin and GDNF signaling requires binding to different co-receptors (GFRα3 or GFRα1, respectively) prior to binding to the signaling receptor, cRet. Approximately 70% of DRG neurons express cRet, but only 35% express either co-receptor. To enhance artemin-induced regeneration, we co-expressed artemin with either GFRα3 or GDNF. Co-expression of artemin and GFRα3 only slightly enhanced regeneration of IB4+ non-peptidergic nociceptive axons, but not myelinated axons. Interestingly, this co-expression also disrupted the ability of artemin to produce topographic targeting and lead to significant increases in cFos immunoreactivity within the deep dorsal laminae. This study failed to demonstrate artemin-induced regeneration of myelinated axons, even with co-expression of GFR-α3, which only promoted mistargeted regeneration.

NT-3 promotes proprioceptive axon regeneration when combined with activation of the mTor intrinsic growth pathway but not with reduction of myelin extrinsic inhibitors

“…With combined treatment of both Rheb and NT-3, many more axons regenerated past the DREZ and some axons were able to penetrate to a depth of about 800 µm corresponding to lamina VIII under combined treatment (Figure 7C, (c)). Labeled axons also appeared patchy often following a tortuous course when compared to normal axons (Kelamangalath et al, 2015). Analysis of the total area occupied by regenerating axons using one-way ANOVA revealed a significant effect (p<0.05) of treatment (F (2,17) =12.15).…”

Time‐restricted release of multiple neurotrophic factors promotes axonal regeneration and functional recovery after peripheral nerve injury

“…However, most of those studies applied just one of the NTFs that are upregulated following injury (7). Increasingly, studies have demonstrated that the application of multiple NTFs rather than a single one holds greater therapeutic promise (8)(9)(10)(11)(12). This is ascribed to the concept that different kinds and subtypes of neurons show distinctive dependence and response to different NTFs.…”

A novel immunocompetent model of metastatic prostate cancer‐induced bone pain

“…60 These reports demonstrated the application of p75 NTR inhibition in multiple injury or pain-related CGRP expression, and afferent process extension. [71][72][73][74][75][76] In our immunocompetent prostate cancer model, the fact that neuronal p75 NTR and CGRP highly colocalize in common nociceptors suggests a role in nociceptive input, synaptic transmission, and sensitization in CIBP.…”