Down‐regulation of HTR1A‐modulated ACC activation contributes to stress‐induced visceral hyperalgesia in rats

Abstract

Background Long‐term stress was suggested to cause visceral hypersensitivity and promote functional gastrointestinal disorders (FGIDs). Some brain regions such as the anterior cingulate cortex (ACC) may play an important role for generating visceral hypersensitivity; however, its molecular mechanisms are not clear. This study aimed to explore the role of 5‐HT1A receptors (HTR1As) in activating ACC and corresponding mechanism, in stress‐induced visceral hyperalgesia rats. Methods The VH rat model was established by chronic water avoidance stress (WAS), and the visceral sensitivity was measured by electromyogram. Rat's anxiety‐like behaviors were evaluated by the open field test (OFT) and elevated plus maze (EPM). To overexpress or down‐regulate HTR1A expression, HTR1A‐specific lentivirus expressing the green fluorescent protein was administered into the ACC. Protein expression levels were observed by Western blot. Results The protein expression of HTR1A in bilateral ACC in WAS group was significantly lower than that in normal control (NC) and Sham‐WAS groups, while the levels of c‐fos in the ACC of WAS rats were significantly higher. Down‐regulation of HTR1As could induce VH in control rats with the increased expression of c‐fos, p‐ERK, and p‐Akt in ACC, while up‐regulation of HTR1As in the ACC could partly inhibit ACC sensitization and stress‐induced visceral hyperalgesia. Conclusions & Inferences Down‐regulation of HTR1As modulates ACC activation probably through activating ERK and Akt pathways, thus contributes to the formation of stress‐induced visceral hyperalgesia.

Up-regulation of HTR1A reverses stress-induced visceral hypersensitivity through modulating interactions among the anterior cingulate cortex, insular cortex and hippocampus

“…The nuclei of the limbic system, such as the ACC, IC and hippocampus, have been reported to be major components of emotional responses and pain perception, disorders of which might result in both visceral hypersensitivity and anxiety-like behaviours. In our previous research, HTR1A in the ACC was demonstrated to be a key receptor in psychological stress-induced IBS, mediating the generation of visceral hypersensitivity and anxiety-like behaviours [18]. However, it remained unclear whether HTR1A mediated these biological process via change in connectivity between the ACC and other nuclei.…”

“…Lentiviral vectors expressing rat HTR1A-targeting shRNA (LV-shRNA-HTR1A), HTR1A-GFP recombinant lentivirus vectors (LV-HTR1A) and control lentivirus GFP vectors (LV-GFP) were purchased from Novobiosci. The transduction efficiencies of these three kinds of lentivirus vectors in vitro and in vivo were tested in our previous study [18].…”

“…In our current study, thirty rats were subjected to lentiviral vector microinjection to regulate HTR1A expression in the ACC. Methods of anaesthesia and microinjection are described in detail in our previous study [18]. After microinjection, all rats were exposed to chronic WAS after three days of recovery.…”

“…For example, HTR1A has been associated with chronic stress-induced visceral hypersensitivity and neuropathic pain in pre-clinical rodent studies, and many clinical trials have suggested that activation of HTR1A (either directly or via 5-HT reuptake inhibition) in the CNS might ameliorate psychiatric and gastrointestinal symptoms of IBS [15,16]. Recently, down-regulation of HTR1A in some nuclei of the limbic system (including the ACC and IC) was observed in rats with viseral hypersensitivity induced by chronic water avoidance stress (WAS), and local up-regulation of HTR1A using lentiviral constructs or direct activation with a selective agonist could reverse the visceral hypersensitivity and anxiety-like behaviours [17,18]. All research mentioned above demonstrated the crucial role that 5-HT and HTR1A in the CNS, especially in some nuclei of the limbic system, play in the formation and maintenance of visceral hypersensitivity or IBS.…”

HTR1A Inhibits the Progression of Triple‐Negative Breast Cancer via TGF‐β Canonical and Noncanonical Pathways

“…[ 13 ] HTR1A, binding with its ligand 5‐HT (also known as serotonin), resulted in conformational changes and signaling pathway activation, such as PI3K/Akt and MAPK/ERK pathways. [ 20 , 21 ] Studies regarding the function of HTR1A are mainly focused on the nervous system, such as regulating depression by regulating self‐tolerance by deregulating gene expression. HTR1A also plays crucial roles in schizophrenia, [ 15 , 16 ] wound healing, [ 17 ] and attention deficit hyperactivity disorder.…”