Low dose ketamine reduces the induction of ERK1/2 and CREB signaling protein in a neuropathic pain model of rats

Abstract

Background: In addition to causing the loss of voluntary sensory and motor function, spinal cord injury (SCI) often creates a state of central neuropathic pain. Rats given SCI display increases in the activated form of transcription factors ERK 1/2 MAPK and CREB in the spinal cord, which correspond to allodynia in a model of neuropathic pain. This study was conducted to determine if low dose ketamine had an effect on the activation of ERK 1/2 and CREB in the development of neuropathic pain.Methods: This study was conducted to evaluate ERK 1/2 and CREB protein in a sham operated (control) group, neuropathic pain and normal saline (NP ＋ NS) group and neuropathic pain and ketamine (NP ＋ Keta) group. To accomplish this, male Sprague-Dawley rats were anesthetized and then subjected to L5-L6 spinal nerve ligation (SNL, neuropathic rats). The total amounts of ERK 1/2 and CREB protein were then assessed by western blot analysis. In addition, changes in the amounts of ERK 1/2 and CREB mRNA were evaluated by RT-PCR.Results: There was a significant increase in the amount of ERK 1/2 and CREB in the NP ＋ NS group when compared with the sham group. However, the amount of ERK 1/2 and CREB protein induced due to SNL were significantly reduced by continuous infusion with ketamine in the NP ＋ Keta group. Conclusions:The results of this study revealed a positive linkage between NMDA receptors and the ERK-CREB signaling pathway. Therefore, NMDA receptors could be the target of future therapeutic approaches. Additionally, the results of the present study provide additional evidence that low dose ketamine effectively prevents and treats central neuropathic pain following SNL.

Ketamine induces rapid and sustained antidepressant-like effects in chronic pain induced depression: Role of MAPK signaling pathway

“…In addition, ketamine restored the decreased p-ERK in the ACC of mice with comorbid neuropathic pain and depressive-like behaviors. These results are supported by recent evidences from pain field suggesting that ketamine's analgesic activity might be partly mediated through the modulation of several members of the MAPK pathways (Choi et al, 2009;Kwon et al, 2014;Mei et al, 2011). Specifically, it was shown that ketamine's analgesic effect is associated with an inhibition of both spinal astrocyte JNK activation (Mei et al, 2011) and the increased expression of p38 and phospho-p38 (Kwon et al, 2014) as well as with a decreased upregulated ERK (Choi et al, 2009) in the spinal cord of rats with neuropathic pain.…”

“…These results are supported by recent evidences from pain field suggesting that ketamine's analgesic activity might be partly mediated through the modulation of several members of the MAPK pathways (Choi et al, 2009;Kwon et al, 2014;Mei et al, 2011). Specifically, it was shown that ketamine's analgesic effect is associated with an inhibition of both spinal astrocyte JNK activation (Mei et al, 2011) and the increased expression of p38 and phospho-p38 (Kwon et al, 2014) as well as with a decreased upregulated ERK (Choi et al, 2009) in the spinal cord of rats with neuropathic pain. In accordance with these findings, it has been shown that a single dose of subanesthetic ketamine which recruits the MAPK signaling cascade (Kohtala et al, 2019;Li et al, 2010) also ameliorates chronic stress-induced deficits in spine number and function (Li et al, 2011), a common characteristic in depression (Banasr et al, 2011).…”

Ketamine reduces the induced spinal p38 MAPK and pro-inflammatory cytokines in a neuropathic rats

“…The NMDA receptor is an excitatory amino acid (EAA) receptor, and NMDA receptor antagonists have been shown to exert a neuroprotective effect in central nervous system ischemia [ 17 ]. Furthermore, elevated EEAs lead to the activation of several MAPKs, including ERK 1/2, JNK, and p38 [ 18 , 19 ]. The key element in this process is the glutamate receptor that increases in number at neural junctions by phosphorylation, elevating the reactivity to glutamate, an excitatory neurotransmitter [ 20 ].…”

N-Acetylcysteine causes analgesia in a mouse model of painful diabetic neuropathy

“…Analgesic drugs, such as dexmetomidine, type-2 cannabinoid receptor agonists, and ketamine alleviate neuropathic pain by restraining MAPK activation in the spinal cord. [70][71][72] In dorsal horn neurons, MAPK phosphorylates and inhibits K v 4.2 channels, which mediate type-A potassium currents and are involved in pain plasticity. [73][74][75] It is possible that NAC treatment in diabetic mice enhances the activity of K v 4.2 channels, therefore reducing excitability of secondary order neurons in the dorsal horns of the spinal cord.…”