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Background: Postoperative ileus (POI) is abdominal surgery‐induced impaired gastrointestinal (GI) motility. We aimed to investigate the effects of DA‐9701, a prokinetic agent formulated from Pharbitis Semen and Corydalis tuber, likely mediated via corticotrophin‐releasing factor (CRF) pathways, in a POI model. Methods: A laparotomy with cecal manipulation was performed to induce POI in guinea pigs. GI transit was measured based on charcoal migration after intragastric administration of DA‐9701 1, 3, and 10 mg kg−1. CRF1 receptor antagonist, CP‐154 526 (subcutaneous) or agonist, human/rat (h/r) CRF (intraperitoneal) was injected. Then, plasma adrenocorticotropic hormone (ACTH) levels were measured, and the average intensity of the CRF expression was analyzed in the proximal colon and hypothalamus, and c‐Fos in the hypothalamus. Key Results: DA‐9701 significantly increased delayed GI transit in POI in a dose‐dependent manner and decreased plasma ACTH levels at 10 mg kg−1. CP‐154 526 significantly decreased plasma ACTH levels but was not as effective on GI transit as DA‐9701 was. h/r CRF did not significantly affect GI transit and plasma ACTH levels. No significant difference was observed in GI transit and plasma ACTH levels in both groups administered DA‐9701 with h/r CRF and h/r CRF alone. CRF expression in the proximal colon decreased after DA‐9701 administration, but not significantly, compared with levels in POI alone. However, CRF expression in the hypothalamus was significantly lower in the DA‐9701‐pretreated POI than in the untreated POI. Conclusions and Inferences: The DA‐9701‐induced improvement in GI transit and inhibition of plasma ACTH levels was mediated by the central CRF pathway. [ABSTRACT FROM AUTHOR]

Background Parathyroid hormone-related protein ( PTHrP) that causes hypercalcemia of malignancy appears to function as an endogenous smooth muscle relaxant. For example, PTHrP released upon bladder wall distension relaxes detrusor smooth muscle to accommodate urine. Here, we explored mechanisms underlying PTHrP-induced suppression of the smooth muscle contractility in the gastric antrum that also undergoes a passive distension. Methods Effects of PTHrP on phasic contractions and electrical slow waves in the antral smooth muscle of the guinea pig stomach were studied using isometric tension and intracellular microelectrode recordings, respectively. Fluorescent immunohistochemistry was also carried out to identify the distribution of PTH/ PTHrP receptors. Key Results Parathyroid hormone-related protein (1-100 nM) reduced the amplitude of phasic contractions and the basal tension. Nω-nitro- l-arginine (L-NA, 100 μM), a nitric oxide ( NO) synthase inhibitor, or 1H-[1,2,4]oxadiazolo-[4, 3-a]quinoxalin-1-one (ODQ, 10 µM), a guanylate cyclase inhibitor, diminished the PTHrP (10 nM)-induced reduction in the amplitude of phasic contractions. SQ22536 (300 μM), an adenylate cyclase inhibitor, attenuated the PTHrP-induced reduction in basal tension. The combination of ODQ (10 μM) and SQ22536 (300 μM) inhibited the PTHrP-induced reductions in both phasic contractions and basal tension. PTHrP (100 nM) had no inhibitory effect on the electrical slow waves in the antral smooth muscle. PTH/ PTHrP receptors were expressed in cell bodies of PGP9.5-positive neurons in the myenteric plexus. Conclusions & Inferences Parathyroid hormone-related protein exerts its inhibitory actions on the antral smooth muscle via both nitric oxide-cyclic guanosine monophosphate (NO-cGMP) and cyclic adenosine monophosphate (AMP) pathways. Thus, PTHrP may act as an endogenous relaxant of the gastric antrum employing the two complementary signaling pathways to ensure the adaptive relaxation of stomach. [ABSTRACT FROM AUTHOR]

