title: Loperamide inhibits sodium channels to alleviate inflammatory hyperalgesia.
abstract: Previous studies demonstrated that Loperamide, originally known as an anti-diarrheal drug, is a promising analgesic agent primarily targeting mu-opioid receptors. However some evidences suggested that non-opioid mechanisms may be contributing to its analgesic effect. In the present study, Loperamide was identified as a Nav1.7 blocker in a pilot screen. In HEK293 cells expressing Nav1.7 sodium channels, Loperamide blocked the resting state of Nav1.7 channels (IC50= 1.86 ± 0.11 μM) dose-dependently and reversibly. Loperamide produced a 10.4 mV of hyperpolarizing shift for the steady-state inactivation of Nav1.7 channels without apparent effect on the voltage-dependent activation. The drug displayed a mild use- and state-dependent inhibition on Nav1.7 channels, which was removed by the local anesthetic-insensitive construct Nav1.7-F1737A. Inhibition of Nav1.7 at resting state was not altered significantly by the F1737A mutation. Compared to its effects on Nav1.7, Loperamide exhibited higher potency on recombinant Nav1.8 channels in ND7/23 cells (IC50= 0.60 ± 0.10 μM) and weaker potency on Nav1.9 channels (3.48 ± 0.33 μM). Notably more pronounced inhibition was observed in the native Nav1.8 channels (0.11 ± 0.08 μM) in DRG neurons. Once mu-opioid receptor was antagonized by Naloxone in DRG neurons, potency of Loperamide on Nav1.8 was identical to that of recombinant Nav1.8 channels. The inhibition on Nav channels may be the main mechanism of Loperamide for pain relief beyond mu-opioid receptor. In the meanwhile, the opioid receptor pathway may also influence the blocking effect of Loperamide on sodium channels, implying a cross-talk between sodium channels and opioid receptors in pain processing.
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wu
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, High Throughput Biology Center and Johns Hopkins Ion Channel Center, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Beiyan
authors.initials: B
authors.lastname: Zou
authors.affiliation: Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA.
authors.forename: Lingli
authors.initials: L
authors.lastname: Liang
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA.
authors.forename: Yuan-Xiang
authors.initials: YX
authors.lastname: Tao
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address: haiboyu@imm.ac.cn.
authors.forename: Haibo
authors.initials: H
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address: wangxl@imm.ac.cn.
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Wang
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, High Throughput Biology Center and Johns Hopkins Ion Channel Center, Johns Hopkins University, Baltimore, MD 21205, USA. Electronic address: min.x.li@gsk.com.
authors.forename: Min
authors.initials: M
authors.lastname: Li
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016466:CHO Cells; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D007249:Inflammation / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D008139:Loperamide / Q000494:pharmacology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D017450:Receptors, Opioid, mu; D011994:Recombinant Proteins; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D008139:Loperamide
keywords: Loperamide; Nav1.7; Opioid receptor; Pain; Sodium channel