Astrocytic c-Jun N-terminal kinase-histone deacetylase-2 cascade contributes to glutamate transporter-1 decrease and mechanical allodynia following peripheral nerve injury in rats

Decrease of glutamate transporter-1 (GLT-1) in the spinal dorsal horn after nerve injury induces enhanced excitatory transmission and causes persistent pain. Histone deacetylases (HDACs)-catalyzed deacetylation might contribute to the decrease of GLT-1, while the detailed mechanisms have yet to be fully elaborated. Spinal nerve ligation (SNL) induced significant increases of HDAC2 and decreases of GLT-1 in spinal astrocytes. Intrathecal infusion of the HDAC2 inhibitors attenuated the decrease of GLT-1 and enhanced phosphorylation of glutamate receptors. GLT-1 and phosphorylated c-Jun N-terminal kinase (JNK) were highly colocalized in the spinal cord, and a large number of pJNK positive cells were HDAC2 positive. Intrathecally infusion of the JNK inhibitor SP600125 significantly inhibited SNL-induced upregulation of HDAC2. SNL-induced HDAC2 up-regulation could be inhibited by the neutralizing anti-tumor necrosis factor-α (TNF-α) binding protein etanercept or the microglial inhibitor minocycline. In cultured astrocytes, TNF-α induced enhanced phosphorylation of JNK and a significant increase of HDAC2, as well as a remarkable decrease of GLT-1, which could be prevented by SP600125 or the HDAC2 specific inhibitor CAY10683. Our data suggest that astrocytic JNK-HDAC2 cascade contributes to GLT-1 decrease and mechanical allodynia following peripheral nerve injury. Neuroimmune activation after peripheral nerve injury could induce epigenetic modification changes in astrocytes and contribute to chronic pain maintenance.

 

Comments:

The passage highlights the involvement of glutamate transporter-1 (GLT-1) and histone deacetylases (HDACs) in the development of persistent pain after nerve injury, specifically in the spinal dorsal horn. Here's a breakdown of the key points:

Decrease of GLT-1: Following nerve injury, there is a decrease in the levels of GLT-1 in the spinal dorsal horn. GLT-1 is responsible for clearing glutamate, a neurotransmitter involved in excitatory transmission. Reduced GLT-1 function leads to enhanced excitatory transmission, contributing to persistent pain.

Role of HDACs: Histone deacetylases (HDACs) are enzymes involved in epigenetic modifications that regulate gene expression. HDACs are implicated in the decrease of GLT-1 levels after nerve injury, although the exact mechanisms are not fully understood.

Spinal nerve ligation (SNL) model: In an experimental model of nerve injury called spinal nerve ligation (SNL), significant increases in HDAC2 and decreases in GLT-1 were observed in spinal astrocytes. Astrocytes are a type of glial cell in the central nervous system, playing a crucial role in regulating neuronal activity.

HDAC2 inhibitors: Infusing HDAC2 inhibitors into the spinal cord attenuated the decrease of GLT-1 and enhanced the phosphorylation (activation) of glutamate receptors. This suggests that inhibiting HDAC2 activity can counteract the negative effects on GLT-1 levels and excitatory signaling.

JNK signaling pathway: GLT-1 and phosphorylated c-Jun N-terminal kinase (JNK) were found to be highly colocalized in the spinal cord, indicating a potential interaction between them. Furthermore, a significant number of cells positive for pJNK (activated JNK) were also positive for HDAC2. This suggests that JNK signaling and HDAC2 may be linked in the regulation of GLT-1.

Inhibition of JNK: Intrathecal infusion of the JNK inhibitor SP600125 inhibited the upregulation of HDAC2 induced by SNL. This suggests that JNK activation contributes to the increased levels of HDAC2 after nerve injury.

Neuroimmune activation: Neuroimmune activation, involving factors such as tumor necrosis factor-α (TNF-α) and microglial activation, plays a role in the development and maintenance of chronic pain. In the SNL model, neutralizing TNF-α or inhibiting microglial activity attenuated the upregulation of HDAC2.

Astrocytes and TNF-α: In cultured astrocytes, TNF-α induced enhanced phosphorylation of JNK, increased HDAC2 levels, and decreased GLT-1. These effects were prevented by inhibiting JNK or using a specific HDAC2 inhibitor, suggesting that TNF-α-induced changes contribute to GLT-1 decrease.

Epigenetic modifications and chronic pain: The data presented indicate that neuroimmune activation after peripheral nerve injury can induce epigenetic modifications in astrocytes. These modifications, involving the JNK-HDAC2 cascade, contribute to the decrease in GLT-1 and the development of mechanical allodynia, a symptom of chronic pain.

Overall, this passage suggests that the JNK-HDAC2 cascade in astrocytes plays a role in the regulation of GLT-1 and chronic pain following nerve injury. Epigenetic modifications and neuroimmune activation are implicated in these processes.