In the spotlight - Striking the pain at its root

By Arthur Berrou

The sensation of pain protects organisms against potential dangers. This role is fulfilled by cell called nociceptive neurons – neurons devoted to pain. Nociceptive neurons convey noxious stimuli using electrical impulses, known as «spikes », from a peripheral tissue such as the skin and into the brain, where it is interpreted as pain. Pain intensity depends on the number of spikes: the more spikes in a short time, the more painful is the sensation. The conversion of a noxious stimulus into electrical signals originates in the terminals of the nociceptive neurons. However, this initial signal at the terminals fades away as it propagates along the nociceptive fiber. It is only when it reaches the « spike initiation zone » (SIZ) that a spike is triggered. Once a spike is triggered, the electrical signal propagates without attenuation up to the brain. This is why the location of the spike initiation zone is important: the closer it is to the terminal, the more reliable the transmission of noxious stimuli.

Alex Binshtok and his team went on a quest to determine where the SIZ is in nociceptive neurons of mice: “to our knowledge, we were the first to study spike initiation in physiological conditions”. PhD student Robert Goldstein used a technique called fluorescence imaging- essentially an ultrasensitive camera that can detect electrical signals in nociceptive neurons. The authors used another witty trick to detect the SIZ. Using local application of chemicals they blocked the mere proteins responsible for spike initiation. Since blocking was done in a spatially restricted manner they could resolve  the exact location of the SIZ. Remarkably, it turns out that the SIZ is in the fibers of nociceptive neurons, just downstream of their terminals (left part of the figure).

Furthermore, the scientists investigated whether the location of the SIZ can change in pathological conditions such as inflammation. Indeed, under conditions of painful inflammation, the location of the SIZ shifted towards the terminal, thereby increasing the excitability of the neuron, and as a consequence pain sensation (right part of the figure). How these findings generalize to nociceptive neurons in the rest of the body still needs to be tested. Nevertheless, it opens a way to new clinical strategies for the treatment of inflammatory pain.

elsc spotlight June 2019
Left: Depicts the normal condition, whereby “spikes” in pain neurons are generated in a restricted region of the nerve terminal (red region).
Right: Pathological conditions (e.g., nerve inflammation), whereby the region generating the spikes expands, with the consequence of an enhanced pain sensation.
Figure adapted from Sharon R. Ha and Matthew N. Rasband. The SIZ of Pain. Neuron, volume 102, issue 4, 22 May 2019, Pages 709-71

 

A link to the original paper:
https://www.sciencedirect.com/science/article/pii/S0896627319302120