Scientists have - for the first time - shown how chemical triggers in the nervous system can amplify the pain experienced by mammals in response to certain stimuli.
The pain system probably evolved to alert them to life-threatening dangers. As they approach objects that are extremely hot or cold or are biting them, they experience intense pain - allowing them to get out of harm's way.
But in certain diseases, that defence mechanism malfunctions and rather than providing a short, sharp shock - it produces long-term, chronic pain, seen with some conditions affecting humans such as neuropathies, arthritic pains or migraines.
Researchers have discovered that, under certain conditions, the molecular sensors that make nerves respond to physical stimuli can be turbo charged - to intensify the electrical signals reaching the brain. The brain interprets those signals as pain.
In animal studies using rat nerve cells, they found that the normal chemical messaging system utilized by the nerves to detect heat and involving calcium ions as 'messengers' was supplemented by what is known as the calcium-activated chlorine channel. It is this combination that amplifies the electrical signal to the brain.
Their research findings are published) in the journal Science Signaling.
The research team used a technique called super-resolution microscopy which allowed them to see in exceptional detail the interaction of the molecules involved in nerve signalling.
This pain amplification mechanism happens in the peripheral nervous system which feeds into - but is separate from - the central nervous system, made up of the spinal column and brain. That division opens-up the possibility that drug therapies to reduce chronic pain could be targeted on the peripheral nervous system rather than the brain.
ANO1 (TMEM16A) is a Ca2+-activated Cl− channel (CaCC) expressed in peripheral somatosensory neurons that are activated by painful (noxious) stimuli. These neurons also express the Ca2+-permeable channel and noxious heat sensor TRPV1, which can activate ANO1.
The authors revealed an intricate mechanism of TRPV1-ANO1 channel coupling in rat dorsal root ganglion (DRG) neurons. Simultaneous optical monitoring of CaCC activity and Ca2+ dynamics revealed that the TRPV1 ligand capsaicin activated CaCCs. However, depletion of endoplasmic reticulum (ER) Ca2+ stores reduced capsaicin-induced Ca2+ increases and CaCC activation, suggesting that ER Ca2+ release contributed to TRPV1-induced CaCC activation. ER store depletion by plasma membrane–localized TRPV1 channels was demonstrated with an ER-localized Ca2+ sensor in neurons exposed to a cell-impermeable TRPV1 ligand.
Proximity ligation assays established that ANO1, TRPV1, and the IP3 receptor IP3R1 were often found in close proximity to each other. Stochastic optical reconstruction microscopy (STORM) confirmed the close association between all three channels in DRG neurons.
These results reveal the existence of ANO1-containing multichannel nanodomains in DRG neurons and suggest that coupling between TRPV1 and ANO1 requires ER Ca2+ release, which may be necessary to enhance ANO1 activation.
The author said: "The painkillers that we currently use act on the central nervous system and brain. Developing painkillers that work on brain function is very hard because the brain is a complex organ and although you might solve one problem, you often get unwanted side effects.
"Opioids are standard analgesics, but they are highly addictive. Therapies based on the peripheral nervous system would potentially have less effect on the brain."
Although the study was conducted on nerve cells from rats and the applicability to the human nervous system is yet to be confirmed, there are reasons to believe that while there is a big difference between the human and rat brains, the peripheral nervous systems bear much closer similarity.
http://www.leeds.ac.uk/news/article/4586/how_animals_dialup_the_pain_they_experience_from_certain_stimuli
https://stke.sciencemag.org/content/13/629/eaaw7963
Interaction between different receptors to boost pain signal
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