Decreased Glutamatergic Synaptic Strength in the Periaqueductal Gray Contributes to Maintenance of Visceral Pain in Male Rats with Experimental Pancreatitis

Visceral pain originating from chronic inflammation of the pancreas is often intractable and difficult to manage clinically. However, the pathogenesis of the central nervous system underlying visceral pain is still poorly understood. The aim of the present study was to investigate the role of the midbrain ventrolateral periaque-ductal gray (vIPAG) in a rat model of chronic visceral pain induced by pancreatitis. In the present study, we used a well-established rat model of chronic pancreatitis induced by tail vein injection of dibutyltin dichloride (DBTC). To assess the DBTC-induced visceral pain, we examined the abdominal withdrawal by von Frey filament test. We further studied the synaptic transmission in the vIPAG by whole-cell patch-clamp electrophysiological recordings. Rats receiving DBTC injection exhibited a significantly increased withdrawal frequency to mechanical stimulation of the abdomen compared to rats injected with vehicle. Interestingly, compared to rats injected with vehicle, we found that neurons dissected from DBTC-treated rats exhibited a significantly decreased synaptic strength, which was revealed by a diminished alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/N-methyl-D-aspartic acid (AMPA/NMDA) ratio in the vIPAG. Moreover, our results further demonstrated that neurons obtained from DBTC-treated rats displayed a higher paired-pulse ratio, as well as less frequent and smaller amplitudes of miniature excitatory postsynaptic currents in the vIPAG compared to rats injected with vehicle. Furthermore, intravIPAG microinjection of AMPA alleviated DBTC-induced abdominal hypersensitivity. Taken together, our findings suggest that diminished glutamatergic synaptic strength via both presynaptic and postsynaptic mechanisms in the midbrain vIPAG is associated with DBTC-induced abdominal hypersensitivity. In addition, activation of AMPA receptors in the vIPAG alleviates DBTC-induced abdominal hypersensitivity. (C) 2019 IBRO. Published by Elsevier Ltd. All rights reserved.