Sinomenine as a novel analgesic : mechanisms and applications

Chronic pain of various origins is a major health care issue affecting a large patient population, also bring significant social and economic cost on the society. Work presented in this thesis concerns novel methods of treatments for chronic pain using experimental models. Sinomenine is a chemical compound isolated originally from the root of the plant Sinomenium Acutum native to China and Japan. It is an alkaloid, structurally belongs to the morphine family. The root of Sinomenium Acutum, known as Qingteng, has been traditionally used in China as a medical remedy for condition likely to be rheumatism. Sinomenine is currently approved in China as an anti-rheumatic agent for clinical sue.

In first part of the thesis, we studied the analgesic effect of sinomenine in chronic experimental pain models of neuropathic and arthritic pain. We showed that sinomenine has significant analgesic effects in rat and mouse models of neuropathic pain as well as in a mouse model (collagen antibody-induced arthritis model, CAIA) of arthritic pain. More importantly, the effect of sinomenine on neuropathic and arthritic pain is maintained upon repeated chronic administration without signs of tolerance or dependence.

In the second part of the thesis, we examined the possible application of sinomenine as an analgesic, we showed that combination with sinomenine with gabapentin, a clinically used drug treating neuropathic pain, produced marked synergistic interaction in rat and mouse models of neuropathic pain and such synergism can still be observed upon repeated administration without signs of tolerance and dependence. We can also show a similar synergistic interaction between gabapentin and dextromethorphan, a low affinity non-competitive NMDA antagonist. The work presented in this thesis suggested that sinomenine could be explored as a novel analgesic in treating neuropathic and arthritic pain. The results also showed combination therapy involving sinomenine, gabapentin and dextromethorphan might be useful in the clinic. The potential mechanisms for the effect of sinomenine and its interaction with other analgesics need to be further studied.

List of scientific papers

I. Gao T, Shi T, Wang D-Q, Wiesenfeld-Hallin Z, Xu X-J. Repeated sinomenine administration alleviates chronic neuropathic painlike behaviors in rodents without producing tolerance. Scand J Pain. 2014; 5(4): 249-255.
https://doi.org/10.1016/j.sjpain.2014.05.006

II. Gao T, Shi T, Wiesenfeld-Hallin Z, Svensson CI, Xu X-J. Sinomenine alleviates mechanical hypersensitivity in mice with experimentally induced rheumatoid arthritis. Scand J Pain. 2015; 7: 9-14.
https://doi.org/10.1016/j.sjpain.2014.12.003

III. Shi T, Gao T, Wang D-Q, Wiesenfeld-Hallin Z, Hao J-X, Xu X-J. Synergistic interaction between sinomenine and gabapentin in treating neuropathic pain. [Manuscript]

IV. Shi T, Hao J-X Wiesenfeld-Hallin Z, Xu X-J. Gabapentin and NMDA receptor antagonists interacts synergistically to alleviate allodynia in two rat models of neuropathic pain. Scand J Pain. 2018;18(4):687-693.
https://doi.org/10.1515/sjpain-2018-0083