Effect of genetic SSTR4 ablation on inflammatory peptide and receptor expression in the non‐inflamed and inflamed murine intestine

Abstract

The recently suggested pivotal role of somatostatin (SOM) receptor 4 (SSTR4) in inflammation and nociception in several non-intestinal organs and in gastrointestinal (GI) physiology, necessitates exploration of the role of SSTR4 in GI pathophysiology. Therefore, the role of SSTR4 in GI activity was explored by investigating the effects of SSTR4 deficiency on intestinal motility, smooth muscle contractility and on the expression of SSTRs and neuropeptides in the healthy and Schistosoma mansoni-infected murine small intestine. Functional experiments revealed no differences in intestinal motility or smooth muscle cell contractility between wild-type and SSTR4 knockout (SSTR4–/–) mice in physiological conditions. As revealed by multiple immunofluorescent labellings, RT-PCR and quantitative real time RT-PCR (qPCR), genetic deficiency of SSTR4 considerably altered the expression of SOM and SSTRs in non-inflamed and inflamed conditions, affecting both extrinsic and intrinsic components of the intestinal innervation, along with SSTR expression in several non-neuronal cell types. Moreover, substance P and calcitonin gene-related peptide expression were significantly elevated in SSTR4–/– mice, confirming the modulatory role of SSTR4 on intestinal pro-inflammatory neuropeptide expression. These data suggest that SSTR4 plays a previously unexpected modulatory role in the regulation of intestinal SSTR expression. Moreover, in addition to the recently described inhibitory effects of SSTR4 on the neuronal release of pro-inflammatory peptides, SSTR4 appears also to be involved in the neuronal expression of both pro- and anti-inflammatory peptides in the murine small intestine.

δ-Opioid Receptor and Somatostatin Receptor-4 Heterodimerization: Possible Implications in Modulation of Pain Associated Signaling

“…Previous studies have shown that amongst all SSTRs, SSTR4 is the only subtype that mediates analgesic effects of SST. Neurogenic and non-neurogenic inflammatory processes were significantly reduced upon administration of SSTR4 specific agonist in animal models [22]. Recently, SSTR specific knockout ( ko ) models have provided new insights for the role of SSTRs in certain pathophysiological conditions such as inflammation and analgesia [22], [23].…”

“…Neurogenic and non-neurogenic inflammatory processes were significantly reduced upon administration of SSTR4 specific agonist in animal models [22]. Recently, SSTR specific knockout ( ko ) models have provided new insights for the role of SSTRs in certain pathophysiological conditions such as inflammation and analgesia [22], [23]. Helyes et al, have described that SSTR4 ko mice are more susceptible to inflammation and exhibit sustained pain than wt mice [23].…”

Selective agonists of somatostatin receptor subtype 1 or 2 injected peripherally induce antihyperalgesic effect in two models of visceral hypersensitivity in mice

“…By contrast, the selective sst 4 agonist administered peripherally under similar conditions than the sst 1 agonist did not influence the VMR to repeated noxious CRD. In the somatic field, there is growing evidence that the sst 1,4 somatostatin agonist, TT-232 [17,51] and the sst 4 agonist, J-2156 [18], exert peripheral anti-inflammatory and analgesic effects in various acute and chronic inflammatory rodent models including chronic arthritis, or mono- and polyneuropathy conditions [45,56,57,61]. Further studies using different models of visceral pain, such as chemically-induced colonic inflammation or post-infectious hyperalgesia [32] will be required to elucidate the exact role of the sst 4 in visceral nociception linked with past or present gut inflammatory components.…”

Pathophysiology of GPCR Homo- and Heterodimerization: Special Emphasis on Somatostatin Receptors

“…These effects are mediated through ORs that comprise three subtypes-µ, δ, and κ, that are structurally related to SSTRs and share ~40% sequence homology. Recent studies have demonstrated that SSTRs also play a critical role in mediating analgesic effects of SST [188,221,222]. For instance, upon direct administration to the central and peripheral nervous system in animal model of post-operative and neoplastic pain, the SST analogue octreotide is both analgesic and morphine-sparing [223,224].…”