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

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-kappa B, the protein levels of expression of I kappa B-alpha, and interaction between I kappa B-alpha and P65 were evaluated in the spinal dorsal horns. Also, in vitro interaction of sequentially deleted I kappa B-alpha 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-kappa B, and inactive transcriptional expression of I kappa B-alpha 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-kappa B activation and inflammatory responses by enhancing the transcription of I kappa B-alpha promoter is proposed in the mechanism.

Automated summary

Metallothionein-2 plays a crucial role in oxaliplatin-induced neuropathic pain and may serve as a potential target for the prevention and treatment of CIPN. Genetic restoration of metallothionein-2 can block and reverse neuropathic pain, while inhibition of metallothionein-2 can trigger pain. Enhancing transcription of I kappa B-alpha promoter by reducing NF-kappa B activation and inflammatory responses is proposed as a mechanism.