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: 2.53). 11/2004; 500(1-3):231-41. DOI: 10.1016/j.ejphar.2004.07.028
Source: PubMed


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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    • "Taken together, we suggest that enteric neurons largely contribute to TRP mRNA detected in our colon samples. Literature data are accumulating for the presence of intrinsic enteric TRPV1 in the gut but its excitatory/secretory functions remain to be elucidated [13], [39], [60], [93]–[99]. "
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    ABSTRACT: Transient Receptor Potential Ankyrin 1 (TRPA1) channels are localized on sensory nerves and several non-neural cells, but data on their functional significance are contradictory. We analysed the presence and alterations of TRPA1 in comparison with TRP Vanilloid 1 (TRPV1) at mRNA and protein levels in human and mouse intact and inflamed colons. The role of TRPA1 in a colitis model was investigated using gene-deficient mice. TRPA1 and TRPV1 expressions were investigated in human colon biopsies of healthy subjects and patients with inflammatory bowel diseases (IBD: ulcerative colitis, Crohn's disease) with quantitative PCR and immunohistochemistry. Mouse colitis was induced by oral 2% dextran-sulphate (DSS) for 10 days. For investigating the functions of TRPA1, Disease Activity Index (weight loss, stool consistency, blood content) was determined in C57BL/6-based Trpa1-deficient (knockout: KO) and wildtype (WT) mice. Sensory neuropeptides, their receptors, and inflammatory cytokines/chemokines were determined with qPCR or Luminex. In human and mouse colons TRPA1 and TRPV1 are located on epithelial cells, macrophages, enteric ganglia. Significant upregulation of TRPA1 mRNA was detected in inflamed samples. In Trpa1 KO mice, Disease Activity Index was significantly higher compared to WTs. It could be explained by the greater levels of substance P, neurokinins A and B, neurokinin 1 receptor, pituitary adenylate-cyclase activating polypeptide, vasoactive intestinal polypeptide, and also interleukin-1beta, macrophage chemoattractant protein-1, monokine induced by gamma interferon-1, tumor necrosis factor-alpha and B-lymphocyte chemoattractant in the distal colon. TRPA1 is upregulated in colitis and its activation exerts protective roles by decreasing the expressions of several proinflammatory neuropeptides, cytokines and chemokines.
    PLoS ONE 09/2014; 9(9):e108164. DOI:10.1371/journal.pone.0108164 · 3.23 Impact Factor
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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 · 3.66 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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    Frontiers in Physiology 07/2011; 2:36. DOI:10.3389/fphys.2011.00036 · 3.53 Impact Factor
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