Functional distinction between NGF-mediated plasticity and regeneration of nociceptive axons within the spinal cord

Abstract

Successful regeneration after injury requires either the direct reformation of the circuit or the formation of a bridge circuit to provide partial functional return through a more indirect route. Presently, little is known about the specificity of how regenerating axons reconnect or reconstruct functional circuits. We have established an in vivo dorsal root entry zone model, which in the presence of NGF, shows very robust regeneration of peptidergic nociceptive axons, but not other sensory axons. Expression of NGF in normal, non-injured animals leads to robust sprouting of only the peptidergic nociceptive axons. Interestingly, NGF-induced sprouting of these axons leads to severe chronic pain, whereas, regeneration leads to protective like pain without chronic pain. Using this model we set out to compare differences in behavioral outcomes and circuit features between these two groups. In this study, we examined pre-synaptic and post-synaptic markers to evaluate the relationship between synaptic connections and behavioral responses. NGF-induced sprouting of CGRP axons resulted in a significant redistribution of synapses and cFos expression into the deeper dorsal horn. Regeneration of only the CGRP axons showed a general reduction in synapses and cFos expression within laminae I and II; however, inflammation of the hindpaw induced peripheral sensitization. This data shows that although NGF-induced sprouting of peptidergic axons induces robust chronic pain and cFos expression throughout the entire dorsal horn, regeneration of the same axons resulted in normal protective pain with a synaptic and cFos distribution similar, albeit significantly less than that shown by the sprouting of CGRP axons.

Neurotrophin selectivity in organizing topographic regeneration of nociceptive afferents

“…Tukey’s multiple comparison test revealed that the nociceptive response significantly recovered (* p <.05) in NGF and artemin groups compared to control GFP and GDNF groups. There was no difference in nociceptive response between NGF and artemin animals at these time points, indicating that CGRP + axon regeneration was primarily responsible for the improvement in thermal nociception and the differential distribution of CGRP fibers alone did not contribute to an alteration in pain response (Lin et al, 2014). …”

“…Under such conditions, the application of anti-NGF to injured spinal cord reduces sprouting of CGRP + axons, neuropathic pain and autonomic dysreflexia (Christensen and Hulsebosch, 1997; Krenz and Weaver, 2000; Brown et al, 2004). Interestingly, after dorsal rhizotomy, NGF-induced regeneration and mistargeting of only CGRP + axons in the absence of other sensory modalities showed normal responses to thermal nociception, without the development of hyperalgesia (Lin et al, 2014). This phenomenon most likely is either due to the lack of sufficient synaptic connectivity to drive hyperexcitability or the requirement of other sensory modalities for co-activation of pain pathways (Lin et al, 2014).…”

“…Interestingly, after dorsal rhizotomy, NGF-induced regeneration and mistargeting of only CGRP + axons in the absence of other sensory modalities showed normal responses to thermal nociception, without the development of hyperalgesia (Lin et al, 2014). This phenomenon most likely is either due to the lack of sufficient synaptic connectivity to drive hyperexcitability or the requirement of other sensory modalities for co-activation of pain pathways (Lin et al, 2014). On the other hand, artemin-induced regeneration of both peptidergic and non-peptidergic nociceptive axons into their normal laminar distribution also showed normal thermal nociceptive responses.…”

Nerve Growth Factor Gene Therapy

“…Axons sprouted toward the local source of NGF in every brain examined, following concentration gradients of NGF 4 . Sprouting is a classic neuronal response to trophic factors applied to the brain 4, 25–29 . Cell hypertrophy, another classic response to a trophic stimulus 4, 30, 31 , was also observed in the brains of three patients that underwent unilateral ex vivo NGF gene transfer; we measured cholinergic cell size in these subjects because the contralateral, untreated side of the brain provided a within-subject control.…”

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.…”