Chemical pain pathways

 We have already examined the neural pathways involved in the detection and perception of pain- now let’s have a look at what happens to allow us to detect pain at a molecular level. This is important, since it is at this level that pain medications are known to act.

At a basic level, when a noxious stimulus is present, vanilloid receptors like VR1 on primary sensory afferent dendrites are activated. Since these are also ion channels, their activation allows Na and Ca ions to enter the dendritic process. The presence of these ions intracellularly leads to depolarisation, and ultimately, the generation of an action potential that travels to the neuronal cell body in the spinal cord. From then on, it all comes down to the neural pathways previously mentioned.

But what constitutes a noxious stimulus? And do different types of pain have different stimuli?

When it comes to acute pain, the noxious stimulus may be a range of things: it could be physical, such as excess heat, acidity, pressure or stretch; or chemical, such as a toxin or cellular metabolites such as ATP or lactic acid released from damaged or overworked cells, respectively. The presence of any of these factors activates VR1 and other receptors such as P2X (activated by ATP) in Aδ neurons. The pain generated is intermittent and short-lasting, and so tends to be most instructive when we are exerting ourselves too much (excess muscle strain).

With regards longer-lasting chronic pain, the stimulus is usually inflammation- the body’s response to tissue damage. In the presence of inflammation, a range of inflammatory mediators are produced. Examples are prostaglandins such as PGE or PGI, which are generated by the transformation of arachidonic acid by the cyclo-oxygenase enzymes, and kinins such as Bradykinin (BK),which are petides cleaved from pre-cursors in the presence of injury.

Both of these mediators bind to their own G-protein coupled (metabotrophic) receptors and work to activate, or at least sensitise, VR1 in the C-fibre sensory neurons. Bradykinins activate/sensitise VR1 via the enzyme Protein Kinase C-ε, while prostaglandins work via Protein Kinase A to open voltage-gated Na channels. The net effect of both these processes is an increased level of depolarisation in the C-fibres. This generates the feeling of dull pain, making us aware of the inflammation. 

These mediators are also responsible for the common experience of hyperalgesia or allodynia following tissue damage - an increased sensitivity to mild or completely harmless stimuli, respectively. This is the reason why lightly touching a broken limb can cause great pain, whereas normally it would tickle at most! Prostaglandins are thought to increase this sensitivity by making VR1 more sensitive to activation by BK, and perhaps also by increasing the number of VR1 receptors present in the dendrite membrane- both of these effects are considered forms of neuroplasticity (ability to intrinscally change function of a fully differentiated neuron).
 

Summary diagram- chemical pathways occuring at the level of sensory process of primary afferent Adelta/ C fibre

Notice: diagrams

All diagrams on this website are my own, generated using Microsoft Powerpoint and Paint.