Pharmacology Notes

The normal consequences of tissue injury involve an immediate response from activation of nociceptors, subsequent local inflammation which induces primary hyperalgesia and, finally, central sensitisation inducing secondary hyperalgesia.

Nociceptors are the pain receptors. They are a class of sensory receptors that generate a response to environmental stimuli that are strong enough to have the potential to cause tissue damage. The sensory thresholds of receptors for noninjurious cutaneous stimuli (eg warmth, touch) are much lower.

The thresholds of nociceptors can be changed by both local and central influences. This is the concept of nociceptor and neuronal plasticity that also includes ‘wind-up’ in the CNS. This is a part of normal nociception as well as being involved in primary and secondary hyperalgesia.

Local tissue inflammation involves the release of a range of chemical mediators that increase the access of immune responsive cells, alter tissue permeability and lower the threshold of nociceptors. Nociceptors are not typically confined to one nerve fibre type, and often contain a variety of ion channels that are sensitive to a range of environmental stimuli. These are called ‘polymodal receptors’.

The inflammatory mediators released at the site of tissue injury, including serotonin, kinins and prostaglandins, result in primary hyperalgesia by increasing nociceptor responsiveness. Responsive ion channels include the heat-activated ion channel vanilloid receptor type 1 (VR1) for which the most well known stimulus is capsaicin (in the diet as hot chillies or in pepper spray). In response to tissue injury and inflammation, high local tissue levels of adenosine triphosphate (ATP) stimulate nociception via the purinergic P2X class of receptor and the low pH environment lowers the threshold for VR1 and P2X receptor activation, in addition to activating acid-sensing ion channels.

Cutaneous sensory afferent fibres responding to acute mechanical, thermal and chemical stimuli conduct the impulses resulting from nociceptor activity to the spinal cord. The primary sensory neurones have their cell bodies in the dorsal root ganglion of the appropriate spinal nerve, with proximal nerve endings entering and synapsing in the dorsal horn of the spinal cord.

Noxious stimuli are detected in the periphery by nociceptors, and the signals are transmitted to the spinal cord by one or both of two nerve fibre systems. Sharp, transient, pricking pain (fast pain) is conducted by A-delta fibres, which are myelinated and respond predominantly to high intensity mechanical or heat stimuli. Delayed, prolonged aching and burning pain (slow pain) is conducted by C fibres, which are unmyelinated. The peripheral terminals of most cutaneous C fibres are polymodal nociceptors, and respond to intense thermal, chemical and mechanical stimuli. A few respond to cold and mechanical stimuli. C fibres also mediate visceral pain. Many visceral and joint C fibres are unresponsive until sensitised by tissue inflammation (see above). These afferent fibres have been termed ‘silent nociceptors’, and their recruitment provides another mechanism for the amplification of peripheral nociceptive input following tissue injury and inflammation.