Physiology and Pharmacology of the Vanilloid Receptor

Abstract

Abstract:The identification and cloning of the vanilloid receptor 1 (TRPV1) represented a significant step for the understanding of the molecular mechanisms underlying the transduction of noxious chemical and thermal stimuli by peripheral nociceptors. TRPV1 is a non-selective cation channel gated by noxious heat, vanilloids and extracellular protons. TRPV1 channel activity is remarkably potentiated by pro-inflammatory agents, a phenomenon that is thought to underlie the peripheral sensitisation of nociceptors that leads to thermal hyperalgesia. Cumulative evidence is building a strong case for the involvement of this receptor in the etiology of both peripheral and visceral inflammatory pain, such as inflammatory bowel disease, bladder inflammation and cancer pain. The validation of TRPV1 receptor as a key therapeutic target for pain management has thrust intensive drug discovery programs aimed at developing orally active antagonists of the receptor protein. Nonetheless, the real challenge of these drug discovery platforms is to develop antagonists that preserve the physiological activity of TRPV1 receptors while correcting over-active channels. This is a condition to ensure normal pro-prioceptive and nociceptive responses that represent a safety mechanism to prevent tissue injury. Recent and exciting advances in the function, dysfunction and modulation of this receptor will be the focus of this review.

Transient Receptor Potential Vanilloid Type 1 Channel (TRPV1) Immunolocalization in the Murine Enteric Nervous System Is Affected by the Targeted C-terminal Epitope of the Applied Antibody

“…Differences in interacting molecules also influence epitope recognition by antibodies. The C-terminal region of TRPV1 contains several modulatory regions, including phosphorylation sites at T705, S801, S775, and S821, as well as binding sites for calmodulin (aa768-802) and phosphatidylinositol 4,5-bisphosphate (aa778-793) (Bhave and Gereau 2004;Messeguer et al 2006). Functional differences between TRPV1 in the plasmalemmal and intracellular TRPV1 have been attributed to different regulatory interactions (Gallego-Sandín et al 2009), but the regulation of intracellular TRPV1 is still largely unknown.…”

Cocarcinogenic Effect of Capsaicin Involves Activation of EGFR Signaling but Not TRPV1

“…TRPV1 is distributed widely in many cell types other than sensory neurons (11). In skin, TRPV1 is also expressed in keratinocytes and fibroblasts (28).…”

“…Capsaicin is a selective agonist of TRPV1 and causes TRPV1 to be desensitized after activation. TRPV1 is widely expressed in primary afferent neurons and also in nonneuronal tissues, including skin keratinocytes, fibroblasts, liver, prostate, and bladder smooth muscle (11). Thus, studying the function of TRPV1 in a broader context than pain perception is relevant.…”

Role of Principal Ionotropic and Metabotropic Receptors in Visceral Pain

“…These channels are, in general, thermoreceptors found on poorly myelinated and nonmyelinated afferents arising from the dorsal root ganglia, nodose ganglia, and the CNS. [106][107][108][109][110] These channels are calcium permeable, nonselective channels with 4 identical subunits and a central pore. TRPA1 is highly expressed on primary afferents.…”