Yan Zhang1, Chaoran Wang2, Lien Wang1, Gregory Scott Parks1, Xiuli Zhang2, Zhimou Guo2, Yanxiong Ke3, Kang-Wu Li4, Mi Kyeong Kim4, Benjamin Vo4, Emiliana Borrelli5, Guangbo Ge2, Ling Yang2, Zhiwei Wang1, M Julia Garcia-Fuster1, Z David Luo4, Xinmiao Liang6, Olivier Civelli7. 1. Department of Pharmacology, University of California, Irvine, Irvine, CA 92697, USA. 2. Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China. 3. School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China. 4. Department of Anesthesiology and Perioperative Care, University of California, Irvine, CA 92697, USA. 5. Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, CA 92697, USA. 6. Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China. Electronic address: liangxm@dicp.ac.cn. 7. Department of Pharmacology, University of California, Irvine, Irvine, CA 92697, USA; Department of Pharmaceutical Sciences, University of California, Irvine, Irvine, CA 92697, USA; Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697, USA. Electronic address: ocivelli@uci.edu.
Abstract
BACKGROUND: Current pain management is limited, in particular, with regard to chronic pain. In an attempt to discover novel analgesics, we combined the approach developed to characterize traditional Chinese medicine (TCM), as part of the "herbalome" project, with the reverse pharmacology approach aimed at discovering new endogenous transmitters and hormones. RESULTS: In a plant used for centuries for its analgesic properties, we identify a compound, dehydrocorybulbine (DHCB), that is effective at alleviating thermally induced acute pain. We synthesize DHCB and show that it displays moderate dopamine receptor antagonist activities. By using selective pharmacological compounds and dopamine receptor knockout (KO) mice, we show that DHCB antinociceptive effect is primarily due to its interaction with D2 receptors, at least at low doses. We further show that DHCB is effective against inflammatory pain and injury-induced neuropathic pain and furthermore causes no antinociceptive tolerance. CONCLUSIONS: Our study casts DHCB as a different type of analgesic compound and as a promising lead in pain management.
BACKGROUND: Current pain management is limited, in particular, with regard to chronic pain. In an attempt to discover novel analgesics, we combined the approach developed to characterize traditional Chinese medicine (TCM), as part of the "herbalome" project, with the reverse pharmacology approach aimed at discovering new endogenous transmitters and hormones. RESULTS: In a plant used for centuries for its analgesic properties, we identify a compound, dehydrocorybulbine (DHCB), that is effective at alleviating thermally induced acute pain. We synthesize DHCB and show that it displays moderate dopamine receptor antagonist activities. By using selective pharmacological compounds and dopamine receptor knockout (KO) mice, we show that DHCB antinociceptive effect is primarily due to its interaction with D2 receptors, at least at low doses. We further show that DHCB is effective against inflammatory pain and injury-induced neuropathic pain and furthermore causes no antinociceptive tolerance. CONCLUSIONS: Our study casts DHCB as a different type of analgesic compound and as a promising lead in pain management.