Bortezomib induces neuropathic pain through protein kinase C-mediated activation of presynaptic NMDA receptors in the spinal cord.

摘要: Chemotherapeutic drugs, including bortezomib, often cause painful peripheral neuropathy, which is a severe dose-limiting adverse effect experienced by many cancer patients. The glutamate N-methyl-d-aspartate receptors (NMDARs) at the spinal cord level are critically involved in synaptic plasticity associated with neuropathic pain. In this study, we determined whether treatment proteasome inhibitor, affects NMDAR activity of dorsal horn neurons. Systemic bortezomib rats did not significantly affect postsynaptic currents elicited puff application NMDA directly to Bortezomib markedly increased baseline frequency miniature excitatory (EPSCs), was completely normalized antagonist 2-amino-5-phosphonopentanoic acid (AP5). AP5 also reduced amplitude monosynaptic EPSCs evoked root stimulation bortezomib-treated, but vehicle-treated, rats. Furthermore, inhibition protein kinase C (PKC) chelerythrine fully reversed and bortezomib-treated Intrathecal injection both profoundly attenuated mechanical allodynia hyperalgesia induced systemic bortezomib. addition, striking membrane translocation PKC-βII, PKC-δ, PKC-e ganglion. Our findings indicate that potentiates nociceptive input from primary afferent nerves via PKC-mediated tonic activation presynaptic NMDARs. Targeting NMDARs PKC may be an effective strategy for treating chemotherapy-induced