ATF2, but not ATF3, participates in the maintenance of nerve injury-induced tactile allodynia and thermal hyperalgesia

Abstract

Transcription factors are proteins that modulate the transcriptional rate of target genes in the nucleus in response to extracellular or cytoplasmic signals. Activating transcription factors 2 (ATF2) and 3 (ATF3) respond to environmental signals and maintain cellular homeostasis. There is evidence that inflammation and nerve injury modulate ATF2 and ATF3 expression. However, the function of these transcription factors in pain is unknown. The purpose of this study was to investigate the contribution of ATF2 and ATF3 to nerve injury-induced neuropathic pain. L5/6 spinal nerve ligation induced tactile allodynia and thermal hyperalgesia. Moreover, nerve damage enhanced ATF2 and ATF3 protein expression in injured L5/6 dorsal root ganglia and spinal cord but not in uninjured L4 dorsal root ganglia. Nerve damage also enhanced ATF2 immunoreactivity in dorsal root ganglia and spinal cord 7 to 21 days post-injury. Repeated intrathecal post-treatment with a small-interfering RNA targeted against ATF2 (ATF2 siRNA) or anti-ATF2 antibody partially reversed tactile allodynia and thermal hyperalgesia. In contrast, ATF3 siRNA or anti-ATF3 antibody did not modify nociceptive behaviors. ATF2 immunoreactivity was found in dorsal root ganglia and spinal cord co-labeling with NeuN mainly in non-peptidergic (IB4+) but also in peptidergic (CGRP+) neurons. ATF2 was found mainly in small- and medium-sized neurons. These results suggest that ATF2, but not ATF3, is found in strategic sites related to spinal nociceptive processing and participates in the maintenance of neuropathic pain in rats.

microRNA‐125b and its downstream Smurf1/KLF2/ATF2 axis as important promoters on neurological function recovery in rats with spinal cord injury

“…In consent with our results, it has been documented that high expression of Smurf1 was observed after SCI in rats 25 . The up‐regulation of ATF2 expression has also been reported in injured L5/6 dorsal root ganglia and spinal cord after nerve injury 26 . Our results from the dual‐luciferase reporter gene assay depicted that Smurf1 was a putative target gene of miR‐125b.…”

Activating transcription factor 3 modulates protein kinase C epsilon activation in diabetic peripheral neuropathy

“…Collectively, this report suggests that ATF3, a stress-inducible gene, modulated the profile expression of p-PKCε and Bcl- XL , which was correlated with the development of neuropathic behavior. Paradoxically, recent reports have indicated that ATF2 – but not ATF3 – is responsible for neuropathic pain 35. Our previous studies reported ATF3 preferentially on small-diameter DRG neurons,11,12 and in those cases, we suggested that the role of ATF3 is more convincing in small-diameter neuropathy.…”

Spared Nerve Injury Causes Sexually Dimorphic Mechanical Allodynia and Differential Gene Expression in Spinal Cords and Dorsal Root Ganglia in Rats

“…The gene Atf3, coding for the transcription factor ATF3, is regarded as a marker of neuronal injury, but also of neuronal regeneration [90,91]. Previous studies have also found upregulation of Atf3 in both DRG and SC in males [92]. The effect of male-only upregulation of Atf3 and Reg3b in SC on behavioural sex difference remains to be studied.…”