Deepening the Mechanisms of Visceral Pain Persistence: An Evaluation of the Gut-Spinal Cord Relationship

Abstract

The management of visceral pain is a major clinical problem in patients affected by gastrointestinal disorders. The poor knowledge about pain chronicization mechanisms prompted us to study the functional and morphological alterations of the gut and nervous system in the animal model of persistent visceral pain caused by 2,4-dinitrobenzenesulfonic acid (DNBS). This agent, injected intrarectally, induced a colonic inflammation peaking on day 3 and remitting progressively from day 7. In concomitance with bowel inflammation, the animals developed visceral hypersensitivity, which persisted after colitis remission for up to three months. On day 14, the administration of pain-relieving drugs (injected intraperitoneally and intrathecally) revealed a mixed nociceptive, inflammatory and neuropathic pain originating from both the peripheral and central nervous system. At this time point, the colonic histological analysis highlighted a partial restitution of the tunica mucosa, transmural collagen deposition, infiltration of mast cells and eosinophils, and upregulation of substance P (SP)-positive nerve fibers, which were surrounded by eosinophils and MHC-II-positive macrophages. A significant activation of microglia and astrocytes was observed in the dorsal and ventral horns of spinal cord. These results suggest that the persistence of visceral pain induced by colitis results from maladaptive plasticity of the enteric, peripheral and central nervous systems.

Carbonic Anhydrase IV Selective Inhibitors Counteract the Development of Colitis-Associated Visceral Pain in Rats

“…The KCC2 downregulation-mediated impairment of spinal cord Cl − homeostasis has been associated with chronic stress-induced visceral hypersensitivity and neonatal cystitis-induced visceral pain in rats [54,55]. Therefore, the modulation of visceral pain mediated by CA inhibitors might involve both the periphery and the spinal cord, which represents an important regulatory station along the pathways of visceral pain signalling [4].…”

“…The dose of AB-118 and NIK-67 was chosen on the basis of previous studies showing CA inhibitors' anti-hyperalgesic effects [8,12,13]. The substances were administered once daily for 14 days to evaluate the effect of CA IV inhibition on visceral pain development (Day 8, acute inflammatory phase of colitis) and on visceral pain persistence (Day 15, post-inflammatory phase of colitis) [4].…”

“…Although IBD-related symptoms have been classically attributed to intestinal inflammation, 20-50% of patients develop a chronic syndrome characterised by pain, bloating and dysmotility, which also persists after the remission of colitis [1][2][3]. The complex nature of this type of pain makes patients partially responsive to anti-inflammatory drugs, anticonvulsants or antidepressants, which are classically used in the management of pain syndromes [4,5].…”

“…Significant and persistent alterations in both the periphery and central nervous system have been documented in animals subjected to intestinal inflammatory damage [4,22]. Although it is not known whether a dysregulation of CA activity occurs in these processes, the commonalities existing between chronic visceral pain and neuropathic pain [4,23] make CA an interesting target to investigate in the search for new therapies for abdominal pain relief in patients affected by IBD.…”

Blockade of Erythropoietin-Producing Human Hepatocellular Carcinoma Receptor B1 in Spinal Dorsal Horn Alleviates Visceral Pain in Rats

“…Sections of full-thickness colon samples (8 μ m thick) were stained with hematoxylin (Leica Biosystems) and eosin (Leica Biosystems) and observed under microscopy. The levels of colonic damage were scored according to the criteria described in previous literature [ 36 , 37 ]: mucosal architecture loss (0–3); goblet cell depletion (0, absent; 1, present); crypt abscess (0, absent; 1, present); cellular infiltration (0–3); and tunica muscularis thickening (0–3).…”