Nociception: Things We Don't Know about Pain

People with congenital insensitivity to pain can feel temperature, but not when it's bad. But those with congenital insensitivity to pain with anhidrosis can't feel temperature at all, and so are at risk of overheating as well as getting cuts, bruises, burns etc. Image credit: Hobbes vs Boyle

Pain evolved as a necessary evil. It tells us when we've done something damaging, or are on the brink of causing more serious harm. It's tempting to wish away pain after stubbing your toe or burning your hand, but life without pain is far from pleasant. People born with very rare genetic conditions giving complete insensitivity to pain end up spending most of their lives in hospital for injuries they simply didn't know they were getting. They must actively learn and constantly be thinking about what things are "bad" to touch, such as knives or boiling water, because they will never feel the warning signs of a light prick or rising warmth.

These people have no trouble experiencing the touch and feel of their surroundings, showing that pain isn't just an excess of touch. Instead, there are nerves which specialise only in detecting and transmitting harmful stimuli. These nerves are called nociceptors.

After the first stage of the transmission of pain signals, our knowledge comes to an end. Image credit: Carlos Martinez

The first step of nociception, how receptors in our skin respond to painful stimuli, is probably the best understood aspect of pain - both mechanical and temperature-based. We know which of the heat-detecting nociceptors^[1] can also be activated by capsaicin, the painful component of chillies that makes us feel like our mouth is on fire despite all evidence to the contrary. We also know which gene is mutated in many people who cannot feel pain.

Yet after the first stage, our understanding wanes considerably.

What role do motor neurons play in basic bodily functions?

As you read this, muscles are contracting and relaxing regularly to move air in and out of your lungs. When you walk to the kitchen for a cup of coffee, muscles in your legs contract and relax in rhythmic sequence to move you forward. For animals to function, motor behaviours like breathing and walking must be reliably controlled by the nervous system. Muscles need to contract in the same order, for roughly the same duration, each time a breath or step is taken. There is a pattern of activity that must be maintained. But the system also has to be flexible enough to respond to changes in the environment, such as obstacles in your path that you have to step around. There are many open questions about how the nervous system controls rhythmic movements, permitting reliability and flexibility. What determines the timing of the motor pattern? Under what conditions can the timing be altered, and how? To what extent can these behaviours be recovered after injury?

How does the nervous system produce the rhythmic sequence of movements required for walking?
Image credit: Eadward Muybridge 1887, via Boston Public Library

Rhythmic motor pattern generation

Example of a motor network, in which motor neurons are not part of the CPG. Image credit: E. McKiernan.

Rhythmic motor behaviours are controlled by networks of neurons which communicate electrically and chemically¹. Although the exact organization of these networks varies, many can be divided into four principal groups of cells. One group includes a subset of neurons in the central nervous system called a central pattern generating (CPG) network, which produces the core rhythm. In some systems, motor neurons, which send signals directly to muscle fibres, participate in generating the rhythm and are part of the first group. However, in other systems, motor neurons do not belong to the CPG network and are considered a second group receiving input from the first. Muscle fibres constitute a third group of cells comprising whole muscles that contract or relax to produce movements. A fourth group, sensory neurons, responds to the movement of muscles and sends feedback to the central nervous system about the output that was produced, or whether there are environmental perturbations, like obstacles.