Background Psychological stress has been shown to impair gastric accommodation (GA), but its mechanism has not been elucidated. This study was conducted to clarify the role of 5- HT2B receptors in a guinea pig model of stress-induced impairment of GA. Methods Gastric accommodation was evaluated by measuring the intrabag pressure in the proximal stomach after administration of a liquid meal. The guinea pigs were subjected to water-avoidance stress. The role of 5- HT2B receptors in impairment of GA was investigated by administering a 5- HT2B receptor agonist ( BW723C86) or antagonist ( SB215505), the traditional Japanese medicine rikkunshito ( RKT), a muscarinic M3 receptor antagonist (1,1-dimethyl-4-diphenylacetoxypiperidium iodide [4-DAMP]), or a nitric oxide synthase inhibitor (N ω-nitro-L-arginine [L- NNA]). Key Results In normal animals, liquid meal-induced GA was inhibited by BW723C86, but was not affected by SB215505. The inhibition of GA by BW723C86 was reversed by co-administration of 4-DAMP. Compared to normal animals, GA in stressed animals was significantly inhibited. SB215505 and RKT significantly suppressed stress-induced impairment of GA. After meal administration, the level of cyclic guanosine monophosphate in gastric fundus tissue increased by approximately twofold in normal animals, but did not change in stressed animals. The inhibition of GA by L- NNA was suppressed by SB215505 or RKT. At a dose that did not affect GA in normal animals, BW723C86 exacerbated the impairment of GA in stressed animals. Conclusions and Inferences Stress-induced impairment of GA may be mediated by an increased responsiveness of 5- HT2B receptors, and activation of the 5- HT2B receptor signaling pathway may have an inhibitory effect on nitric oxide function. [ABSTRACT FROM AUTHOR]

Background Gastroesophageal reflux can cause high acidity in the esophagus and trigger heartburn and pain. However, because of the esophageal mucosal barrier, the acidity at the nerve terminals of pain-mediating C-fibers in esophageal mucosa is predicted to be substantially lower. We hypothesized that the esophageal dorsal root ganglia ( DRG) C-fibers are activated by mild acid (compared to acidic reflux), and express receptors and ion channels highly sensitive to acid. Methods Extracellular single unit recordings of activity originating in esophageal DRG C-fiber nerve terminals were performed in the innervated esophagus preparation ex vivo. Acid was delivered in a manner that bypassed the esophageal mucosal barrier. The expression of mRNA for selected receptors in esophagus-specific DRG neurons was evaluated using single cell RT- PCR. Key Results Mild acid ( pH = 6.5-5.5) activated esophageal DRG C-fibers in a pH-dependent manner. The response to mild acid at pH = 6 was not affected by the TRPV1 selective antagonist iodo-resiniferatoxin. The majority (70-95%) of esophageal DRG C-fiber neurons ( TRPV1-positive) expressed mRNA for acid sensing ion channels ( ASIC1a, ASIC1b, ASIC2b, and/or ASIC3), two-pore-domain (K2P) potassium channel TASK1, and the proton-sensing G-protein coupled receptor OGR1. Other evaluated targets ( PKD2L1, TRPV4, TASK3, TALK1, G2A, GPR4, and TDAG8) were expressed rarely. Conclusions & Inferences Guinea pig esophageal DRG C-fibers are activated by mild acid via a TRPV1-independent mechanism, and express mRNA for several receptors and ion channels highly sensitive to acid. The high acid sensitivity of esophageal C-fibers may contribute to heartburn and pain in conditions of reduced mucosal barrier function. [ABSTRACT FROM AUTHOR]

