A3 adenosine receptor agonist prevents the development of paclitaxel-induced neuropathic pain by modulating spinal glial-restricted redox-dependent signaling pathways

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) 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 (PN) in spinal cord generated in response to activation of the superoxide-generating enzyme, NADPH oxidase. PN 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 Gi/Gq-coupled A3 adenosine receptor (A3AR) with selective A3AR agonists (i.e., IB-MECA) blocked the development of chemotherapy induced-neuropathic pain evoked by distinct agents, including paclitaxel, without interfering with anticancer effects. The mechanism(s) 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 (NFκB) and mitogen activated protein kinases (ERK and p38) resulting in a decreased production of neuroexcitatory/pro-inflammatory cytokines (TNF-α, IL-1β) 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 A3AR activation in neuropathic pain while providing the foundation to consider use of A3AR agonists as therapeutic agents in CIPN patients.

The A3Adenosine Receptor: History and Perspectives

“…In particular it has been found that these effects were due to the inhibition of an astrocyte-associated neuroinflammatory 92 response in a model of oxaliplatin-induced peripheral neuropathy (Janes et al, 2014b). Furthermore A 3 AR agonists were found to prevent the development of paclitaxel-induced neuropathic pain by modulating spinal glial-restricted redox-dependent signaling pathways (Janes et al, 2014a). Importantly, the activation of A 3 AR in humans by potent, selective, and orally bioavailable A 3 AR agonists is not associated with cardiac or hemodynamic side effects at variance with A 1 and A 2A ARs and could represent a viable therapeutic strategy for chronic pain of distinct etiologies.…”

Mechanisms Involved in the Development of Chemotherapy-Induced Neuropathy

“…Endocannabinoids are broken down by fatty acid amide hydrolase (FAAH), and blocking this enzyme to increase endocannabinoid levels can reverse cold and mechanical sensitivity [43] and decrease C-fiber sensitization in a cisplatin model of CIPN [44]. Recently, translational research aimed at augmentation of signaling by A3 adenosine receptors has been suggested as an effective treatment for paclitaxel-related CIPN [45]. …”

Regulator Versus Effector Paradigm: Interleukin-10 as Indicator of the Switching Response

“…These conditions include physical and psychological stressful events like exercise, exposure to extreme thermal conditions, different kinds of pain, depression, sleep deprivation, hypoxia, etc. [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]. In general, an increased IL-10 level during these events is associated with better outcome and adaptation.…”