onsdag den 13. februar 2013

TRPA1 involvement in autonomic dysfunction in ME?

In my previous blog posts I referred to articles that make it plausible that TRPA1 is involved in the biochemistry of co-morbid ME conditions like Multiple Chemical Sensitivity and inflammation/pain.

But what about autonomic dysfunctions like Postural Orthostatic Tachycardia Syndrome and Orthostatic Intolerance? Is there a connection? Is TRPA1 involved in regulation of the vasculature?

The answer is: YES, TRPA1 and other TRP channels have influence on regulation of the vasculature.

My favorite article today is this one:
Evidence for the pathophysiological relevance of TRPA1 receptors in the cardiovascular system in vivo

The conclusion from this article:
“TRPA1 is involved in mediating vasodilation. TRPA1 can also influence changes in blood pressure of possible relevance to autonomic system reflexes and potentially to vasovagal/neurocardiogenic syncope disorders.”

There are other fine articles describing TRP in the vasculature:

TRPA1 channels in the vasculature

Transient receptor potential channels and vascular function

Cerebral Blood Flow and TRP

We already know that Cerebral Blood Flow is disturbed in ME/CFS patients:

Cerebral blood flow is reduced in chronic fatigue syndrome as assessed by arterial spin labeling

Postural neurocognitive and neuronal activated cerebral blood flow deficits in young chronic fatigue syndrome patients with postural tachycardia syndrome

…and these articles describe the connection between TRP and Cerebral Blood Flow:

Transient receptor potential (TRP) channels, vascular tone and autoregulation of cerebral blood flow

Endothelium-dependent cerebral artery dilation mediated by TRPA1 and Ca2+-Activated K+ channels

The connection between chemical sensitivity, TRPA1 and cerebral blood flow

TRPA1 receptors mediate environmental irritant-induced meningeal vasodilatation

mandag den 11. februar 2013

TRPA1/TRPV4/PAR in inflammation/pain

Injury and inflammation trigger the activation of proteases from the circulation, immune cells and epithelial tissues that regulate cells by cleaving protease-activated receptors (PARs), members of a family of four G protein coupled receptors (GPCRs).

These G protein-coupled receptors of nociceptive neurons can sensitize transient receptor potential (TRP) ion channels, which amplify neurogenic inflammation and pain. Protease-activated receptor 2 (PAR2), a receptor for inflammatory proteases, is a major mediator of neurogenic inflammation and pain.

PAR2 is co-expressed with substance P and calcitonin gene-related peptide by a subpopulation of primary spinal afferent neurons that control neurogenic inflammation and pain transmission. Activation of PAR2 on sensory nerve endings evokes the local release of these neuropeptides, which stimulate extravasation of plasma proteins, infiltration of neutrophils and vasodilation (neurogenic inflammation). PAR2 activation also promotes the central release of neuropeptides that activate second order spinal neurons that transmit pain. These mechanisms contribute to painful inflammation of the intestine, pancreas and joints. Therefore, it is of considerable interest to understand the mechanisms by which PARs regulate the activity of nociceptive neurons.

Members of the TRP family, including TRPV1, TRPV4 and TRPA1 mediate neurogenic inflammation and pain, and are major down-stream targets of PAR2 . Activation of these non-selective cation channels stimulates the influx of extracellular Ca2+ ions and the release of neuropeptides in peripheral tissues and the spinal cord, which induces neurogenic inflammation and pain. During injury and inflammation, several factors are generated that can directly activate these channels. Elevated temperatures, protons and lipid mediators activate TRPV1, mechanical shear stress, osmotic stimuli and lipid mediators activate TRPV4, and products of reactive oxygen species and reactive prostaglandin metabolites activate TRPA1. However, indirect mechanisms, particularly those triggered by GPCRs, play a prominent role in TRP channel activation. Many GPCRs that induce neurogenic inflammation and pain indirectly regulate TRP channels, which mediate their pro-inflammatory and pronociceptive actions.

Reference: Protease-activated Receptor-2 (PAR2) and Transient Receptor Potential Vanilloid 4 (TRPV4) Coupling is Required for Sustained Inflammatory Signaling

I think it is of particular interest, that TRP can be activated of Reactive Oxygen Species (ROS), because oxidative stress levels are raised in chronic fatigue syndrome and are associated with clinical symptoms

Some researchers believe that ME/CFS, fibromyalgia, irritable bowel syndrome and other pain syndromes share a common biochemistry via sensitization. This review article describes TRPA1 mediated neural cross-talk induced by oxidative stress as model for some pain syndromes:

TRPV1 and TRPA1 act as a nocisensor to mediate not only an afferent signal to the dorsal horn of the spinal cord, but also an efferent signal in the periphery through secretion of inflammatory agents, such as substance P and calcitonin gene-related peptide in nociceptive sensory neurons.

