A(3) adenosine receptor agonist prevents the development of paclitaxel-induced neuropathic pain by modulating spinal glial-restricted redox-dependent signaling pathways

作者：Janes Kali; Esposito Emanuela; Doyle Timothy; Cuzzocrea Salvatore; Tosh Dillip K; Jacobson Kenneth A; Salvemini Daniela^*

来源：Pain, 2014, 155(12): 2560-2567.

DOI：10.1016/j.pain.2014.09.016

• A3
• Adenosine
• Chemotherapy-induced peripheral neuropathy
• Neuroinflammation
• Neuropathic pain
• Paclitaxel
• Spinal cord

Chemotherapy-induced peripheral neuropathy accompanied by chronic neuropathic pain is the major dose-limiting toxicity of several anticancer agents including the taxane paclitaxel (Taxol). A critical mechanism underlying paclitaxel-induced neuropathic pain is the increased production of peroxynitrite in spinal cord generated in response to activation of the superoxide-generating enzyme, NADPH oxidase. Peroxynitrite in turn contributes to the development of neuropathic pain by modulating several redox-dependent events in spinal cord. We recently reported that activation of the G(i)/G(q)-coupled A(3) adenosine receptor (A(3)AR) with selective A(3)AR agonists (ie, IB-MECA) blocked the development of chemotherapy induced-neuropathic pain evoked by distinct agents, including paclitaxel, without interfering with anticancer effects. The mechanism or mechanisms of action underlying these beneficial effects has yet to be explored. We now demonstrate that IB-MECA attenuates the development of paclitaxel-induced neuropathic pain by inhibiting the activation of spinal NADPH oxidase and two downstream redox-dependent systems. The first relies on inhibition of the redox-sensitive transcription factor (NF kappa B) and mitogen activated protein kinases (ERK and p38) resulting in decreased production of neuroexcitatory/proinflammatory cytokines (TNF-alpha, IL-1 beta) and increased formation of the neuroprotective/anti-inflammatory IL-10. The second involves inhibition of redox-mediated posttranslational tyrosine nitration and modification (inactivation) of glia-restricted proteins known to play key roles in regulating synaptic glutamate homeostasis: the glutamate transporter GLT-1 and glutamine synthetase. Our results unravel a mechanistic link into biomolecular signaling pathways employed by A(3)AR activation in neuropathic pain while providing the foundation to consider use of A(3)AR agonists as therapeutic agents in patients with chemotherapy-induced peripheral neuropathy.

• 出版日期2014-12