Cyclooxygenase-dependent alterations in substance P-mediated contractility and tachykinin NK1 receptor expression in the colonic circular muscle of patients with slow transit constipation.
ABSTRACT Tachykinins are important neurotransmitters regulating intestinal motility. Slow transit constipation (STC) represents an extreme colonic dysmotility with unknown etiology that predominantly affects women. We examined whether the tachykinin system is involved in the pathogenesis of STC. Isolated sigmoid colon circular muscle from female STC and control patients was studied using functional and quantitative reverse transcriptase-polymerase chain reaction methods. A possible alteration of neurotransmission was investigated by electrical field stimulation (EFS) and ganglionic stimulation by dimethylphenylpiperazinium (DMPP). Substance P (SP)-mediated contractions in circular muscle strips were significantly diminished in STC compared with age-matched control (P < 0.001). In contrast, contractile responses to neurokinin A, the selective tachykinin NK(2) receptor agonist, [Lys(5),MeLeu(9),Nle(10)]NKA(4-10), and acetylcholine were unaltered in STC. The reduced responses to SP in STC were fully restored by indomethacin, partially reversed by tetrodotoxin (TTX), but unaffected by atropine or hexamethonium. The restoration by indomethacin was blocked by the NK(1) receptor antagonist CP99994 [(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine] and TTX. In STC colonic muscle, there was a significant increase of NK(1) receptor mRNA expression, but no difference in NK(2) mRNA level. DMPP generated biphasic responses, relaxation at lower and contraction at higher concentrations. Although the responses to DMPP were similar in STC and control, an altered contractile pattern in response to EFS was observed in STC circular muscle. In conclusion, we postulate that the diminished contractile response to SP in STC is due to an increased release of inhibitory prostaglandins through activation of up-regulated NK(1) receptors. Our results also indicate some malfunction of the enteric nervous system in STC.
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ABSTRACT: Since the discovery of two cyclooxygenase isoforms (COX-1, COX-2), efforts have been made to characterize the roles played by these enzymes in the regulation of physiological functions, as well as to explore their involvement in the pathophysiology of inflammatory disorders. In the digestive tract, the majority of evidence has been obtained at mucosal level, where both isoforms regulate various functions, and contribute to the development of inflammatory and neoplastic disorders. The role of COX isoforms in the gut neuromuscular compartment, where their expression has been detected in different species, is still unclear. However, the characterization of actions exerted by COX-derived prostanoids on gut motility has been under investigation for many years, and it is becoming increasingly appreciated that these mediators subserve complex regulatory patterns of COX on digestive motility. More recently, several studies have strengthened the concept that both COX-1 and COX-2 are involved in the modulation of gastrointestinal neuromuscular activity under normal conditions, and that changes in their regulatory activities occur in the presence of various digestive disorders, including inflammatory bowel diseases and postoperative ileus. Despite a large body of preclinical evidence, studies aimed at translating these findings into clinically relevant applications are needed, in an attempt to identify novel therapeutic approaches for treatment of gut disorders associated with motility alterations. This review illustrates and discusses current knowledge of the roles played by COX pathways in the regulation of gastrointestinal neuromuscular functions, both under normal conditions and in the presence of gut disorders.Pharmacology [?] Therapeutics 10/2009; 125(1):62-78. · 7.79 Impact Factor
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ABSTRACT: Recurrent abdominal pain is reported by a third of patients with diverticulosis, particularly those with previous episodes of acute diverticulitis. The current understanding of the etiology of this pain is poor. Our aim was to assess visceral sensitivity in patients with diverticular disease and its association with markers of previous inflammation and neuropeptides. Patients with asymptomatic and symptomatic diverticular disease underwent a flexible sigmoidoscopy and biopsy followed 5-10 days later by visceral sensitivity testing with barostat-mediated rectal distension. Inflammation was assessed by staining of serotonin (5HT) and CD3 positive cells. mRNA levels of tumor necrosis factor alpha (TNF α) and interleukin-6 (IL-6) were quantitated using RT-PCR. Neuropeptide expression was assessed from percentage area staining with substance P (SP) and mRNA levels of the neurokinin 1 & 2 receptors (NK1 & NK2), and galanin 1 receptor (GALR1). Thirteen asymptomatic and 12 symptomatic patients were recruited. The symptomatic patients had a lower first reported threshold to pain (28.4 mmHg i.q.r 25.0-36.0) than the asymptomatic patients (47 mmHg i.q.r 36.0-52.5, P < 0.001). Symptomatic patients had a higher median overall pain rating for the stimuli than the asymptomatic patients (P < 0.02). Symptomatic patients had greater median relative expression of NK1 and TNF alpha mRNA compared with asymptomatic patients. There was a significant correlation between barostat VAS pain scores and NK 1 expression (Figure 4, r(2) 0.54, P < 0.02). Patients with symptomatic diverticular disease exhibit visceral hypersensitivity, and this may be mediated by ongoing low grade inflammation and upregulation of tachykinins.Neurogastroenterology and Motility 01/2012; 24(4):318-e163. · 2.94 Impact Factor