1. Academic Validation
  2. Makatoxin-3, a thermostable Nav1.7 agonist from Buthus martensii Karsch (BmK) scorpion elicits non-narcotic analgesia in inflammatory pain models

Makatoxin-3, a thermostable Nav1.7 agonist from Buthus martensii Karsch (BmK) scorpion elicits non-narcotic analgesia in inflammatory pain models

  • J Ethnopharmacol. 2022 Apr 24;288:114998. doi: 10.1016/j.jep.2022.114998.
Yonggen Chen 1 Erjin Xu 1 Ming Sang 2 Zhiheng Wang 2 Yuxin Zhang 1 Juan Ye 2 Qian Zhou 2 Chenglei Zhao 2 Chunping Hu 2 Wuguang Lu 3 Peng Cao 4
Affiliations

Affiliations

  • 1 Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210028, China; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China.
  • 2 Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210028, China.
  • 3 Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210028, China; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China. Electronic address: luwuguang@njucm.edu.cn.
  • 4 Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210028, China; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China. Electronic address: cao_peng@njucm.edu.cn.
Abstract

Ethnopharmacological relevance: Chronic pain management represents a serious healthcare problem worldwide. The use of opioid analgesics for pain has always been hampered by their side effects; in particular, the addictive liability associated with chronic use. Finding a morphine replacement has been a long-standing goal in the field of analgesia. In traditional Chinese medicine, processed Buthus martensii Karsch (BmK) scorpion has been used as a painkiller to treat chronic inflammatory arthritis and spondylitis, so called "Scorpio-analgesia". However, the molecular basis and the underline mechanism for the Scorpio-analgesia are still unclear.

Aim of the study: The study aims to investigate the molecular basis of "Scorpio analgesia" and identify novel analgesics from BmK scorpion.

Materials and methods: In this study, the analgesic abilities were determined using formalin-, acetic acid- and complete Freund's adjuvant-induced pain models. The effect of BmK venom and processed BmK venom on Nav1.7 were detected by whole-cell voltage-clamp recordings on HEK293-hNav1.7 stable cell line. Action potentials in Dorsal root ganglion (DRG) neurons induced by Makatoxin-3-R58A were recorded in current-clamp mode. The content of Makatoxin-3 was detected using competitive enzyme-linked immunosorbent assay based on the Makatoxin-3 antibody. High performance liquid chromatography, western blot and circular dichroism spectroscopy were used to analysis the stability of Makatoxin-3.

Results: Here we demonstrate that Makatoxin-3, an α-like toxin in BmK scorpion venom targeting Nav1.7 is the critical component in Scorpio-analgesia. The analgesic effect of Makatoxin-3 could not be reversed by naloxone and is more potent than Nav1.7-selective inhibitors and non-steroidal anti-inflammatory drugs in inflammatory models. Moreover, a R58A mutant of Makatoxin-3 is capable of eliciting analgesia effect without inducing pain response.

Conclusions: This study advances ion channel biology and proposes Nav1.7 agonists, rather than the presumed Nav1.7-only blockers, for non-narcotic relief of chronic pain.

Keywords

Analgesic; Buthus martensii Karsch (BmK) scorpion; Chronic pain; Makatoxin-3; Nav1.7 agonists.

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