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Transient Receptor Detection

Pain occurs as a symptom as stimuli activate nociceptors because of an imbalance in the homeostasis of the tissue due to changes in the chemical, temperature and mechanical(12,15,17). This detection in the surrounding can be altered and therefore cause persistent pain in the body(1) and this sensitisation is therefore increased and modulated(8), such as in the visceral region. An example is Irritable Bowel Syndrome (IBS) which has chronic pain as a symptom.

A receptor that has been seen to be present and upregulated in this disease are Transient Receptor Potential (TRP) channels, and in particular, Transient Receptor Potential Vanilloid type 1 (TRPV1) and Transient Receptor Potential Ankyrin Type 1 (TRPA1)(15,18). In this review, TRPV1 and other channels, such as TRPA1 induced pain are looked at. As possible drug targets, there have been studies with various antagonists, that have seen downregulation of expression of TRPV1, however, there are problematic side effects such as hyperthermia(3,17).

What are transient potential receptor channels? TRP channels are polymodal(12) channels, so it is activated by various stimuli such as temperature, where the threshold is at 44C(10), pH, endovanilloids and plant products like capsaicin(3). These channels are found a variety of cells, but especially in the somatic and visceral cells, where around one-third of the TRP channels found in the gut is TRPV1(2). There are five families within TRP channels.

They are Ankyrin (TRPA), Canonical (TRPC), Melastatin (TRPM), Mucopilin (TRPML), Vanilloid (TRPV) and Polycystic (TRPP)(17). There various diseases linked to mutations in the genes for these channels, such as polycystic kidney disease for TRPPs and for mutated TRPML1, neurodegenerative lysosomal storage disorder(9). These genes that code for the TRP families seem to have similar roles in populations(2) as homologs have been found between species(8), for example, orthologs for TRPV1 have been found between the mouse and humans(6).

Most TRP channels are ionotropic channels with high affinities for the major cations, Na+, K+ and Ca2+(15,17). TRPV1 has a high affinity for Ca2+(3,5) which can be affected by inflammatory mediators, such as histamine which allows for more Ca2+ to enter the neuron, thus lowering the threshold(5,18). The TRP ion channel structure has “six transmembrane polypeptide subunits with a putative pore-loop region with a cytoplasmic amino terminus with three Ankyrin repeat domains and cytoplasmic carboxy-terminus” which are the characteristics of TRP channels(6).

TRPA1, however, is a G-protein coupled receptor (GCPR), and when activated, like the other channels, will also increase its intracellular Ca2+(4,14). As the TRP channels are ion channels and GCPRs, they are targeted by analgesic antagonists(14). TRPV1 (and other TRPs, like TRPA1) and why it makes things painful. Stimulation of TRP channels are associated with pain such as migraines, which can be caused by a number of other factors, but neurogenic inflammation has a major contribution. There are many TRPV1 channels found on the trigeminal neurons found in the brain.

When they are activated due to the presence of Substance P (SP), histamine and CGRP which are mediators of neurogenic inflammation, it results in pain and the pulsating sensation when the nerve presses against the blood vessels(2,13,17). There are also studies which have shown the presence of TRP channels in Primary Sensory Neurons (PSN) which can be found in the “regulation of homeostasis in vascular, immune, protective, restorative systems and trophic processes”(17), this has been proved by a study done by Davies, who saw that lowering the surrounding pH of TRPV1 like channels activated them.

The TRPV4 channel, in particular, is found in the nociceptive neurons allowing to mediate “algesic responses” when there is a change in these systems or processes(2). In the case of visceral pain, inflammation also plays a huge part as well as changes in the internal environment. TRPV1, TRPV4, and TRPA1 are the major receptors associated with pain in the gastrointestinal tract (GI tract)(2,4,6). As these channels can be found in the vagal and spinal afferent neurons in the visceral region, the muscle and mucosa layers of the gut are affected, and when pain occurs, chemical and mechanical stimulus have changed(2,4,15).

Pro-inflammatory mediators such as bradykinins, prostaglandins, Nerve Growth Factor (NGF) and various cytokines released by activated macrophages and leukocytes, are one of the main contributors to increased visceral “hyperalgesia”(3,4). TRPA1 and TRPV1 when in the presence of these mediators, the response is usually hypersensitivity. In a study done by Brierley with TRPA1-/- mice, when bradykinin was injected to these models, a lesser response was seen, compared to this, with wild-type TRPA1 mice, a response of 50-60% was seen.

