Hyperalgesia means the animal, or some part of it, is now feeling pain in response to a stimulus that really shouldn’t cause pain. So for example light touch. If light touch causes apparent pain, that is described as hyperalgesia. There can be many causes, drug, infection, CNS disorder (typically some sort of rewiring in the spinal cord).

However, inflammation can also cause it. So the Lewis –Triple response is a form of “neurogenic” inflammation… and by causing depolarisation and activation of free nerve endings FNEs in around an injury it can end up causing hyperalgesia (nociceptive primary afferent nerves fire more easily than they should).

Here’s how it works. It’s all about “anti-dromic” neurotransmission.

Normally, chemoreceptors detect pain and itch then they transmit this info to the brain.

When action potentials move from the nerve ending towards the synapse in the CNS this is called orthodromic transmission. It’s just “normal”(!). Sorry about the spelling in the figure!

However in those unusual situations when action potentials flow backwards, this is highly unusual in animals, it is called “anti-dromic”. Also, free nerve endings… normally thought of as sensory receptors can also actually release a neurotransmitter such as substance P. The fact that action potentials can spread outward though, means that although action potentials may start to spread in, as normal, when they hit the “junction” they spread back outwards towards the skin.

So what effect does that released substance P have? Well it can cause vasodilation, and activation of mast cells… but it also facilitates the firing of other nerve terminals making them more likely to fire in response to touch (i.e., hyperalgesia), but also this can spread the inflammation and pain further around the site of injury…

A whole series of local mediators of inflammation like K+, bradykinin and prostaglandins can initiate this sequence….

Why is it called the Lewis “Triple” response? Because from an observational standpoint (i.e., not knowing anything about the complex processes that take place within the tissue), you see three things as a result. (1) Pain, itch and hypersensitivity (2) oedema as the blood vessels are made leaky by all the local mediators and fluid is extruded (“plasma extravasation”) (3) Flare … which is the redness resulting from all the local vasodilation which is taking place. If you have a riding crop or similar, try wacking yourself on your ventral forearm and in theory you should see it develop? Sadly I don’t have a riding crop so I can’t try this and show you or I daresay I would be tempted to demonstrate!

Hope this helps.

@RichardBJ1