Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022104 (irritable bowel syndrome)
 8,033 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interstitial cystitis, a sterile bladder condition, is characterized by urinary frequency, urgency, burning and suprapubic pain. Increasing evidence indicates that interstitial cystitis is a heterogeneous syndrome that reflects an immune response to a variety of triggers. More than 50% of the patients have allergies, 30% have the irritable bowel syndrome and almost 20% suffer from migraine headaches. Increased numbers of mast cells have been reported in interstitial cystitis. Mast cell activation, which is critical if these cells were to be implicated in this syndrome, has been investigated by electron microscopy, which definitively shows mast cell secretion. Recently, methylhistamine, the major metabolite of histamine, and the specific mast cell marker, tryptase, were shown to be significantly elevated in urine of interstitial cystitis patients. Bladder biopsies from 53 patients were analyzed blindly for the number and degree of activation of mast cells using 4 different stains for light microscopy, as well as electron microscopy. Controls included 16 patients with incontinence and chronic bacterial cystitis. Mast cells in controls were less than 10/mm.2 and were all nearly intact. Surprisingly, mast cells from 11 cancer patients averaged 50/mm.2 but almost all were intact. In contrast, mast cells from 26 interstitial cystitis patients averaged 40/mm.2 and more than 90% were activated to various degrees. Therefore, bladder mast cell activation is a characteristic pathological finding in at least a subset of patients with interstitial cystitis.
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PMID:Activation of bladder mast cells in interstitial cystitis: a light and electron microscopic study. 786 1

Tachykinins are widely distributed in the peripheral nervous system of the respiratory, urinary and gastrointestinal tract, stored in enteric neurons and in peripheral nerve endings of capsaicin-sensitive primary afferent neurons from which are released by stimuli having both pathological and physiological relevance. The most studied effects produced by tachykinins in these systems are smooth muscle contraction, plasma protein extravasation, mucus secretion and recruitment/activation of immune cells. The use of tachykinin receptor-selective antagonists and knockout animals has enabled to identify the involvement of tachykinin NK(1), NK(2) and NK(3) receptors as mediators of peripheral effects of tachykinins in different systems/species. The bulk of data obtained in experimental animal models suggests that tachykinins could contribute to the genesis of symptoms accompanying various human diseases including asthma/bronchial hyperreactivity, cystitis of various aetiology, inflammatory bowel diseases and irritable bowel syndrome. Tachykinin receptor antagonists are expected to afford therapeutically relevant effects.
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PMID:Peripheral tachykinin receptors as targets for new drugs. 1169 23

The peptide substance P and its tachykinin receptor, neurokinin-1 (NK1), have been the focus of considerable research for their role in a variety of both central and peripheral diseases. Recent preclinical data, as well as relevant clinical findings, support the potential therapeutic value of NK1 receptor antagonists in centrally mediated disease states, including anxiety and depression. In addition, a separate body of literature supports the use of NK1 receptor antagonists as inhibitors of centrally mediated emetic and cough responses. The role of NK1 receptor antagonists as analgesic agents with potential to treat migraine headache has also been investigated. NK1 receptors are also found in a number of peripheral regions, including the bladder, gastrointestinal tract and bone marrow. Preclinical models have been employed to address the potential therapeutic uses for NK1 receptor antagonists in diseases associated with inflammatory responses, including asthma, irritable bowel syndrome and cystitis of the bladder. Finally, other more recent publications suggest a role for NK1 receptor antagonists as tumour suppressants and haematopoietic agents. These applications for NK1 receptor antagonists are discussed in this review.
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PMID:Potential therapeutic targets for neurokinin-1 receptor antagonists. 1515 33

