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

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.