(253) - Chemotherapy-induced pain is promoted by enhanced spinal adenosine kinase levels via astrocyte-dependent mechanisms

Abstract

Development of chronic pain associated with chemotherapy-induced peripheral neuropathy (CIPN) compromises the effectiveness of chemotherapies to treat cancers and greatly impacts thousands of lives. The causative mechanisms remain poorly understood. However, emerging evidence implicates unchecked neuroinflammation as a determinant factor in its development. We now demonstrate that the dysregulation of adenosine metabolism and loss of its signaling govern the extent of neuroinflammation in oxaliplatin-treated rodents. Adenosine kinase (ADK), a prominent regulator of extracellular and intracellular levels of the potent neuroprotective purine, adenosine, increased in the cytoplasm of astrocytes in the spinal cord of oxaliplatin-treated rats. Inhibiting its activity with intrathecal (i.th.) ADK inhibitor, ABT702, prevented the development of pain and restored anti-inflammatory and neuroprotective A3AR signaling. Increased ADK was associated with increased expression of the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome protein and pro-inflammatory/neuroexcitatory cytokine, interleukin-1β (IL-1β). Inhibiting NLRP3 activity with i.th. administration of its inhibitor, MCC950, prevented the development of pain. Moreover, supplementing A3AR signaling with the highly selective A3AR agonist, MRS5698, attenuated the oxaliplatin activation of NLRP3/IL-1β pathways and the development of pain. Our previous findings suggest that the beneficial effects of A3AR agonists in neuropathic pain are associated with increased IL-10. Indeed, i.th. MRS5698 increased IL-10 expression in oxaliplatin-treated rats, which in turn was found to suppress NLPR3 and IL-1β expression in the spinal cord and attenuate pain. These findings provide new molecular insights linking the development of CIPN with astrocyte-based adenosine/ADK axis and NLRP3 inflammasome to govern neuroinflammation. Our data also implicate IL-10 in the mechanism of action of selective A3AR agonists and strengthen the pharmacological rationale for clinical evaluation as an adjunct to chemotherapy. This study was funded by the NIH/National Cancer Institute (NIH RO1 CA169519; D.S.) and the NIDDK Intramural Research Program (Z01 DK031117-26; K.J.).