The nucleus tractus solitarius mediates hyperalgesia induced by chronic pancreatitis in rats

Abstract

BACKGROUNDCentral sensitization plays a pivotal role in the maintenance of chronic pain induced by chronic pancreatitis (CP). We hypothesized that the nucleus tractus solitarius (NTS), a primary central site that integrates pancreatic afferents apart from the thoracic spinal dorsal horn, plays a key role in the pathogenesis of visceral hypersensitivity in a rat model of CP.AIMTo investigate the role of the NTS in the visceral hypersensitivity induced by chronic pancreatitis.METHODSCP was induced by the intraductal injection of trinitrobenzene sulfonic acid (TNBS) in rats. Pancreatic hyperalgesia was assessed by referred somatic pain via von Frey filament assay. Neural activation of the NTS was indicated by immunohistochemical staining for Fos. Basic synaptic transmission within the NTS was assessed by electrophysiological recordings. Expression of vesicular glutamate transporters (VGluTs), N-methyl-D-aspartate receptor subtype 2B (NR2B), and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subtype 1 (GluR1) was analyzed by immunoblotting. Membrane insertion of NR2B and GluR1 was evaluated by electron microscopy. The regulatory role of the NTS in visceral hypersensitivity was detected via pharmacological approach and chemogenetics in CP rats.RESULTSTNBS treatment significantly increased the number of Fos-expressing neurons within the caudal NTS. The excitatory synaptic transmission was substantially potentiated within the caudal NTS in CP rats (frequency: 5.87 ± 1.12 Hz in CP rats vs 2.55 ± 0.44 Hz in sham rats, P < 0.01; amplitude: 19.60 ± 1.39 pA in CP rats vs 14.71 ± 1.07 pA in sham rats; P < 0.01). CP rats showed upregulated expression of VGluT2, and increased phosphorylation and postsynaptic trafficking of NR2B and GluR1 within the caudal NTS. Blocking excitatory synaptic transmission via the AMPAR antagonist CNQX and the NMDAR antagonist AP-5 microinjection reversed visceral hypersensitivity in CP rats (abdominal withdraw threshold: 7.00 ± 1.02 g in CNQX group, 8.00 ± 0.81 g in AP-5 group and 1.10 ± 0.27 g in saline group, P < 0.001). Inhibiting the excitability of NTS neurons via chemogenetics also significantly attenuated pancreatic hyperalgesia (abdominal withdraw threshold: 13.67 ± 2.55 g in Gi group, 2.00 ± 1.37 g in Gq group, and 2.36 ± 0.67 g in mCherry group, P < 0.01).CONCLUSIONOur findings suggest that enhanced excitatory transmission within the caudal NTS contributes to pancreatic pain and emphasize the NTS as a pivotal hub for the processing of pancreatic afferents, which provide novel insights into the central sensitization of painful CP.

Anterior Cingulate Cortex Mediates Hyperalgesia and Anxiety Induced by Chronic Pancreatitis in Rats

“…In addition, the neurocircuitry in the ACC that is the basis of the modulation of painful CP has received little attention. Our previous studies support the hypothesis that the NTS is an important central site for the processing of visceral pain caused by CP and angina pectoris [27,28]. We propose that the ACC may receive direct visceral pain inputs from the NTS, and neuroplastic changes within the ACC are involved in hyperalgesia and comorbid anxiety under the condition of painful CP.…”

Acupuncture Regulates Symptoms of Parkinson’s Disease via Brain Neural Activity and Functional Connectivity in Mice

“…In other studies, the stimulation of the vagus nerve had neuroprotective effects in the PD model (Farrand et al, 2020 ). From these perspectives, the elevated levels of c-Fos-positive cells found in the Sol seem to be related to the mechanism of anti-inflammation process against PD pathogenesis (Bonaz et al, 2017 ; Bai et al, 2019 ). However, further studies are warranted to reveal the exact mechanism associated with the increase of c-Fos neurons by acupuncture.…”

Spinal VGLUT3 lineage neurons drive visceral mechanical allodynia but not visceromotor reflexes

“…Future studies will be directed to determine if DSS-induced inflammation might cause a reduction of inhibitory inputs and/or an increase of excitatory inputs to spinal VGLUT3 lineage neurons, such that low-threshold colorectal distension can sufficiently activate VGLUT3 neurons, followed by T neuron activation to drive affective pain. One hallmark for inflammatory visceral pain manifestation is the development of referred cutaneous mechanical hypersensitivity (Bai et al, 2019;Bielefeldt et al, 2006;Bourdu et al, 2005;Cao et al, 2021;Gao et al, 2021;Jain et al, 2022;Laird et al, 2000;Laird et al, 2002;Lv et al, 2019;Traub et al, 2008;Zhou et al, 2008).…”

“…Future studies will be directed to determine if DSS-induced inflammation might cause a reduction of inhibitory inputs and/or an increase of excitatory inputs to spinal VGLUT3 lineage neurons, such that low-threshold colorectal distension can sufficiently activate VGLUT3 neurons, followed by T neuron activation to drive affective pain. One hallmark for inflammatory visceral pain manifestation is the development of referred cutaneous mechanical hypersensitivity (Bai et al, 2019; Bielefeldt et al, 2006; Bourdu et al, 2005; Cao et al, 2021; Gao et al, 2021; Jain et al, 2022; Laird et al, 2000; Laird et al, 2002; Lv et al, 2019; Traub et al, 2008; Zhou et al, 2008). Such referred hypersensitivity was also abolished in VGLUT3 Lbx1 -Abl mice, suggesting that VGLUT3 neurons must be part of previously proposed spinal circuits receiving convergent inputs from cutaneous and visceral afferents (Cervero, 2009; Cui et al, 2022; Fang et al, 2021; Fuentes and Christianson, 2018; Gebhart and Bielefeldt, 2016; Luz et al, 2015; Qiao and Tiwari, 2020).…”