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

Abstract

Central sensitization is essential in maintaining chronic pain induced by chronic pancreatitis (CP), but cortical modulation of painful CP remains elusive. Here, we examined the role of the anterior cingulate cortex (ACC) in the pathogenesis of abdominal hyperalgesia in a rat model of CP induced by intraductal administration of trinitrobenzene sulfonic acid (TNBS). TNBS treatment resulted in long-term abdominal hyperalgesia and anxiety in rats. Morphological data indicated that painful CP induced a significant increase in FOS-expressing neurons in the nucleus tractus solitarii (NTS) and ACC, and some FOS-expressing neurons in the NTS projected to the ACC. In addition, a larger portion of ascending fibers from the NTS innervated pyramidal neurons, the neural subpopulation primarily expressing FOS under the condition of painful CP, rather than GABAergic neurons within the ACC. CP rats showed increased expression of vesicular glutamate transporter 1, and increased membrane trafficking and phosphorylation of the N-methyl-D-aspartate receptor (NMDAR) subunit NR2B and the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) subunit GluR1 within the ACC. Microinjection of NMDAR and AMPAR antagonists into the ACC to block excitatory synaptic transmission significantly attenuated abdominal hyperalgesia in CP rats, which was similar to the analgesic effect of endomorphins injected into the ACC. Specifically inhibiting the excitability of ACC pyramidal cells via chemogenetics reduced both hyperalgesia and comorbid anxiety, whereas activating these neurons via optogenetics failed to aggravate hyperalgesia and anxiety in CP rats. Taken together, these findings provide neurocircuit, biochemical, and behavioral evidence for involvement of the ACC in hyperalgesia and anxiety in CP rats, as well as novel insights into the cortical modulation of painful CP, and highlights the ACC as a potential target for neuromodulatory interventions in the treatment of painful CP.

Regional activity alterations in Parkinson’s disease patients with anxiety disorders: A resting-state functional magnetic resonance imaging study

“…ACC is mainly related to selfconcentration of attention, self-regulation of emotion, and situational memory extraction (Alexander et al, 2021;Scotti-Muzzi et al, 2021). Previous study has reported that ACC was involved in anxiety disorder caused by physiological diseases (Chaibi et al, 2021;Ren et al, 2021). Our study consistently found that the increased ReHo values in PD-A patients were positively correlated with the HAMA scores, suggesting that alteration of ReHo in ACC might cause the dysfunction of self-emotion and consciousness regulation in PD patients, and thus inducing anxiety symptoms.…”

Third Special Issue on Mechanisms of Pain and Itch

“…In this study, CP was induced by intraductal administration of trinitrobenzene sulfonic acid, and this model resulted in long-term abdominal hyperalgesia and anxiety in rats. Using chemogenetics, the authors found that specific inhibition of ACC pyramidal cells not only reduced the hyperalgesia but also alleviated anxiety, a major comorbidity of chronic pain in male Sprague-Dawley rats [6]. This study further supported an important role of the ACC in the regulation of pain and anxiety.…”

Low-Intensity Focused Ultrasound Alleviates Chronic Neuropathic Pain-Induced Allodynia by Inhibiting Neuroplasticity in the Anterior Cingulate Cortex

“…Structural remodeling was detected in the ACC, manifested by an increase in dendritic spine density and the number of synapses in a rat model of CCI-induced pain, thereby mediating the occurrence of pain. Furthermore, recent research has found that the enhancement of neural remodeling in the ACC caused by injecting trinitrobenzenesulfonic acid into the pancreatic duct is involved in the development and maintenance of visceral pain sensitivity and anxiety in rats, which supports a strong link between ACC neuroplasticity and chronic pain [ 51 ]. In our present study, WB and IF staining both demonstrated that the expression levels of neuroplasticity-related proteins (MAP2, GAP43, and tau) decreased significantly.…”