Functional aspects and mechanisms of TRPV1 involvement in neurogenic inflammation that leads to thermal hyperalgesia

Abstract

Neurogenic inflammation is produced by overstimulation of peripheral nociceptor terminals by injury or inflammation of tissues. Excessive activity of sensory neurons produces vasodilation, plasma extravasation and hypersensitivity. Mechanistically, neurogenic inflammation is due to the release of substances from primary sensory nerve terminals that act directly or indirectly at the peripheral terminals, either activating or sensitizing nociceptors, endothelial cells and immunocytes. Notably, small-diameter sensory neurons that are sensitive to capsaicin play a key role in the generation of neurogenic inflammation. The cloning of the vanilloid receptor 1 (TRPV1) has been a breakthrough that has propelled our understanding of the molecular mechanisms involved in neurogenic inflammation. TRPV1 pivotally contributes to the integration of various stimuli and modulates nociceptor excitability, thus making it a true gateway for pain transduction. In addition, TRPV1 is the endpoint target of intracellular signalling pathways triggered by inflammatory mediators. Phosphorylation-induced potentiation of TRPV1 channel activity, along with an incremented TRPV1 surface expression are major events underlying the nociceptor activation and sensitization that leads to thermal hyperalgesia. The important contribution of TRPV1 receptor to the onset and maintenance of neurogenic inflammation has validated it as a therapeutic target for inflammatory pain management. As a result, the development of specific TRPV1 antagonists is a central focus of current drug discovery programs.

The vanilloid receptor TRPV1 is activated and sensitized by local anesthetics in rodent sensory neurons

“…(G) Mean current amplitudes ± SEM measured in experiments described in E and F with 30 mM lidocaine or with 1 μM capsaicin (n = 10; unpaired Student's t test). *P < 0.05; **P < 0.01; ***P < 0.001. mation and to peripheral and central sensitization (34)(35)(36). In order to investigate whether the effect of lidocaine on TRPV1 is sufficient to evoke release of neuropeptides in native tissues, CGRP release was measured from hairy skin treated with lidocaine.…”

“…The LA-induced release of neuropeptides as demonstrated in this study might be even more critical in the clinical setting whenever LAs are injected in high concentrations into the skin, to nerves and plexus, or intrathecally. The release of neuropeptides from peripheral and central terminals of sensory neurons induces vascular leakage and dilatation and is thought to contribute to neurogenic inflammation in the periphery and to central sensitization in the spinal dorsal horn (35). Neurogenic inflammation and central sensitization might well underlie the known side effects after spinal anesthesia, transient neurologic symptoms including pain and/or dysesthesia (48).…”

Contribution of the Putative Inner-Pore Region to the Gating of the Transient Receptor Potential Vanilloid Subtype 1 Channel (TRPV1)

“…Among the ion channels that have been proposed to function as important signaling molecules involved in the perception of noxious chemical and thermal stimuli in primary afferent neurons, there is one specific channel with unique polymodal activation properties that have led to it be considered as a potential target for the treatment of pain: the transient receptor potential vanilloid type 1 (TRPV1) channel (Caterina et al, 1997). This nonselective cation channel can be activated by pungent vanilloid compounds such as capsaicin or resiniferatoxin, low pH (Ͻ6.5), noxious heat (Ͼ43°C), and by voltage (Planells-Cases et al, 2005;Tominaga and Tominaga, 2005;Szallasi et al, 2006). These stimuli, when applied alone, produce only submaximal activation, whereas the ceiling for maximal response can only be reached by their synergistic interaction at the TRPV1 receptor (Tominaga et al, 1998;Vlachova et al, 2001).…”

Endogenous expression of thermo-sensitive ion channels TRPV1 and TRPV4 in immune tissues of avian species (duck, Anas platyrhynchos)

“…TRPV sub type 1 (TRPV1), also known as the "Capsaicin receptor" is a Ca 2+ -permeable nonselective cation channel and the founder member of the TRPV subfamily (Caterina et al, 1997). So far, TRPV1 gene has been sequenced from different species and its endogenous expression has been detected in several tissues and cells of certain species representing primarily mammals (Planells-Cases et al, 2005). Recently TRPV channels have been detected in mammalian immune cells where these channels play important roles in antigen detection, clonal selection, cytokine production and immune activation (Feske et al, 2012;Majhi et al, 2015).…”