Downregulation of metallothionein-2 contributes to oxaliplatin-induced neuropathic pain

Abstract

Background We previously reported a correlation between small doses of oxaliplatin penetrating onto the spinal cord and acute pain after chemotherapy. Here, we propose that MT2 within the spinal dorsal horns participates in the development of oxaliplatin-induced neuropathic pain and may be a pharmacological target for the prevention and treatment of chemotherapy-induced peripheral neuropathy (CIPN). Methods The rat model of CIPN was established by 5 consecutive injections of oxaliplatin (0.4 mg/100 g/day). Genetic restoration of neuron-specific metallothionein-2 was implemented 21 days before oxaliplatin treatment, and also, genetic inhibition by metallothionein-2 siRNA was performed. Mechanical allodynia and locomotor activity were assayed. Cell-specific expression of metallothionein-2, the mRNA levels of pro-inflammatory cytokines, nuclear translocation of NF-κB, the protein levels of expression of IκB-α, and interaction between IκB-α and P65 were evaluated in the spinal dorsal horns. Also, in vitro interaction of sequentially deleted IκB-α promoter with metallothionein-2 was used to assess the signal transduction mechanism. Results We found that oxaliplatin induced downregulation of metallothionein-2 in rat spinal cord neurons. By contrast, genetic restoration of metallothionein-2 in the spinal dorsal horn neuron blocked and reversed neuropathic pain in oxaliplatin-treated rats of both sexes, whereas genetic inhibition of metallothionein-2 triggered neuropathic pain in normal rats. Overall locomotor activity was not impaired after the genetic alterations of metallothionein-2. At the molecular level, metallothionein-2 modulated oxaliplatin-induced neuroinflammation, activation of NF-κB, and inactive transcriptional expression of IκB-α promoter, and these processes could be blocked by genetic restoration of metallothionein-2 in the spinal dorsal horn neurons. Conclusions Metallothionein-2 is a potential target for the prevention and treatment of CIPN. A reduction of NF-κB activation and inflammatory responses by enhancing the transcription of IκB-α promoter is proposed in the mechanism.

Animal models of chemotherapy‐induced peripheral neuropathy for hematological malignancies: A review

“…After the treatment, the behaviors showed mechanical pain and cold hyperalgesia, and the conduction velocity of the sciatic nerve was significantly reduced, indicating that the rats had obvious peripheral nerve damage, which was consistent with the pathological characteristics of OIPN, and the modeling was considered successful. This is almost similar to previous experimental studies in rats 56,57 . In addition, elevated levels of inflammatory cytokines, particularly Interleukin‐1β (IL‐1β) and TNF‐α, contribute to the central sensitization and pain behavior associated with neuropathic pain.…”

“…This is almost similar to previous experimental studies in rats. 56 , 57 In addition, elevated levels of inflammatory cytokines, particularly Interleukin‐1β (IL‐1β) and TNF‐α, contribute to the central sensitization and pain behavior associated with neuropathic pain. In addition to modeling with SD rats, Wistar rats have been used to validate the feasibility of the modeling method by evaluating various physiological indicators and pathological changes.…”

Positive interaction between GPER and β-alanine in the dorsal root ganglion uncovers potential mechanisms: mediating continuous neuronal sensitization and neuroinflammation responses in neuropathic pain

“…There is increasing evidence of the critical roles of oestrogen in the peripheral and central nervous systems [ 1 – 3 ]. Oestrogen targets neurons to regulate neural development, plasticity, and neuroprotective actions in behavioural and cognitive functions [ 4 ].…”

Tetrandrine alleviates oxaliplatin-induced mechanical allodynia via modulation of inflammation-related genes

“…In the context of chronic pain, the interaction between neurons, astrocytes, and microglial cells may be mediated by the activated cytokine and chemokine signaling pathways. Oxaliplatin can induce the production of certain pro-inflammatory cytokines in SC cells, including IL-18, TNF-α, and MMP2 ( Huang et al, 2021 ; Bai et al, 2023 ). These cytokines can bind to their respective receptors, enhancing glutamate activity and inhibiting inhibitory synaptic transmission, leading to increased excitability of neurons in the SC and subsequently chronic pain ( Liu et al, 2017 ; Zhang et al, 2017 ).…”