Bulleyaconitine A Inhibits Visceral Nociception and Spinal Synaptic Plasticity through Stimulation of Microglial Release of Dynorphin A

Neural Plast. 2020 May 23:2020:1484087. doi: 10.1155/2020/1484087. eCollection 2020.

Abstract

Background: Visceral pain is one of the most common types of pain and particularly in the abdomen is associated with gastrointestinal diseases. Bulleyaconitine A (BAA), isolated from Aconitum bulleyanum, is prescribed in China to treat chronic pain. The present study is aimed at evaluating the mechanisms underlying BAA visceral antinociception.

Methods: The rat model of chronic visceral hypersensitivity was set up by colonic perfusion of 2,4,6-trinitrobenzene sulfonic acid (TNBS) on postnatal day 10 with coapplication of heterotypic intermittent chronic stress (HeICS).

Results: The rat model of chronic visceral hypersensitivity exhibited remarkable abdominal withdrawal responses and mechanical hyperalgesia in hind paws, which were dose-dependently attenuated by single subcutaneous of administration of BAA (30 and 90 μg/kg). Pretreatment with the microglial inhibitor minocycline, dynorphin A antiserum, and κ-opioid receptor antagonist totally blocked BAA-induced visceral antinociception and mechanical antihyperalgesia. Spontaneous excitatory postsynaptic currents (sEPSCs) in spinal dorsal horn lamina II neurons were recorded by using whole-cell patch clamp. Its frequency (but not amplitude) from TNBS-treated rats was remarkably higher than that from naïve rats. BAA (1 μM) significantly reduced the frequency of sEPSCs from TNBS-treated rats but not naïve rats. BAA-inhibited spinal synaptic plasticity was blocked by minocycline, the dynorphin A antiserum, and κ-opioid receptor antagonist. Dynorphin A also inhibited spinal synaptic plasticity in a κ-opioid receptor-dependent manner.

Conclusions: These results suggest that BAA produces visceral antinociception by stimulating spinal microglial release of dynorphin A, which activates presynaptic κ-opioid receptors in afferent neurons and inhibits spinal synaptic plasticity, highlighting a novel interaction mode between microglia and neurons.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aconitine / administration & dosage
  • Aconitine / analogs & derivatives*
  • Analgesics / administration & dosage*
  • Animals
  • Dynorphins / metabolism*
  • Female
  • Microglia / drug effects*
  • Microglia / metabolism
  • Neuronal Plasticity / drug effects*
  • Nociception / drug effects*
  • Posterior Horn Cells / drug effects
  • Posterior Horn Cells / physiology
  • Rats, Sprague-Dawley
  • Synapses / drug effects*
  • Synapses / physiology
  • Synaptic Transmission / drug effects
  • Visceral Pain / metabolism
  • Visceral Pain / prevention & control*

Substances

  • Analgesics
  • Dynorphins
  • bulleyaconitine A
  • Aconitine