Background Dietary iron supplementation is associated with gastrointestinal ( GI) side effects including vomiting, nausea, and diarrhea. Although inorganic iron in high concentrations may be damaging to the intestinal mucosa, we hypothesize that there are physiological effects on the GI tract that occur at concentrations achieved by supplementation. Thus, our aim was to investigate the effect of intraluminal ferrous sulfate ( FeSO4) on jejunal motility. Methods Segments of guinea pig jejunum were cannulated and the intraluminal pressure recorded with a transducer, while movements were recorded with a video camera. Peristaltic threshold was the oral pressure that evoked four consecutive propulsive contractions. The nutrients decanoic acid (1 mM), l-phenylalanine (50 mM), or the micronutrient FeSO4 (1 mM) were infused intraluminally. We also tested the effect of FeSO4 on electrochemically detected serotonin (5- HT, 5-hydroxytryptamine) released from in vitro tissues, both at rest and following mechanical stimulation. Key Results The jejuna peristaltic threshold was significantly decreased by all three nutrients: FeSO4: 31 ± 2-23 ± 3 mm H2O; decanoic acid: 27 ± 2-14 ± 2 mm H2O; and l-phenylalanine: 30 ± 3-14 ± 3mm H2O. Of the three, only decanoic acid induced segmentation, while FeSO4 inhibited decanoic acid-induced segmentation. Resting 5- HT release was increased by FeSO4 (128% of control), but mechanically evoked 5- HT release was reduced (70% of control). Conclusions & Inferences These data suggest that some luminal effects of inorganic iron on jejunal motility could be mediated through a pathway involving altered release of 5- HT. A better understanding of the interaction between luminal iron and 5- HT containing enterochromaffin cells could improve iron supplementation strategies, thus reducing side effects. [ABSTRACT FROM AUTHOR]

Background In the subserosal layer between the longitudinal muscle layer and mesothelium, heterogeneous populations of interstitial cells are distributed. As the distribution of nerve elements in this layer is sparse as compared with the nerve plexus layer or tunica muscularis, there may be unique communication among subserosal interstitial cells ( SSICs). This study aimed to explore functional properties of SSICs. Methods In subserosal preparations of the guinea-pig proximal colon, changes in intracellular Ca2+ ([ Ca2+]i) were visualized using Fluo-4 Ca2+ imaging. Immunohistochemistry was also performed to identify the SSICs exhibiting Ca2+ transients. Key Results A majority of SSICs responded to adenosine triphosphate ( ATP, 10 μM) by increasing [ Ca2+]i, but remained quiescent during the application of acetylcholine (10 μM). ATP-induced Ca2+ responses were mimicked by adenosine 5′-diphosphate (10 μM), MRS2365 (10 nM) but not α, β-methylene ATP (10 μM) or uridine triphosphate (10 μM), and could be reproduced in Ca2+-free solution, suggesting that ATP acts via P2Y receptors, most likely P2Y1 subtype, but not P2X receptors. Live staining of the same preparations after Ca2+ imaging indicated the ATP-sensitive SSICs were not positive for c-Kit antibody, a specific marker for gastrointestinal interstitial cells of Cajal ( ICC). Immunohistochemistry identified vimentin (mesenchymal cell marker)+/Kit- and SK3 (fibroblast-like cell ( FLC) marker)+/Kit- cells that had a similar morphology to the ATP-sensitive SSICs in Ca2+ imaging. Conclusions & Inferences A majority of the SSICs in the guinea-pig proximal colon, presumably FLC, are capable of responding to ATP and thus may contribute to smooth muscle relaxation upon stimulation with ATP released from non-neuronal cells. [ABSTRACT FROM AUTHOR]

