Published online Oct 28, 2019. doi: 10.3748/wjg.v25.i40.6077
Peer-review started: July 19, 2019
First decision: August 18, 2019
Revised: September 6, 2019
Accepted: September 11, 2019
Article in press: September 11, 2019
Published online: October 28, 2019
Processing time: 102 Days and 12.2 Hours
Central sensitization plays a pivotal role in the maintenance of chronic pain induced by chronic pancreatitis (CP). Previous studies concerning the central processing of painful CP usually center on the spinal dorsal horn. However, much less focus has been directed on the nucleus tractus solitarius (NTS), another primary central site for pancreatic afferents, during painful CP.
We aimed to investigate the plastic changes of caudal NTS as well as its role in the development of painful CP in rats.
Chronic pancreatitis was established by intraductal injection of trinitrobenzene sulfonic acid (TNBS) in rats. Abdomen mechanical hypersensitivity was assessed by von Frey filament test. Then, immunohistochemical staining for Fos was performed to lay morphological evidence for NTS activation during painful CP, while patch-clamp recordings were performed to explore the changes of basic excitatory transmission of NTS in CP rats. Next, the expression of VGluT1, NMDAR subunit NR2B, and AMPAR subunit GluR1 was analyzed by immunoblottings. Membrane insertion of NR2B and GluR1 was evaluated by electron microscopy. Finally, AMPAR antagonist CNQX or NMDAR antagonist AP-5 was microinjected into the NTS to block the glutamatergic transmission on postoperative day (POD) 14 and then abdominal withdraw threshold (AWT) was tested. Chemogenetic method was also utilized to activate or inhibit the activity of excitatory NTS neurons on POD 14 and then AWT was tested.
TNBS treatment increased the number of Fos-expressing neurons within the caudal NTS. Both the frequency and amplitude of sEPSC of second-order neurons within the caudal NTS were substantially potentiated in CP rats. TNBS treatment upregulated the expression of VGluT2, and enhanced the phosphorylation and postsynaptic trafficking of NR2B and GluR1 within the caudal NTS. Blocking excitatory synaptic transmission increased the AWT of CP rats. Chemogenetic inhibition of the excitability of excitatory NTS neurons also significantly attenuated pancreatic hyperalgesia.
These data suggest that both presynaptic and postsynaptic mechanisms contribute to the enhanced excitatory transmission within the caudal NTS, which mediates visceral hypersensitivity under the condition of painful CP.
The results obtained deepen our understanding of central sensitization in pancreatic pain and support the caudal NTS, apart from the thoracic spinal cord, as another important central site for the processing of pancreatic pain, which may provide new clues for gastroenterologists and pain physicians in the treatment of CP.