Pelvic pain associated with menstruation, i.e., dysmenorrhea, is a chronic pelvic pain that not only interferes with a woman's wellbeing for a large part of her life but also often co-occurs with other chronic painful conditions such as interstitial cystitis and irritable bowel syndrome and others. Little has been known about mechanisms underlying these chronic pelvic pains. This paper reviews 37 years of research in my laboratory at Florida State University on such mechanisms. Our research, mostly on rats, has contributed to the following findings: (1) Female reproductive organs are innervated in a topographic fashion by afferents in the pelvic (vagina/cervix) and hypogastric (cervix/uterine horn) nerves. (2) The input contributes to uterine and vaginal perceptions (nociception) that are modified by reproductive status. (3) Throughout the CNS, neurons responsive to stimulation of the reproductive tract also respond to stimulation of skin and other internal organs, in a manner modifiable by reproductive status and peripheral pathophysiology. (4) This dynamic physiological convergence may reflect extensive anatomical divergence of and interconnections between pathways entering the CNS via gateways through the spinal cord, dorsal column nuclei, and solitary nucleus. (5) The convergence also indicates the existence of extensive cross-system, viscero-visceral interactions within the CNS, that, while organized for coherent bodily functioning, serves as a substrate by which pathophysiology in one organ can influence physiology and responses to pathophysiology in other organs. (6) Some cross-system effects observed so far include: (a) Bladder inflammation reduces the rate of uterine contractions and the effects of drugs on the uterus. (b) Colon inflammation produces signs of inflammation in the otherwise healthy bladder and uterus. (c) A surgical model of endometriosis produces vaginal hyperalgesia, exacerbates pain behaviors induced by a ureteral stone, and reduces volume voiding thresholds if the bladder. These cross-system effects, which likely involve CNS mechanisms, likely also underlie co-occurrence of painful clinical conditions. Research continues on details of these mechanisms and their relevance for clinical diagnosis and therapy. None of this work could have been done without collegial support of colleagues and technical staff at Florida State University.
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PMID:A life of pelvic pain. 1613 51

A population of rat lumbar laminae VII and X putative spinothalamic (STT) neurons that co-contain cholecystokinin-8 (CCK) and galanin (GAL) are sexually dimorphic. Males have a significantly greater number of these neurons, as well as having greater optical densities for both neuropeptides than females. Optical densities for GAL and CCK immunoreactivities in these lumbar neurons in rats that have the testicular feminization mutation (Tfm) are not significantly different from females; however, the number of these lumbar neurons in Tfm rats is significantly smaller than in females. These data suggest that androgens, as well as functional androgen receptors (that Tfm rats lack), are necessary for the establishment of these sexual dimorphisms. Functionally, these CCK- and GAL-containing neurons in the deep lumbar laminae may contribute to the establishment of known sex differences in the affective component of somatic and visceral nociception, as well as the sexually dimorphic nature of some pelvic diseases, e.g., irritable bowel syndrome or cystitis.
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PMID:Androgens regulate the sexually dimorphic production of co-contained galanin and cholecystokinin in lumbar laminae VII and X neurons. 1676 34

Irritable bowel syndrome and interstitial cystitis frequently overlap. We have shown that acute colitis sensitizes urinary bladder afferents to both mechanical and chemical stimuli and that chronic colitis similarly produces neurogenic cystitis. We hypothesize that chronic irritation of the colon releases neuropeptides from bladder afferents, leading to receptor sensitization and neurogenic inflammation. Female Sprague-Dawley rats received intrarectal trinitrobenzenesulfonic acid (TNBS) or vehicle 3 days following either systemic capsaicin (CP) pretreatment or vehicle. Ten days later, action potentials of single-unit pelvic C-fiber afferents with receptive fields in the bladder were recorded under urethane anesthesia during graded bladder distensions (UBD) or intravesical capsaicin (vCP) administration. In controls, UBD increased bladder afferent firing in proportion to intravesical pressure. At intravesical pressures of 30 mmHg and above, the percent increase in afferent firing was significantly accentuated following TNBS compared with controls (1,222 +/- 176 vs. 624 +/- 54%, P < 0.01). The response to vCP was also enhanced (4,126 +/- 775 vs. 1,979 +/- 438%, P < 0.01). Systemic depletion of neuropeptides from sensory nerves abolished these effects. Histological examination of the bladders revealed an increase in mast cell density in TNBS-treated animals compared with controls (18.02 +/- 1.25 vs. 3.11 +/- 0.27 mast cells/x100 field, P < 0.01). This effect was significantly ameliorated with CP (10.25 +/- 0.95, P < 0.5 vs. TNBS-treated animals). In summary, chronic colonic irritation in the rat sensitizes urinary bladder afferents to noxious stimuli and causes mast cell infiltration in the bladder. Depletion of neuropeptides from sensory afferents diminishes these effects, suggesting they play an important role.
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PMID:Sensitization of pelvic nerve afferents and mast cell infiltration in the urinary bladder following chronic colonic irritation is mediated by neuropeptides. 1692 45