Background Enteric viscerofugal neurons provide cholinergic synaptic inputs to prevertebral sympathetic neurons, forming reflex circuits that control motility and secretion. Extracellular recordings of identified viscerofugal neurons have not been reported. Methods Preparations of guinea pig distal colon were maintained in organotypic culture for 4-6 days ( n = 12), before biotinamide tracing, immunohistochemistry, or extracellular electrophysiological recordings from colonic nerves. Key Results After 4-6 days in organ culture, calcitonin gene-related peptide and tyrosine hydroxylase immunoreactivity in enteric ganglia was depleted, and capsaicin-induced firing (0.4 μmol L−1) was not detected, indicating that extrinsic sympathetic and sensory axons degenerate in organ culture. Neuroanatomical tracing of colonic nerves revealed that viscerofugal neurons persist and increase as a proportion of surviving axons. Extracellular recordings of colonic nerves revealed ongoing action potentials. Interestingly, synchronous bursts of action potentials were seen in 10 of 12 preparations; bursts were abolished by hexamethonium, which also reduced firing rate (400 μmol L−1, P < 0.01, n = 7). DMPP (1,1-dimethyl-4-phenylpiperazinium; 10−4 mol L−1) evoked prolonged action potential discharge. Increased firing preceded both spontaneous and stretch-evoked contractions (χ2 = 11.8, df = 1, P < 0.001). Firing was also modestly increased during distensions that did not evoke reflex contractions. All single units (11/11) responded to von Frey hairs (100-300 mg) in hexamethonium or Ca2+-free solution. Conclusions & Inferences Action potentials recorded from colonic nerves in organ cultured preparations originated from viscerofugal neurons. They receive nicotinic input, which coordinates ongoing burst firing. Large bursts preceded spontaneous and reflex-evoked contractions, suggesting their synaptic inputs may arise from enteric circuitry that also drives motility. Viscerofugal neurons were directly mechanosensitive to focal compression by von Frey hairs. [ABSTRACT FROM AUTHOR]

Mechanoreceptors to the internal anal sphincter (IAS) contribute to continence and normal defecation, yet relatively little is known about their function or morphology. We investigated the function and structure of mechanoreceptors to the guinea pig IAS. Extracellular recordings from rectal nerve branches to the IAS in vitro, combined with anterograde labeling of recorded nerve trunks, were used to characterize extrinsic afferent nerve endings activated by circumferential distension. Slowly adapting, stretch-sensitive afferents were recorded in rectal nerves to the IAS. Ten of 11 were silent under basal conditions and responded to circumferential stretch in a saturating linear manner. Rectal nerve afferents responded to compression with von Frey hairs with low thresholds (0.3-0.5 mN) and 3.4 ± 0.5 discrete, elongated mechanosensitive fields of innervation aligned parallel to circular muscle bundles (length = 62 ± 16 mm, n = 10). Anterogradely labeled rectal nerve axons typically passed through sparse irregular myenteric ganglia adjacent to the IAS, before ending in extensive varicose arrays within the circular muscle and, to a lesser extent, the longitudinal muscle overlying the IAS. Few (8%) IAS myenteric ganglia contained intraganglionic laminar endings. In eight preparations, mechanotransduction sites were mapped in combination with successful anterograde fills. Mechanotransduction sites were strongly associated with extensive fine varicose arrays within the circular muscle ( P < 0.05), and not with any other neural structures. Mechanotransduction sites for low-threshold, slowly adapting mechanoreceptors innervating the IAS are likely to correspond to extensive fine varicose arrays within the circular muscle. [ABSTRACT FROM AUTHOR]

Background H2S actions in the gut involve neural activation. This study aimed to reveal the signaling mechanisms responsible for the pro-secretory effect of H2S by using TRPV1 and unselective TRP blockers and inhibitors of other signaling cascades hitherto described to be targeted by H2S elsewhere. Methods Ussing chamber voltage clamp technique was used to study actions of the H2S donor NaHS on secretion in guinea-pig and human colon. NaHS effects on guinea-pig primary afferents were also evaluated. Key Results NaHS evoked secretion was significantly reduced in guinea-pig and human tissue by the selective TRPV1 blockers capsazepine, AMG9801, SB705498, BCTC; LY294002 (Phosphatidylinositol-3 kinase (PI3K) inhibitor), SKF96365 (store operated calcium channel blocker), 2-APB (inositol triphosphate blocker), and atropine but not by HC030031 (TRPA1 blocker) or L- and T-type calcium channel antagonists. Actions of TRPV1 antagonists suggested non-competitive inhibition at multiple sites. In guinea-pig colon, Gd3+and La3+ (unselective TRP blockers) had no effects while ruthenium red reduced NaHS effects; in human colon Gd3+attenuated NaHS response. NaHS response was inhibited by neurokinin-1 and -3 receptor blockers in guinea-pig and neurokinin-1 and -2 receptor blockade in human tissue. There was cross-desensitization between NaHS and capsaicin responses. NaHS induced capsazepine and LY294002 sensitive afferent discharge. Conclusions & Inferences H2S evokes mucosal secretion by targeting TRPV1 expressing afferent nerves which activate cholinergic secretomotor neurons via release of substance P acting in a species dependent manner on neurokinin-1, -2 or -3 receptors. Besides TRPV1 signaling H2S may target intracellular calcium dependent pathways and PI3K. [ABSTRACT FROM AUTHOR]

