Evodiamine suppresses capsaicin-induced thermal hyperalgesia through activation and subsequent desensitization of the transient receptor potential V1 channels.

Emiko Iwaoka,Koichi Noguchi,Shunji Aoki,Yi Dai,Shenglan Wang,Satoshi Yamamoto,Yoko Kogure,Nobuyuki Matsuyoshi

doi:10.1007/s11418-015-0929-1

Abstract

Evodiae fructus (EF), a fruit of Evodia rutaecarpa Bentham, has long been used as an analgesic drug in traditional Chinese and Japanese medicine. However, the underlying molecular mechanism of its pharmacological action is unclear. Here, using calcium imaging, whole-cell patch-clamp recording, and behavioral analysis, we investigated the pharmacological action of EF and its principal compound, evodiamine, on the transient receptor potential (TRP) V1 channels. Dorsal root ganglion (DRG) neurons and TRPV1- or TRPA1-transfected human embryonic kidney-derived (HEK) 293 cells were used for calcium imaging or whole-cell patch-clamp recording. Twenty male adult Sprague-Dawley rats were used for the capsaicin-induced thermal hyperalgesia behavioral analyses. We found that evodiamine induced significant increases in intracellular calcium and robust inward currents in a subpopulation of isolated rat DRG neurons, most of which were also sensitive to capsaicin. The effect of evodiamine was completely blocked by capsazepine, a competitive antagonist of TRPV1. Evodiamine induced significant inward currents in TRPV1-, but not TRPA1-transfected HEK293 cells. Pretreatment with evodiamine reduced capsaicin-induced currents significantly. Furthermore, the in vivo pre-treatment of evodiamine suppressed thermal hyperalgesia induced by intraplantar injection of capsaicin in rats. These results identify that the analgesic effect of EF and evodiamine may be due to the activation and subsequent desensitization of TRPV1 in sensory neurons.

Highlights

The transient receptor potential channel subfamily V member 1 (TRPV1), known as the capsaicin receptor, is expressed by a subset of the small-sized dorsal root ganglion (DRG) or trigeminal ganglia neurons [1]
We found that evodiamine induced significant increases in intracellular calcium and robust inward currents in a subpopulation of isolated rat Dorsal root ganglion (DRG) neurons, most of which were sensitive to capsaicin
We found that either the extract of Evodiae fructus (EF) or evodiamine caused a rapid elevation in intracellular calcium levels in a subpopulation of small-sized isolated rat DRG neurons; almost all of the evodiamine-sensitive neurons responded to capsaicin (Fig. 2a–c)

Summary

Introduction

The transient receptor potential channel subfamily V member 1 (TRPV1), known as the capsaicin receptor, is expressed by a subset of the small-sized dorsal root ganglion (DRG) or trigeminal ganglia neurons [1]. TRPV1 is activated by capsaicin, protons, or noxious heat (with a thermal threshold [43 °C), which causes pain in vivo [1, 2]. J Nat Med (2016) 70:1–7 acts as a molecular amplifier in the sensory neuron. These insights have renewed the interest in TRPV1 as an important site of analgesia. Whether evodiamine directly excites TRPV1 in sensory neurons has not been clarified yet. To the best of our knowledge, we report for the first time that evodiamine activates TRPV1 in sensory neurons. Our patch-clamp analyses indicate that the antinociceptive effect of evodiamine may be attributed to the evodiamineinduced activation and subsequent desensitization of TRPV1

Materials and methods

Results and discussion

Background

Conclusion