Expression of activating transcription factor 3 (ATF3) in uninjured dorsal root ganglion neurons in a lower trunk avulsion pain model in rats

Abstract

Purpose Clinically, neuropathic pain is frequent and intense following brachial plexus injury. It is thought that brachial plexus pain is not generated by avulsed roots, but rather by non-avulsed roots, since the avulsed root could not possibly transmit action potentials to central nerves. The aim of this study was to evaluate pain behavior and activation of sensory neurons in a brachial plexus avulsion (BPA) model in rats. Methods Fifteen male Wistar rats were used. In the BPA group, the C8-T1 roots were avulsed from the spinal cord with forceps at the lower trunk level (n = 5). In the naïve group, rats did not receive any procedures (n = 5). In the sham-operated group, the lower trunk was simply exposed (n = 5). Mechanical hyperalgesia of forelimbs corresponding to C6 and C7 dermatomes was measured using von Frey filaments every third day for 3 weeks. Activation of DRG neurons was immunohistochemically examined using anti-ATF3 (a marker for neuron activation) antibodies 21 days after surgery. Von Frey and immunohistochemical data between groups were analyzed using a Kruskal-Wallis test, followed by Mann-Whitney U tests. Bonferroni corrections were performed. Results Animals in the BPA group displayed significant mechanical hyperalgesia at the dermatome innervated by uninjured nerves continuing through day 21 compared with animals in the sham-operated group. ATF3-immunoreactive small and large DRG neurons were significantly activated in the BPA group (10.6 ± 9.5 and 5.2 ± 4.1 %, 39.7 ± 6.7 and 25.2 ± 10.3 %, 78.0 ± 9.1 and 53.7 ± 29.3 %) compared with the sham-operated group (0.7 ± 0.9 and 0 ± 0 %, 2.8 ± 2.0 and 1.0 ± 2.0 %, 3.9 ± 2.7 and 8.6 ± 10.1 %) at every level of C5, 6, and 7. In the naïve group, no DRG neurons were activated. ATF3-immunoreactive small and large DRG neurons were significantly activated at the level of C7 compared with C6 and C5, and significantly activated at the level of C6 compared with C5 in the BPA group. Conclusions Expression of ATF3 in uninjured DRG neurons may contribute to pain following brachial plexus avulsion injury. Consequently, spared spinal sensory nerves may represent therapeutic targets for treatment of this pain.

Signatures of Altered Gene Expression in Dorsal Root Ganglia of a Fabry Disease Mouse Model

“…The deregulated genes that emerged from our analysis largely overlap with genes from previous reports on other painful disorders, although the direction of regulation does not always match. Upregulation of the transcription factor Atf3 is in line with previous reports that showed induction of Atf3 in DRGs in different models of nerve injury (Tsujino et al, 2000 ; Shortland et al, 2006 ; Matsuura et al, 2013 ), as well as upon exposure to noxious stimuli (Braz and Basbaum, 2010 ). Also, the adenosine receptor Adora2b which was upregulated in FD mice promotes chronic pain through neuro-immune interactions (Hu et al, 2016 ).…”

Peripheral and Central Neuroinflammatory Changes and Pain Behaviors in an Animal Model of Multiple Sclerosis

“…As significant changes in T cell infiltration were observed in the TG in clinical EAE (day 16), we next examined whether ATF-3 (a marker of neurons with damaged primary afferents) is induced in peptidergic (CGRP+) and non-peptidergic (IB4+) small diameter neurons, and NF200+ large diameter myelinated neurons using immunohistochemistry. This was of interest as injured DRG neurons have been linked to pain behaviors in mice with peripheral nerve injury ( 23 ) and rats with brachial plexus avulsion ( 24 ). We found a small, though significant, increase in the percentage of total ATF-3 immunopositive cell bodies in the TG of EAE (1% ± 0.2) compared to control (0.1% ± 0.05) mice (Unpaired Student’s t -test, n = 4–5, p < 0.01).…”

IGF-1 via PI3K/Akt/S6K signaling pathway protects DRG neurons with high glucose-induced toxicity

“…Activating transcription factor 3 (ATF3) is considered as a reliable indicator of neuronal damage [ 8 ] and could be induced by a diverse array of noxious stimuli in DRG neurons [ 9 , 10 ]. Additionally, recent studies indicate the involvement of ATF3 upregulation in the genesis and maintenance of neuropathic pain in a wide range of pathological models [ 11 , 12 , 13 ]. However, the role of ATF3 expression in DNP remains unclear.…”