Background Endothelin (ET) modulates motility of the internal anal sphincter through unclear receptor subtypes. Methods We measured relaxation of guinea pig internal anal sphincter strips caused by ET-related peptides and binding of 125I-ET-1 to cell membranes prepared from the internal anal sphincter muscle. Visualization of 125I-ET-1 binding sites in tissue was performed by autoradiography. Key Results In the guinea pig internal anal sphincter, ET-1 caused a marked relaxation insensitive to tetrodotoxin, atropine, or ω-conotoxin GVIA. ET-2 was as potent as ET-1. ET-3 caused a mild relaxation. The relative potencies for ETs to cause relaxation were ET-1 = ET-2 > ET-3. The ET-1-induced relaxation was inhibited by BQ-123, an ETA antagonist, but not by BQ-788, an ETB antagonist. These indicate that ETA receptors mediate the relaxation. The relaxant response of ET-1 was attenuated by LY 83583, KT 5823, Rp-8CPT-cGMPS, tetraethyl ammonium, 4-aminopyridine and N(omega)-nitro-l-arginine, but not significantly affected by NG-nitro-l-arginine methyl ester, NG-methyl-l-arginine, charybdotoxin, apamin, KT 5720, and Rp-cAMPS. These suggest the involvement of cyclic guanosine 3′,5′-cyclic monophosphate (cGMP), and potassium channels. Autoradiography localized 125I-ET-1 binding to the internal anal sphincter. Binding of 125I-ET-1 to the cell membranes prepared from the internal anal sphincter revealed the presence of two subtypes of ET receptors, ETA and ETB receptors. Conclusions & Inferences Taken together, these results demonstrate that ETA receptors mediate relaxation of guinea pig internal anal sphincter through the cGMP pathway. [ABSTRACT FROM AUTHOR]

Conventional preparations that record the effect of contractions on intestinal flow assess primarily net propulsion and not flow events that like mixing are essential for digestion and absorption. Here we recorded the flow of an ink bolus in response to peristaltic contractions of segments of guinea pig intestine. It took three to four contraction/relaxation cycles to disperse a tiny and compact ink bolus throughout the intestinal segment. This was achieved by stretching, propulsion and separation of the bolus into portions during the contraction phase, and return and confluence of the bolus portions during the relaxation phase. As the contraction advanced through the intestinal segment, it generated rapid retrograde flow through its narrow lumen; eddies (flow vortices) formed at upstream shoulder of the contracting segment and dispersed the ink radially. The contraction cleared much of the fluid from the intestinal segment; during the subsequent relaxation, fluid returned into the segment, and carried portions of the ink upstream into the segment where it coalesced with residual portions. The current video observations of luminal flow confirm earlier predictions on luminal flow derived from computations. These flow events are likely an important mechanism through which intestinal contractions promote digestion and absorption. [ABSTRACT FROM AUTHOR]