This hypersensitivity in TRPA1 is due to enhanced Protein Kinase A phosphorylation by prostaglandins and increased expression of TRPA1 by bradykinins(3). In TRPV1, increased expression is also observed like TRPA1, as TRPV1 is receptive to pro-inflammatory mediators as well(3,14). As a result of hypersensitivity and upregulation of expression of these channels(17), TRPV1 agonists such as capsaicin, will cause more pain or “heat hyperalgesia”(9,10,16) when binding to TRPV1, but also cause decreased “mechanosensory function” if bound to TRPA1(4).

Hypersensitivity induced pain is prevalent in Irritable Bowel Syndrome (IBS) as well as other diseases like Pancreatitis, which also has inflammatory-induced pain(15). In IBS, there are three times more TRPV1 and TRPA1 channels that are expressed in the mucosal, submucosal and muscle layers of the gut, thus affecting the motility of the gut as well(6,11,15). As heat is one of the major symptoms of inflammation, in pancreatitis, heat associated with inflammation, is detected by TRPV1(10).

These changes associated with these diseases are due to increased sensitivity which is not returned back to normal after an acute phase of these diseases causing chronic hypersensitivity. In Pancreatitis, inflammation caused by the release of substance P (SP) and CGRP in the colonic mucosa leads to leukocyte migration to the site of SP and CGRP. Like IBS, if there is a failure to revert back to normal, the situation becomes chronic(12) and as a result, there is an “altered activity” of the excitability of the nerves in the visceral region and tissue damage due to prolonged inflammation response(1,2,16).

In these diseases, pain is usually not treated as there are not many analgesics that are able to target TRP channels due to the many adverse side effects associated with inhibition of these channels. It is also hard to treat due to the fact that many of the TRP channels are “coupled” in such a way that symptoms would mainly be treated(2,17) How to target TRPV1 with antagonists, and the pros and cons with this, also are there other ways?

Current treatments for dealing with pain is currently to use Non-Steroidal Anti-Inflammatory drugs (NSAIDs) and opiates, although treatment is effective, the demand for more specific targeting drugs is essential as there are unwanted GI tract and cardiovascular side effects(3) and having a serious effect on the central nervous system(17). Targeting TRP channels can be one of the ways to reduce or stop pain altogether, and there have been many antagonists produced for this desired effect.

An example of a few antagonists produced is dose-dependant capsaicin antagonist BCTC(5,8), competitive antagonist capsazepine(5,10) and AMG9810(11), these antagonists were produced to block the activation of TRPV1. However, although these antagonists were able to reduce the effect of pain at first, AMG9810, an antagonist that was able to reach clinical trials, there were many side effects involved after administration.

One serious side effect was the number of increased hyperthermia found in a lot of patients, this, in turn, resulted in increased noxious pain in patients, revealing that this antagonist was scrapped by Neurogen and Merck(3,11). Another example of an antagonist for TRPV1 was SB-705498, which also reached clinical trials, it targeted migraine pain by “suppressing and reverse sensitization”(13), however, it was also stopped due to its low efficacy(13).

This saw the use of antagonists to block TRP receptors was not working, thus other ways of treating pain at another way are being more researched. Other ways of reducing pain was to target TRPV1 and TRPA1 channels is to target them at a genetic level by antisense drugs, which in this case would include a RNAi and siRNA, a recent study of these have been done to animal models and so far, the results have given good responses when treatment is given after 7 days. The only problem in this drug is siRNA is not able to cross the Blood Brain Barrier when carried out in vivo(8).

Other than blocking the receptor directly, it is also possible to aim to other channels such as Na+ voltage gated channels which are able to contribute to the production of action potentials in the pain centers of the brain. This process uses Lidocaine to block these Na+ channels, and when TRPV1 is stimulated, there is not enough depolarisation to reach the threshold, thus no action potential is produced(17). Conclusion Pain is a major symptom that is not easily treated due to the serious side effects when TRP channels are the target of the antagonists produced for reduction of pain.

This poses to be a problem as TRP channels, in particular, TRPV1 and TRPA1 contributes to a portion of the pain that occurs in the visceral region, due to the large proportion of the gut that expresses these receptors. Although blocking the receptors is one way to achieve the desired effect, it is possible to target other possibilities as TRP channels are polymodal, it is feasible that aiming for one or more of the stimuli could help achieve the goal, like in the studies of Christoph and Sousa-Valente.

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