Peripheral inflammation produces multiple inflammatory mediators that act on their cognate receptors to activate intracellular signal transduction pathways and thereby modify the expression and function of TRPV1 and TRPA1 (peripheral sensitization). During tissue damage and inflammation, oxidative stress, such as reactive oxygen species or reactive carbonyl species is also generated endogenously.

The highly diffusible nature might account for the actions of free radical formation far from the site of injury, thereby producing systemic pain conditions without central sensitization through neural cross-talk.

Reference: Transient receptor potential A1 receptor-mediated neural cross-talk and afferent sensitization induced by oxidative stress: implication for the pathogenesis of interstitial cystitis/bladder pain syndrome

A thorough description of ROS and TRP is provided in this article:
Role of Reactive Oxygen Species and Redox in Regulating the Function of Transient Receptor Potential Channels

And further description of peripheral sensitization influenced by chemokines/TRP activation is found in this article: Chemokines as Pain Mediators and Modulators 

This knowledge opens the possibility that TRPA1 antagonist can be used against inflammatory pain:
Patent application: NOVEL TRPA1 ANTAGONISTS

Transient Receptor Potential in Multiple Chemical Sensitivity

I have previously written about Transient Receptor Potential Ion Channels, because they are mentioned in research on ME/CFS and co-morbid conditions.

TRP is also involved in chemosensation and maybe in Multiple Chemical Sensitivity (MSC).

TRPA1/TRPV1 in chemosensation

Transient Receptor Potential Ankyrin 1 (TRPA1) is a member of the TRP family. TRPA1 function as a sensory neuronal TRP ion channel, in airway chemosensation and inflammation. TRPA1 is activated by chlorine, reactive oxygen species and noxious constituents of smoke and smog, initiating irritation and airway reflex responses.

Together with Transient Receptor Potential Vanilloid 1 (TRPV1), TRPA1 may contribute to chemical hypersensitivity, chronic cough and airway inflammation in asthma.

Trigeminal chemosensory nerve endings in the nasal mucosa are in the first line of defense against noxious chemical challenges.

TRPA1 is expressed in 20–36.7 percent of trigeminal neurons, 20–56.5 percent of dorsal root ganglion neurons, and 28.4 percent of neurons in nodose ganglia.

Neuropeptides such as Substance P and Calcitonin Gene Related Peptide (CGRP), released from chemically stimulated nerve endings, promote neurogenic inflammatory vasodilation and leakage, contributing to narrowing or obstruction of the nasal passages.

Since most TRPA1 agonist can react with thiols, cellular and extracellular reduced glutathione levels will affect the reach and potency of inhaled airway irritants. Once glutathione is depleted, either as a consequence of disease or during extended exposures, TRPA1 may respond much more strongly. With each breath more reactive agonist is delivered, leading to an increase in covalent modifications and heightened TRPA1 activity. This cumulative effect may result in robust TRPA1-induced irritation even at low sub-acute exposure levels, for example during periods of increased photochemical smog exposures, or low level indoor air pollution. Once irreversibly modified, channels may remain active for extended periods of time even when the irritant stimulus is removed.

(I think it is interesting that TRPA1 reacts more strongly when glutathione is depleted, because a study found decreased levels of cortical glutathione in CFS patients )

Reference: Breathtaking TRP Channels: TRPA1 and TRPV1 in Airway Chemosensation and Reflex Control

Reference: Chapter 11 TRPA1 : A Sensory Channel of Many Talents

Research on this topic is to be found in the Project Reporter from National Insitutes of Health

Project Leader Gerry Oxford has this project:

“Increased exposure to chemical irritants in the air we breathe may be responsible for the increased incidence of migraine as well as more recently described disorders such as Sick building syndrome (SBS) and Multiple Chemical Sensitivity (MCS).”

“It has been demonstrated that a member of the transient receptor potential (TRP) superfamily of ligand-gated ion channels, TRPA1, is activated by a novel mechanism involving covalent interaction between many chemicals and the receptor-channel leading to excitation of sensory neurons expressing TRPA1 and elevations in intracellular calcium.In this proposal, we will examine a specific hypothesis linking inhaled chemical irritants to the induction of headache symptoms. We propose that chemical activation of TRPA1 homomers, or TRPA1/TRPV1 heteromers on trigeminal neurons innervating the meninges results in release of calcitonin gene-related peptide (CGRP), a potent vasodilator implicated in migraine. The resultant vasodilatation provokes headache symptoms.”

The knowledge about TRPA1 is used in a patent application:
Treatment of Respiratory Disorders using TRPA1 Antagonists