Polarized outputs of myenteric interneurons in guinea-pig small intestine have been well studied. However, the variety of motility patterns exhibited suggests that some interneuron targets remain unknown. We used antisera selected to distinguish interneuron varicosities and known myenteric neuron types to investigate outputs of three interneuron classes in guinea-pig jejunum; two classes of descending interneurons immunoreactive (IR) for somatostatin (SOM) or nitric oxide synthase (NOS)/vasoactive intestinal peptide (VIP), and one class of ascending interneurons [calretinin/enkephalin (ENK)-IR]. Varicosities apposed to immunohistochemically identified cell bodies were quantified by confocal microscopy. Intrinsic sensory neurons (calbindin-IR) were apposed by few varicosities. Cholinergic secretomotor neurons (neuropeptide Y-IR) were apposed by many SOM-IR varicosities. Longitudinal muscle excitatory motor neurons (calretinin-IR) were apposed by some VIP- and ENK-IR varicosities, but few SOM-IR varicosities. Ascending interneurons (calretinin-IR) were apposed by many varicosities of all types. NOS-IR interneurons and inhibitory motor neurons were apposed by numerous VIP-IR and SOM-IR varicosities. NOS-IR short inhibitory motor neurons were apposed by significantly fewer ENK-IR varicosities than other NOS-IR neurons. Based on the specific chemical coding of ascending (ENK) and descending (SOM) interneurons, we conclude that cholinergic secretomotor neurons and short inhibitory neurons are located in descending reflex pathways, while ascending interneurons and NOS-IR descending interneurons are focal points at which ascending and descending pathways converge. [ABSTRACT FROM AUTHOR]

Proteinase-activated receptor-1 (PAR1) and PAR2 mediate contraction in the guinea-pig gallbladder. To investigate and compare the effects mediated by PARs in the human gallbladder with those in the guinea-pig gallbladder, we measured contractions of isolated human and guinea-pig gallbladder strips caused by PAR agonists. Results in human were similar to those in guinea-pig gallbladder. The PAR1 agonists, thrombin, TFLLR-NH2 and SFLLRN-NH2, as well as the PAR2 agonists, trypsin, SLIGKV-NH2 and SLIGRL-NH2, caused contraction in both human and guinea-pig gallbladders. These indicate the existence of PAR1 and PAR2 mediating gallbladder contraction. Furthermore, the existence of PAR1 and PAR2 in the human gallbladder was confirmed by reverse transcription-polymerase chain reaction. In contrast, FSLLR-NH2, a PAR1 control peptide, and VKGILS-NH2, a PAR2 control peptide, as well as three PAR4 agonists, GYPGKF-NH2, GYPGQV-NH2 and AYPGKF-NH2, did not cause any contraction or relaxation. The contractile responses to TFLLR-NH2, SFLLRN-NH2 and trypsin in both human and guinea-pig gallbladders were insensitive to atropine and tetrodotoxin, suggesting direct effects. These results demonstrate that, similar to the guinea-pig gallbladder, both PAR1 and PAR2 but not PAR4 mediate muscle contraction in the human gallbladder. PAR1 and PAR2 may play important roles in the control of both human and guinea-pig gallbladder motility. [ABSTRACT FROM AUTHOR]

Persistent changes in gastrointestinal motility frequently accompany the resolution of colitis, through mechanisms that remain to be determined. Trinitrobenzene sulfonic acid (TNBS) colitis in the guinea pig decreases the rate of propulsive motility, causes hyperexcitability of AH neurons, and induces synaptic facilitation. The changes in motility and AH neurons are sensitive to cyclooxygenase-2 (COX-2) inhibition. The aim of this investigation was to determine if the motility and neurophysiological changes persist following recovery from colitis. Evaluations of inflammation, colonic motility and intracellular electrophysiology of myenteric neurons 8 weeks after TNBS administration were performed and compared to matched control conditions. Myeloperoxidase levels in the colons were comparable to control levels 56 days after TNBS treatment. At this time point, the rate of colonic motility was decreased relative to controls following treatment with TNBS alone or TNBS plus a COX-2 inhibitor. Furthermore, the electrical properties of AH neurons and fast synaptic potentials in S neurons were significantly different from controls and comparable to those detected during active inflammation. Collectively, these data suggest that altered myenteric neurophysiology initiated during active colitis persists long term, and provide a potential mechanism underlying altered gut function in individuals during remission from inflammatory bowel disease. [ABSTRACT FROM AUTHOR]

