Excessive activation of TRPA1 and TRPV1 by ROS may induce central sensitization – does it concern ME?

Researchers from Japan have made a study to clarify how reactive oxygen species (ROS) impact on synaptic transmission.  They investigated the effects of ROS on synaptic transmission in rat spinal cord substantia gelatinosa (SG) neurons using whole-cell patch-clamp recordings:

Reactive oxygen species enhance excitatory synaptic transmission in rat spinal dorsal horn neurons by activating TRPA1 and TRPV1 channels

They wanted to understand more about central neuropathic pain (CNP) in the spinal cord such as chronic pain after spinal cord injury (SCI). It is known that ROS is involved, but how?

The results were:

·         ROS enhance excitatory synaptic transmission in rat spinal dorsal horn neurons.

·         These excitatory effects are induced by the activation of TRPA1 and TRPV1 channels.

·         ROS enhance the spontaneous release of glutamate from presynaptic terminals onto SG neurons.

·         ROS in the spinal cord can play an important role in central sensitization and result in chronic pain.

And the conclusion was: “This is the first report to show that ROS enhance excitatory synaptic transmission in rat spinal dorsal horn neurons via TRPA1 and TRPV1 channels. Our results suggest that ROS play an important role in the activation of SG neurons and provide insight into our understanding of the mechanisms of CNP in the spinal cord, such as that following SCI.”

I was very excited when I read that, because it is hypothesized that central sensitization is involved in ME/CFS and the co-morbidities Multiple Chemical Sensitivity (MSC) and fibromyalgia.

And furthermore, I have my own hypothesis that the ME/CFS co-morbidity Postural Orthostatic Tachycardia Syndrome also fit in. And it all come down to TRPA1 activation.

The next step in my hypothesis is that nitric oxide (nitrosative stress/mitochondrial dysfunction?) and an autoimmune attack also are involved. Something must keep those TRPA1s going!

The Japanese researchers mentioned some other studies:

·         A number of reports had shown that the major sources of ROS are dorsal root ganglion (DRG) neurons and microglia in the spinal cord.

·         A group reported that reactive nitrogen species (RNS), especially peroxynitrite, contribute to central neuropathic pain in the spinal cord.

·         ROS convert polyunsaturated fatty acids into α,β-unsaturated aldehydes, which activate TRPA1 channels.

They also pointed out that in addition to ROS, RNS (peroxynitrite) may also have enhanced the excitatory postsynaptic currents in the present study.

And ROS induce inward currents in SG neurons via TRPA1 channels, and a previous study has shown that inward currents are also involved in NMDA receptor activation.

The good news is that the effect of ROS exposure is reversible, and the bad news is that long-term exposure to ROS has the potential to elicit plastic changes in the neurons.

I think the mechanisms described in this fine study could be used to explain some of the biochemistry that has gone bad in ME.

ROS (TRPA1 activation) after an inflammatory response will resolve. But sustained ROS (TRPA1 activation) could be plastic changes in the neurons or it could be sustained by some auto antibody. And perhaps some yet to be discovered auto antibody is involved.

Could auto antibodies be involved in spinal cord injury??? Look what I found:

Roles of Autoantibodies in Central Nervous System Injury:

“Stroke, traumatic brain injury (TBI), and spinal cord injury (SCI) cause irreversible damage to the nervous system. Although these are neurological disorders, pathology and loss of function also occur outside the nervous system and are often not easily explained by paralysis or impaired neural function. Emerging data indicate that much of the pathological sequelae that accompanies CNS trauma has characteristics of a self-directed immunological disease. Here, we outline those data, describing basic mechanisms of B cell activation and autoantibody synthesis after CNS injury. A summary of the anti-CNS autoantibodies that have been identified in humans and animals is provided along with a discussion of how autoantibodies may affect survival of neuronal and non-neuronal tissues and whether autoimmune reactions are feasible therapeutic targets after CNS trauma.”

And it becomes even more exciting because this articles

Orthostatic hypotension following spinal cord injury: understanding clinical pathophysiology

states that:

“Over time (days to weeks) the spinal shock resolves, but Spinal Cord Injury patients are frequently troubled with sudden falls in blood pressure upon postural change, or following prolonged periods of sitting (orthostatic hypotension) characterised by dizziness, lightheadedness or even syncopal events.”

If the orthostatic hypotension occurs right after injury, it could be ROS (TRPA1 activation) because of inflammation, if it continues, could it be auto antibodies? (I am just guessing)

I have already mentioned TRPA1’s role in blood pressure and possible relevance to autonomic system reflexes and potentially to vasovagal/neurocardiogenic syncope disorders: TRPA1 involvement in autonomic dysfunction in ME?

Do you follow my chain of thoughts? Or else, please continue reading:

Caveolae, eNOS and TRPA1?

Does excessive activation of TRPA1 and TRPV1 by ROS concern ME?