Levo-tetrahydropalmatine attenuates oxaliplatin-induced mechanical hyperalgesia in mice

Chemotherapy for cancer treatment often induces a form of unique peripheral neuropathy characterized by provoked and ongoing pain, which is increasingly considered as a serious side effect associated with some chemotherapeutic agents, including taxanes, platinum agents (e.g., oxaliplatin) and vinca alkaloids. The occurrence rate of chemotherapy-induced neuropathic pain varies substantially from 30–75% in the cancer patients, depending on the treatment regimens. Besides pain, other common peripheral sensory symptoms include paresthesias and dysesthesias, numbness and tingling, and sensitivity to touch and temperature. In addition, motor symptoms are also reported, including weakness and gait and balance disturbances1. Unfortunately, this kind of neuropathic pain is only partially reversible even long after the cessation of treatment and in some rare cases damage can be permanent. Currently, there is no effective pharmacotherapies that is considered safe and widely useful for the clinical control of chemotherapy-induced neuropathic pain. Thus, the development of alternative effective analgesics has been considered a crucial clinical need. Corydalis yanhusuo is a perennial herb in the Papaveraceae family and has long been used in traditional Chinese medicine. Contemporary phytochemistry studies of Corydalis yanhusuo started in 1960s and Hsu and Kin were the first to isolate l-tetrahydropalmatine (l-THP) from Corydalis yanhusuo and did the first pharmacological characterization of the compound2,3. l-THP has been identified as one of the major active components of Corydalis yanhusuo and it has been used clinically in China for more than 40 years as an analgesic with sedative/hypnotic properties4. However, although l-THP has been used for the treatment of headache and other mild pain in China, relatively few preclinical studies support these use and there is no study to examine the potential effectiveness of l-THP for the treatment of chronic neuropathic pain. Given the long clinical use of l-THP which has proved its human safety, exploring novel applications of this compound may expand its clinical usage. In this study, we described the potent anti-hyperalgesic effect of l-THP in a mice model of oxaliplatin-induced neuropathic pain. We also conducted antagonist studies to understand the receptor mechanisms of the anti-hyperalgesic actions. Our results revealed a primary dopamine D1 receptor mediated effect.