Activating metabotropic glutamate receptor‑7 attenuates visceral hypersensitivity in neonatal maternally separated rats

Abstract

Increasing evidence has indicated that metabotropic glutamate receptor-7 (mGluR7) is an important target for reducing anxiety and stress-associated behaviours. Notably, mood disorders exhibit high levels of comorbidity with gastrointestinal dysfunction; however, the role of mGluR7 outside of the central nervous system is currently unknown. Activating mGluR7 likely increases colonic secretory function. Therefore, the present study aimed to evaluate the possible effects of mGluR7 on the visceral hypersensitivity of irritable bowel syndrome (IBS) in rats. The expression levels of mGluR7 were assessed in the colon tissues of rats with neonatal maternal separation (NMS)-induced visceral hypersensitivity using reverse transcription-quantitative polymerase chain reaction, western blotting and immunohistochemistry. In addition, the mGluR7 agonist AMN082 (3 or 10 mg/kg; i.p.) was administered 1 h prior to the visceral hypersensitivity test, and the effects of AMN082 were then observed on the nuclear factor (NF)-κB signalling pathway. The mRNA and protein expression levels of mGluR7 were upregulated in the colon mucosa of NMS rats compared with in normal control rats. Notably, administration of AMN082 (10 mg/kg) attenuated colorectal distension (CRD)-induced visceral hypersensitivity in NMS rats. In addition, interleukin-10 and transforming growth factor-β mRNA expression levels were upregulated, whereas interferon-γ mRNA expression levels were downregulated in the NMS + AMN082 group compared with in NMS rats. The number of cluster of differentiation 3+ T cells in the intestinal mucosa and myeloperoxidase activity were decreased in NMS + AMN082 rats. Furthermore, AMN082 treatment reduced the protein expression levels of phosphorylated-NF-κB in the colon tissue of NMS rats. These results indicated that activation of mGluR7 may attenuate CRD-induced visceral hypersensitivity in experimental IBS and reduce the abnormal immune cytokine response. In addition, it was suggested that the role of AMN082 in modulating the inflammatory response may be partially associated with inhibiting NF-κB activation. These data suggested that targeting mGluR7 may be useful in the treatment of stress-associated IBS.

Early-life stress and inflammation: A systematic review of a key experimental approach in rodents

“…As with IL-6, findings regarding IL-10 expression in animals exposed to a second stress are mixed. Consistent with a pro-inflammatory state, five studies have reported decreased IL-10 expression in RMS animals, in the striatum, concurrently with increased IL-1β, IL-6, and TNF-α ( Dallé et al, 2017 ), the ventral hippocampus, together with higher IL-1β ( Wang et al, 2017 ), splenocytes cultured with LPS, along with non-significantly elevated TNF-α ( Kiank et al, 2009 ), the serum, together with increased IL-1β and TNF-α ( Réus et al, 2013 ), and colon tissue, alongside increased interferon gamma ( Shao et al, 2019 ). However, most studies have reported no effect of RMS on IL-10 expression, including in whole blood cultured with or without LPS or concanavalin A ( Desbonnet et al, 2010 ; O’Mahony et al, 2009 ), serum ( Breivik et al, 2015 ; Carboni et al, 2010 ; Wang et al, 2017 ), plasma ( Kruschinski et al, 2008 ), PFC ( Pinheiro et al, 2015 ; Wang et al, 2017 ), colon ( Pierce et al, 2014 , 2016 ), bladder ( Pierce et al, 2016 ), and lung ( Kruschinski et al, 2008 ), and an increase in IL-10 has been reported by three studies, in the genitourinary tract ( Pierce et al, 2014 ), hippocampus ( Pinheiro et al, 2015 ), and bladder ( Pierce et al, 2016 ).…”

Maternal separation in rodents: a journey from gut to brain and nutritional perspectives

“…This study suggests that TLR4 signalling in the PVN mediates increased CRF immunostaining and visceral hypersensitivity associated with MS. Interestingly, multiple MS-induced intestinal phenotypes, including visceral hyperalgesia and gut leakiness, can be prevented by CRF receptor antagonist administration (180,259,285–287) . GR antagonists or agonists of the metabotropic glutamate receptor type 7 (mGluR7) also prevent stress-induced visceral hyperalgesia (278,288–290) .…”

“…polymorphonuclear neutrophils) (262,305) and an increase in mucosal mast cell density (81,253,262,271,308) . MS also increases the expression of numerous cytokines including IL-6, IL-1β, TNFα, IFNγ, IL-4, IL-2 and IL-22 in the colonic mucosa (42,64,262,268,276,278,286,303,305,313) . Increased IFNγ and decreased IL-10 expression were prevented by mGluR7 agonist administration (278) in MS animals.…”

Electroacupuncture Improves IBS Visceral Hypersensitivity by Inhibiting the Activation of Astrocytes in the Medial Thalamus and Anterior Cingulate Cortex

“…e global prevalence of IBS is 10%, which seriously affects the quality of life [1,2]. Visceral hypersensitivity is the most important pathophysiological feature about IBS [3,4], but the mechanism is still unclear.…”