Chronic neuropathic pain can cause serious physical as well as emotional harm to the patients. The analgesics currently commonly used in clinic have their limitations because of their side effects. Traditional Chinese Medicines have their own characteristics and advantages in treating pain, however, most of their underlying mechanisms are unclear and the majority of the researches mainly focused on the peripheral analgesic mechanisms. Sinomenine is the most important effective ingredient of Caulis Sinomenii in pain treatment, here, the central analgesic mechanisms of sinomenine in chronic neuropathic pain are explored. NMDA receptors in the spinal dorsal horn are critically involved in central sensitization and maintenance of neuropathic pain. Cyclin-dependent kinase 5 (CDK5) is a serine/threonine kinase and is involved in regulating NMDA receptor function. In this study, neuropathic pain was induced by ligation of the left L5 and L6 spinal nerves in rats. Nerve injury significantly increased the protein levels of calpain, CDK5 and P25 in the dorsal spinal cord ipsilateral to spinal nerve ligation (SNL) and induced hyperalgesia and allodynia in rats. The amplitude of NMDA receptor-mediated excitatory postsynaptic currents (EPSCs) and the NMDA-EPSC to AMPA-EPSC ratio in spinal lamina II neurons were significantly increased after nerve injury. Intrathecal application of sinomenine significantly reduced pain hypersensitivity and attenuated the increase in NMDA-EPSCs of dorsal horn neurons in nerve-injured rats. The expressions of calpain, CDK5 and P25 at the spinal level were also significantly inhibited after sinomenine treatment. Furthermore, sinomenine could significantly inhibit the voltage-gated calcium currents, especially the N- and P/Q-type currents in the dorsal horn neurons of the spinal cord and the dorsal root ganglion (DRG) neurons. Our data indicate that intrathecal application of sinomenine could inhibit the voltage-gated calcium channel function in spinal cord and DRG, which contributes to modulating the NMDA receptor function and chronic neuropathic pain through the calpain and p25 of CDK5 pathway. Supported by the National Key Research and Development Program of China (No. 2016YFC1305903) and the National Natural Science Foundation of China (No. 81373999 and No. 81774377).