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TRPV1 and the gut: From a tasty receptor for a painful vanilloid to a key player in hyperalgesia

Department of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, A-8010 Graz, Austria.
European Journal of Pharmacology (Impact Factor: 2.68). 11/2004; 500(1-3):231-41. DOI: 10.1016/j.ejphar.2004.07.028
Source: PubMed

ABSTRACT Capsaicin, the pungent ingredient in red pepper, has been used since ancient times as a spice, despite the burning sensation associated with its intake. More than 50 years ago, Nikolaus Jancso discovered that capsaicin can selectively stimulate nociceptive primary afferent neurons. The ensuing research established that the neuropharmacological properties of capsaicin are due to its activation of the transient receptor potential ion channel of the vanilloid type 1 (TRPV1). Expressed by primary afferent neurons innervating the gut and other organs, TRPV1 is gated not only by vanilloids such as capsaicin, but also by noxious heat, acidosis and intracellular lipid mediators such as anandamide and lipoxygenase products. Importantly, TRPV1 can be sensitized by acidosis and activation of various pro-algesic pathways. Upregulation of TRPV1 in inflammatory bowel disease and the beneficial effect of TRPV1 downregulation in functional dyspepsia and irritable bladder make this polymodal nociceptor an attractive target of novel therapies for chronic abdominal pain.

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Available from: Peter Holzer, Jan 17, 2015
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    • "January 2013 | Volume 6 | Article 191 | 7 concerns inflammation , a well recognized co - factor in multi - ple disease processes that impact homeostatic systems . In spinal dorsal horn , TRPV1 is part of a chronic pathological transforma - tion of afferent signaling ( allodynia / hyperalgesia ; Holzer , 2004 ) but whether analogous changes occur in the NTS are unknown . Markers of inflammation , e . "
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    ABSTRACT: The brainstem nucleus of the solitary tract (NTS) holds the first central neurons in major homeostatic reflex pathways. These homeostatic reflexes regulate and coordinate multiple organ systems from gastrointestinal to cardiopulmonary functions. The core of many of these pathways arise from cranial visceral afferent neurons that enter the brain as the solitary tract (ST) with more than two-thirds arising from the gastrointestinal system. About one quarter of ST afferents have myelinated axons but the majority are classed as unmyelinated C-fibers. All ST afferents release the fast neurotransmitter glutamate with remarkably similar, high-probability release characteristics. Second order NTS neurons receive surprisingly limited primary afferent information with one or two individual inputs converging on single second order NTS neurons. A- and C-fiber afferents never mix at NTS second order neurons. Many transmitters modify the basic glutamatergic excitatory postsynaptic current often by reducing glutamate release or interrupting terminal depolarization. Thus, a distinguishing feature of ST transmission is presynaptic expression of G-protein coupled receptors for peptides common to peripheral or forebrain (e.g., hypothalamus) neuron sources. Presynaptic receptors for angiotensin (AT1), vasopressin (V1a), oxytocin, opioid (MOR), ghrelin (GHSR1), and cholecystokinin differentially control glutamate release on particular subsets of neurons with most other ST afferents unaffected. Lastly, lipid-like signals are transduced by two key ST presynaptic receptors, the transient receptor potential vanilloid type 1 and the cannabinoid receptor that oppositely control glutamate release. Increasing evidence suggests that peripheral nervous signaling mechanisms are repurposed at central terminals to control excitation and are major sites of signal integration of peripheral and central inputs particularly from the hypothalamus.
    Frontiers in Neuroscience 01/2012; 6:191. DOI:10.3389/fnins.2012.00191 · 3.70 Impact Factor
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    • "However, it is unlikely that TRPV1 or 4 are involved in physiological acid sensing, since they are activated only if the extracellular pH is reduced to values below 6 (Holzer, 2004, 2007), which probably happens only under pathophysiological conditions (Behrendorff et al., 2010). The KCNK family members are blocked by very small increases in the extracellular concentration of H + (Holzer, 2004); therefore, most probably they also do not play a significant role in physiological regulation of the ductal bicarbonate secretion. The ligand-gated P2X are assembled as homo-and heteromultimers of different subunits (P2X1–P2X7; Dunn et al., 2001). "
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    ABSTRACT: Acinar and ductal cells of the exocrine pancreas form a close functional unit. Although most studies contain data either on acinar or ductal cells, an increasing number of evidence highlights the importance of the pancreatic acinar-ductal functional unit. One of the best examples for this functional unit is the regulation of luminal pH by both cell types. Protons co-released during exocytosis from acini cause significant acidosis, whereas, bicarbonate secreted by ductal cells cause alkalization in the lumen. This suggests that the first and probably one of the most important role of bicarbonate secretion by pancreatic ductal cells is not only to neutralize the acid chyme entering into the duodenum from the stomach, but to neutralize acidic content secreted by acinar cells. To accomplish this role, it is more than likely that ductal cells have physiological sensing mechanisms which would allow them to regulate luminal pH. To date, four different classes of acid-sensing ion channels have been identified in the gastrointestinal tract (transient receptor potential ion channels, two-pore domain potassium channel, ionotropic purinoceptor and acid-sensing ion channel), however, none of these have been studied in pancreatic ductal cells. In this mini-review, we summarize our current knowledge of these channels and urge scientists to characterize ductal acid-sensing mechanisms and also to investigate the challenge of the acinar acid load on ductal cells.
    Frontiers in Physiology 07/2011; 2:36. DOI:10.3389/fphys.2011.00036 · 3.50 Impact Factor
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    • "When TRPV1-expressing sensory nerve fibers are activated, they release peptide transmitters from their peripheral endings and in this way modify GI vascular, immune and smooth muscle functions (Holzer, 1998; Barthó et al., 2004, 2008; Holzer, 2004; Mózsik et al., 2007). Following tissue irritation or injury, some of these reactions (e.g., vasodilatation and plasma protein extravasation) contribute to the process of neurogenic inflammation. "
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    ABSTRACT: Approximately 20 of the 30 mammalian transient receptor potential (TRP) channel subunits are expressed by specific neurons and cells within the alimentary canal. They subserve important roles in taste, chemesthesis, mechanosensation, pain and hyperalgesia and contribute to the regulation of gastrointestinal motility, absorptive and secretory processes, blood flow, and mucosal homeostasis. In a cellular perspective, TRP channels operate either as primary detectors of chemical and physical stimuli, as secondary transducers of ionotropic or metabotropic receptors, or as ion transport channels. The polymodal sensory function of TRPA1, TRPM5, TRPM8, TRPP2, TRPV1, TRPV3 and TRPV4 enables the digestive system to survey its physical and chemical environment, which is relevant to all processes of digestion. TRPV5 and TRPV6 as well as TRPM6 and TRPM7 contribute to the absorption of Ca²⁺ and Mg²⁺, respectively. TRPM7 participates in intestinal pacemaker activity, and TRPC4 transduces muscarinic acetylcholine receptor activation to smooth muscle contraction. Changes in TRP channel expression or function are associated with a variety of diseases/disorders of the digestive system, notably gastro-esophageal reflux disease, inflammatory bowel disease, pain and hyperalgesia in heartburn, functional dyspepsia and irritable bowel syndrome, cholera, hypomagnesemia with secondary hypocalcemia, infantile hypertrophic pyloric stenosis, esophageal, gastrointestinal and pancreatic cancer, and polycystic liver disease. These implications identify TRP channels as promising drug targets for the management of a number of gastrointestinal pathologies. As a result, major efforts are put into the development of selective TRP channel agonists and antagonists and the assessment of their therapeutic potential.
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