Prevention of Paclitaxel-Induced Neuropathy Through Activation of the Central Cannabinoid Type 2 Receptor System

BACKGROUND: Peripheral neuropathy is a major dose-limiting toxicity of chemotherapy, especially after multiple courses of paclitaxel. The development of paclitaxel-induced neuropathy is associated with the activation of microglia followed by the activation and proliferation of astrocytes, and the expression and release of proinflammatory cytokines in the spinal dorsal horn. Cannabinoid type 2 (CB2) receptors are expressed in the microglia in neurodegenerative disease models. METHODS: To explore the potential of CB2 agonists for preventing paclitaxel-induced neuropathy, we designed and synthesized a novel CB2-selective agonist, namely, MDA7. The effect of MDA7 in preventing paclitaxel-induced allodynia was assessed in rats and in CB2+/+ and CB2-/- mice. We hypothesized that the CB2 receptor functions in a negative-feedback loop and that early MDA7 administration can blunt the neuroinflammatory response to paclitaxel and prevent mechanical allodynia through interference with specific signaling pathways. RESULTS: We found that MDA7 prevents paclitaxel-induced mechanical allodynia in rats and mice in a dose- and time-dependent manner without compromising paclitaxel's antineoplastic effect. MDA7's neuroprotective effect was absent in CB2-/- mice and was blocked by CB2 antagonists, suggesting that MDA7's action directly involves CB2 receptor activation. MDA7 treatment was found to interfere with early events in the paclitaxel-induced neuroinflammatory response as evidenced by relatively reduced toll-like receptor and CB2 expression in the lumbar spinal cord, reduced levels of extracellular signal-regulated kinase 1/2 activity, reduced numbers of activated microglia and astrocytes, and reduced secretion of proinflammatory mediators in vivo and in in vitro models. CONCLUSIONS: Our findings suggest an innovative therapeutic approach to prevent chemotherapy-induced neuropathy and may permit more aggressive use of active chemotherapeutic regimens with reduced long-term sequelae. (Anesth Analg 2012;114:1104-20)