Electrophysiological recording methods provided evidence for presynaptic release of ATP from enteric neurones and postganglionic sympathetic fibres in the enteric nervous system (ENS) of guinea-pig intestine ( J Physiol Lond 2003; 550: 493–504). The released ATP acted at postsynaptic P2Y1 receptors to evoke slow synaptic excitation in neurones in the submucosal division of the ENS. Here, we report the cloning and characterization of the P2Y1 receptor, which was found in the guinea-pig submucosal layer. A 1178 bp cDNA clone was isolated from guinea-pig submucosal RNA by reverse transcription polymerase chain reaction (RT–PCR). The cDNA contained an open-reading frame of 1119 bp, encoding a 373 amino acid polypeptide of the same length and with 95% identity to the human P2Y1 receptor. Stable expression of the guinea-pig cDNA in human embryonic kidney (HEK)293 cells was accompanied by a marked increase in sensitivity for elevation of free intracellular calcium evoked by ATP or related nucleotides. The potency order for ATP and its analogues was: 2-methio-adenosine diphosphate > 2-methio-adenosine triphosphate > ADP > ATP- γ-S > ATP. The selective P2Y1 receptor antagonist, MRS2179, was a competitive antagonist for the receptor with a pA2 value of 6.5. The results add to existing evidence for expression of a functional P2Y1 purinergic receptor in neurones of the submucosal division of the ENS. [ABSTRACT FROM AUTHOR]

Background: The accumulation of eosinophils is mediated by the chemokine receptor‐3 (CCR3)‐eotaxin axis. Increased expression of eotaxin and its receptor is associated with inflammatory bowel disease (IBD). Activation of eosinophils causes the release of cationic proteins that are neurotoxic such as eosinophil‐derived neurotoxin (EDN). Damage to enteric neurons alters neurally controlled functions of the gut correlated with intestinal inflammation. We hypothesized that inhibition of the CCR3‐eotaxin axis will prevent inflammation‐induced functional changes to the gastrointestinal tract. Methods: Hartley guinea pigs were administered with trinitrobenzene sulfonate (TNBS; 30 mg/kg in 30% ethanol) intrarectally to induce colitis. A CCR3 receptor antagonist (SB 328437 [SB3]) was injected intraperitoneally 1 hour postinduction of colitis. Animals were euthanized 7 days post‐treatment and colon tissues were collected for ex vivo studies. The EDN‐positive eosinophils in the colon, indicating eosinophil activation, were quantified by immunohistochemistry. Effects of SB3 treatment on gross morphological damage, enteric neuropathy, and colonic dysmotility were determined by histology, immunohistochemistry, and organ bath experiments. Key Results: The number of EDN‐positive eosinophils was significantly increased in the lamina propria in close proximity to myenteric ganglia in inflamed colon. The TNBS‐induced inflammation caused significant damage to colonic architecture and inhibition of colonic motility. Treatment with SB3 antagonist attenuated inflammation‐associated morphological damage in the colon, reduced infiltration of EDN‐positive eosinophils and restored colonic motility to levels comparable to control and sham‐treated guinea pigs. Conclusion & Inferences: This is the first study demonstrating that inhibition of CCR3‐eotaxin axis alleviates enteric neuropathy and restores functional changes in the gut associated with TNBS‐induced colitis. Eosinophil accumulation is mediated by the chemokine receptor‐3 (CCR3)‐eotaxin axis. Treatment with a CCR3 receptor antagonist attenuated inflammation‐associated morphological damage in the colon, reduced infiltration of EDN‐positive eosinophils, and restored colonic motility to levels comparable to control and sham‐treated guinea pigs. Inhibition of CCR3‐eotaxin axis alleviates enteric neuropathy and restores functional changes in the gut associated with TNBS‐induced colitis. [ABSTRACT FROM AUTHOR]