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Understanding Pain, A Ten Week Ecourse: Part 6

By Jonahthan Blood Smyth

Week 6. Plasticity, up regulation and peripheral sensitization

Welcome to the sixth instalment of my Ten+ Week Ecourse, I hope you find it interesting and stimulating.

Part Six continues with the physiology of the nerves, the way the system functions. This gives us some insights into how a series of repetitive messages from a nerve can be converted into the great variety of sensations we experience.

You are welcome to publish this course in your newsletters or on your web site, on condition you do not alter it and that you keep the resource box at the bottom of each instalment.

Last time we talked about the way the pain travels up from the spinal cord and progresses on to the brain. We have seen there are many points where incoming impulses can be influenced either to increase or reduce their impact.

Plasticity and up-regulation

The ideas of plasticity and up-regulation are important to get a firm hold of if we are going to understand the ways the nervous system works in normal and abnormal circumstances.

The nervous system is very plastic, which means it can adapt and learn, making the changes semi-permanent in its systems. Patterns of nervous behaviour evolve, become imprinted and eventually may remain. In helpful circumstances we term this learning. In pain, enormous changes may result, causing severe pain or even long-lasting disability.

Up-regulation is harder to understand. The pain-producing system is normally very quiet and inactive. It takes a lot of intense, potentially damaging stimulation to wake it up. That’s a very good thing as far as I’m concerned!

However, once the pain system is activated it doesn’t take much to produce pain, even innocuous input such as touch can do it. Up-regulation refers to the increased responses of the pain producing system to decreased inputs.

Understanding the words

To understand this we need to do a bit with words. Medical terms are difficult but the terminology of pain is important and helps us avoid confusion.

An unpleasant sensory and emotional experience, associated with actual or potential tissue damage, or described in terms of such damage. (IASP definition)

An exaggerated painful response to a normally painful stimulus.

A painful response to a normally non-painful stimulus.

Neuropathic pain
A form of pain generated by abnormal processing of either the peripheral or central nervous systems.

The Story of an Injury

When an injury occurs it sets off a whole chain of complicated events which can go various ways. The incoming barrage of painful stimuli coming from the injury causes an area of primary hyperalgesia around the injured area. In this area the thresholds for nerve firing are reduced, there is exaggerated pain when nerve firing levels are reached and spontaneous pain is generated.

This is the normal pain response we all feel after injury, and the level of pain inhibits us from doing stupid things, such as continuing to do the damaging activity. So it’s protective and helps us survive.

However, as you may have noticed, an injury does not just have a limited area of pain around it but there is an extended region of pain. This area is not damaged and the pain is called secondary hyperalgesia.

Primary hyperalgesia is thought to be produced by sensitization of peripheral pain receptors in the injured area. And secondary hyperalgesia is thought to be produced by altered processing of spinal cord cells, a process known as central sensitization.

Peripheral sensitization

This is an important process in the up-regulation of the nervous system which occurs in pain episodes.

An injury releases an inflammatory soup of chemicals into the surrounding area, a soup which affects the nerve receptors very profoundly. Tissue pH is known to affect nociceptors, and in combination with chemical inflammatory chemicals, these two types of chemical effects change the way peripheral nerves work.

This chemical stimulation of the peripheral nerve endings causes them to react much more vigorously to incoming stimuli. Outputs from these nerves change in a variety of ways:

  1. Spontaneous discharge occurs. Because they are so excited by the inflammatory chemicals, the nerves fire off on their own and without any stimulus.
  2. The thresholds for activating the nerves reduce, making it a lot easier for them to be fired.
  3. The increased polarization of nerves which occurs after firing (making the nerve less able to fire again for a while) is inhibited. This makes them more easily fired again.
  4. When the thresholds for firing are exceeded, the nerves fire at increased discharge rates.

All these effects contribute to the peripheral nerves in injured areas massively increasing the pain input into the central nervous system. And the central nervous system responds with electrical, chemical and genetic changes in its cells, greatly altering the nature of its output.

Silent nociceptors

It’s odd but there is a significant number of pain receptors in tissues which remain inactive under almost all normal conditions.

It is estimated that one-third of the total population of pain receptors are silent, as they are called. They wake up only in the presence of inflammatory chemicals from damage or injury.

Once these silent nerves are activated, they respond by showing marked sensitization to incoming stimuli, following the behaviour described from 1 to 4 just above.


Acting together, the mechanisms described above cause an increase in the sensitivity of peripheral nerve receptors. They respond by greatly increasing their outputs to the central nervous system, leading to profound changes in our behaviour as we feel greatly increased pain levels.

Up-regulation is the term given to this heightened response which peripheral nerves develop in response to certain stresses.

Next we move on the second part of this story, the role which central sensitization plays in our pain responses.

Understanding Pain, A Ten+ Week Ecourse by Jonathan Blood Smyth. The Physiotherapy Site is your resource for orthopaedics, joint replacement, physiotherapy and pain.

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