The NK(2) receptor belongs to the family of tachykinin neurotransmitters. It has been reported to be involved in several pathological conditions, and selective antagonists are potentially useful drugs for the treatment of asthma, irritable bowel syndrome, cystitis, and depression. Starting from in-house capped dipeptide libraries, we were able to identify a number of molecules with sub-nanomolar binding affinity for the hNK(2) receptor. All were characterized by a rigid core structure with a strong constraint induced by an alpha,alpha-cyclopentaneglycine fragment. Herein we report the further elaboration of three initial basic structures. The planar benzothiophene group was substituted with a series of biphenyl and heterobiphenyl moieties that are well tolerated in terms of receptor affinity. The new compounds also maintained good antagonist potency in an in vitro functional assay, and a number of them showed significant in vivo activity after intravenous administration in our guinea pig model.
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PMID:alpha,alpha-Cyclopentaneglycine dipeptides capped with biaryls as tachykinin NK(2) receptor antagonists. 1839 14

NK(2) antagonists have been reported to be potentially useful for the treatment of a number of chronic diseases, such as asthma, irritable bowel syndrome, cystitis, and depression. Starting from an in-house prepared library of capped dipeptides, we have identified a series of molecules with subnanomolar binding affinity for the hNK(2) receptor. These molecules are composed by three well-defined regions: a planar aromatic acyl system as N-terminal capping group, a rigid and quite lipophilic core, and a flexible and relatively hydrophilic C-terminal capping group. Here we report how we were able to manipulate the N-terminal capping group to obtain significant in vivo activity after i.v. and i.d. administration.
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PMID:Cinnamic acids and mono-substituted benzoic acids as useful capping groups for the preparation of hNK2 receptor antagonists. 1864 Aug 35

Pain is a complex subjective experience, associated with neurovegetative, affective and cognitive rapid changes. Biological, psychosocial and contextual factors may contribute. Chronic inflammation, of whatever cause, is the leading contributor to chronic pain. The mast cell directs both the inflammatory process and the shift to chronic pain, mediating through the production of Nerve Growth Factor (NGF) and other neurotrophic molecules. Women, in the fertile age, are biologically more vulnerable to chronic inflammation, as fluctuations of estrogens are agonist factors of mast cells degranulation, mostly in the premenstrual phase. Pain is defined as "nociceptive" when it indicates an ongoing damage; "neuropathic" when it becomes a disease per se. Chronic Pelvic Pain (CPP) indicates an invalidating, persistent or recurrent pelvic pain, persisting for more than 6 months. CPP is the main complaint of 10-15% of gynaecologic consultations, leading to 40% of diagnostic laparoscopies and 15% of hysterectomies. Comorbidity, i.e. the coexistence of pathologies and painful syndromes in different pelvic organs, is another common feature. Cystitis, vulvar vestibulitis, endometriosis, irritable bowel syndrome all play an important role and contribute to identifying the hyperactive mast cell and related chronic inflammation as the common pathophysiologic factor. The paper reviews nociception characteristics, the emerging role of mast cells, the pathophysiology of comorbidity, biological, psychosexual and contextual predictors, and stresses the need to move from a "hyperspecialistic" perspective to a multisystemic reading of CPP, with special attention to the urologic perspective.
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PMID:[Perception of chronic pelvic pain in women: predictors and clinical implications]. 2108 54

Components of the so-called endocannabinoid system, i.e., cannabinoid receptors, endocannabinoids, as well as enzymes involved in endocannabinoid synthesis and degradation, have been identified both in the gastrointestinal and in the urinary tract. Evidence suggests that the endocannabinoid system is implicated in many gastrointestinal and urinary physiological and pathophysiological processes, including epithelial cell growth, inflammation, analgesia, and motor function. A pharmacological modulation of the endocannabinoid system might be beneficial for widespread diseases such as gastrointestinal reflux disease, irritable bowel syndrome, inflammatory bowel disease, colon cancer, cystitis, and hyperactive bladder. Drugs that inhibit endocannabinoid degradation and raise the level of endocannabinoids, non-psychotropic cannabinoids (notably cannabidiol), and palmitoylethanolamide, an acylethanolamide co-released with the endocannabinoid anandamide, are promising candidates for gastrointestinal and urinary diseases.
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PMID:Endocannabinoids and the Digestive Tract and Bladder in Health and Disease. 2640 70


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