TRP/TRPV1 Flashcards
What are TRP channels?
The most important ion channel family that detects and transmits noxious stimuli is the transient receptor potential (TRP) channel family. In general, TRP channels act as molecular sensors of multiple stimuli, ranging from changes in pH, chemical agents, temperature, and osmolarity.
Where is TRPA1 expressed? What compounds activate it?
TRPA1 is exclusively expressed by peptidergic C fibres. Furthermore, it has been found that all TRPA1+ neurons express TRPV1. (Other way round is not true).
Isothiocyanates are natural compounds that can activate the TRPA1 channel. These types of compounds are found in natural products such as wasabi, mustard, and horseradish, among others (Jordt et al., 2004).
Does TRPA1 have a role in inflammatory pain?
Bradykinin is released during tissue damage and inflammation; this inflammatory mediator indirectly activates TRPA1 channels to mediate the pain response. This effect requires bradykinin to interact with its receptor (B2R) activating the PLC-dependent signaling pathway, which promotes phosphatidylinositol 4,5, biphosphate (PIP2) hydrolysis to produce inositol triphosphate (IP3) and diacylglycerol (DAG). Both metabolic intermediates can activate the TRPA1 channel (Bandell et al., 2004).
The TRPA1 knockout mouse fails to display a pain-like behaviour in bradykinin-evoked nociceptor excitation, confirming that TRPA1 is an important mediator of inflammatory pain (Bautista et al., 2006).
Where is TRPM8 expressed and what activates it?
This channel is expressed in a wide range of nociceptors and non-nociceptors. Furthermore, it is largely absent from non-peptidergic C fibres. This channel is activated by warm and noxious cold temperatures in the range of 23°C–10°C, respectively, and by natural compounds such as menthol.
Is TRPM8 involved in neuropathic pain?
Tissue inflammation or nerve injury can result in extreme hypersensitivity to innocuous cooling stimuli or noxious cold, and regarding this it has been suggested that the TRPM8 channel is involved in cold allodynia (pain caused by a normally innocuous cold stimulus) (Allchorne et al., 2005).
What activates the TRPV1 channel?
The TRPV1 channel is the most well-characterized TRP channel to date. TRPV1 can be activated by various stimuli, including temperature (~42°C), pH, and a wide range of both endogenous and exogenous compounds. Its main exogenous ligand is capsaicin, a compound from chili peppers.
Where is the TRPV1 channel expressed?
In the PNS, this channel is expressed in all c fibres and some alpha-delta fibres.
TRPV1 is expressed in several regions of the CNS, specifically in laminae I and II of the dorsal horn of the spinal cord, where it modulates the synaptic transmission of nociceptive signals from the periphery (Spicarova and Palecek, 2009). TRPV1 is primarily expressed in the presynapse, although there have been studies that demonstrated its postsynaptic expression, albeit this has not been shown to be related to nociception (Spicarova and Palecek, 2008).
How does inflammation sensitise the TRPV1 channel? (1)
Under normal conditions, only temperatures near 42°C activate TRPV1, but this thermal threshold decreases to 35°C–37°C after acidification of the medium (Tominaga et al., 1998). This phenomenon is very important during inflammation, because this condition drastically decreases the pH (up to a pH of 6.4) and rapidly activates TRPV1.
Furthemore substances released during inflammation such asNGF, substance P, bradykinin, and prostaglandins have been shown to activate several kinases, such as PKC, mitogen-activated protein kinase (MAP kinase; MAPK), and protein kinase A (PKA). These activated kinases then phosphorylate various residues within the TRPV1 sequence, inducing TRPV1 sensitization (Cheng and Ji, 2008).
How does inflammation sensitise the TRPV1 channel?
As well as phosphorylating TRPV1, activation of MAPK by NGF after inflammation has been shown to increase TRPV1 expression levels. The increased protein levels promote long-term nociceptive neuron sensitization (Ji et al., 2002). In addition, TRPV1 phosphorylation by tyrosine kinases increases the traffic of TRPV1-containing vesicles to the plasma membrane, causing an increase in the number of functional channels in the membrane (Zhang et al., 2005).
What was the first evidence of the role of TRPV1 in peripheral pain processing?
The first evidence of the role of TRPV1 in peripheral pain processing was generated by observations made in mice injected with the TRPV1 antagonist capsazepine. Capsazepine injection attenuated inflammation-induced thermal hyperalgesia (Caterina et al., 2000; Davis et al., 2000).
Why is it believed that targetting TRPV1 will result in analgesia?
TRPV1 integrates multiple proinflammatory stimuli.
Extensive studies have indicated that different stimuli usually act synergistically, that is, capsaicin, heat, protons, and voltage can enhance the efficacy and/or potency of one another. This polymodal gating of TRPV1 is regarded as the essential mechanism underlying the function of nociceptive neurons.
Does TRPV1 have a role in neuropathic pain?
There is contradictory evidence regarding the role of TRPV1 in neuropathic pain. It has been found that in TRPV1−/− mice, there is no change in pain perception after nerve damage (Bolcskei et al., 2005; Caterina et al., 2000); however, pharmacological inhibition of TRPV1 decreases pain in several animal models of neuropathic pain (Kanai et al., 2005; Yamamoto et al., 2008b).
Desensitization to topical TRPV1 agonists (e.g., capsaicin creams and patches) has been in clinical use for decades to alleviate chronic painful conditions like diabetic neuropathy (Knotkova et al., 2008).
Does TRPV1 have an important role in cancer-induced chronic pain?
In bone cancer, TRPV1 is overexpressed in DRG neurons, and this increased expression induces neuropathic pain. This overexpression enhances the response of TRPV1 to capsaicin (Pan et al., 2010).
