Pain
Peripheral Pain System
Nociceptors
These cells are relatively unspecialised compared to other somatosensory receptor cells; they arise from cell bodies in the dorsal root ganglia, or in the trigeminal ganglion, that send single axonal processes to the Peripheral Nervous System (PNS) and to the CNS Spinal Cord or Brainstem. Due to the unspecialised nature of free nerve endings common to nociceptive neurones the types of nociceptors are generally classified by the properties of the axons associated with them.
Axon Structure & Function
All axons have the same basic structure, although some vary in the following ways:
- Diameter: Neurone diameter varies with neurone type.
- Myelin: Myelinated neurones are neurones that are ‘wrapped’ in sheath composed of myelin. Myelin is a lipid-rich substance that is produced by Schwann Cells in the PNS and Oligodendrocytes in the CNS. Myelin has important effects of conduction velocities of neurones: spaces between the cells (either Schwann or Oligodendrocytes) that wrap around the neuronal axon are known as Nodes of Ranvier, within these spaces lie voltage gated sodium channels that allow the continuation of cell depolarisation. By having the channels sporadically spaced along the axon the cell allows conduction to be faster rather than having to undergo continued depolarisation through a longer and more closely located series of sodium channels. There are both myelinated and non-myelinated neurones and this affects their function and behavioural properties.
- Cell bodies: The location of the axons cell body may vary; peripheral neurones most commonly have their cell bodies location in the Dorsal Root Ganglion.
The basic neurone structure can be seen in the diagram below:
Action Potential Events
Axon Types
Axons are classified according to their physical and behavioural properties. These include axon diameter, conduction velocity, targets, sensitivity, threshold etc. Somatic sensory receptors transmit innocuous (non-painful) signals along myelinated neurones that are rapid conductors, whereas nociceptive neurones are generally unmyelinated and have relatively slow conduction velocities. [32, 40, 49]
- A
Fibres:
These nerve fibres are unmyelinated and are of an intermediate diameter
size, these factors result in the neurone having a conduction velocity of
approximately 3 metres per second (ms-1). These neurones are sensitive to
dangerously intense mechanical or mechanothermal stimuli. Their nerve endings
are clustered to create sensitive spots – ‘receptive fields’. - C Fibres: These fibres are unmyelinated and have a small axon diameter. Their conduction velocity is the slowest of all somatosensory neurones and is approximately 0.5 ms-1. These serve as a general slow pain pathway; their generality is due to their polymodal nature. Polymodal neurones respond to a variety of stimuli: Thermal, Mechanical & Chemical.
The conduction of nociceptive information is relatively slow compared to
other neurological transmission velocities; however, within the nociceptive
branch there is a slow and a fast mode of transmission in the C and Ad fibres
respectively. In general, there are hence three major classes or nociceptors:
A mechanosensitive
nociceptors, A
mechanothermal nociceptors and Polymodal nociceptors (specifically associated
with C Fibres). The receptive fields of all pain-sensitive neurones are quite
large, particularly at thalamic and cortical levels. This is likely to be
due to the fact that the detection of pain is of greater importance than the
specific localisation of that pain.
Nociceptive fibres can be identified from other fibres by their response properties; nociceptive fibres have a higher threshold, requiring a higher stimulus intensity for a response to occur, also, as already mentioned, the conduction velocities indicate fibre nature and in addition the fibres response to blocking agents, such as TTX (Tetradotoxin) can help fibre classification. Threshold of nociceptive neurones vary with location, some areas being more sensitive and hence have a lower threshold and excitation of a nociceptor does not always result in the sensation of pain. [7, 28]
Threshold
Every neurone has a threshold; this is the electrical state at which an Action Potential (AP) is produced. This threshold is reliant on the type of sodium channels present in the neurone. Nociceptive neurones contain unique voltage-gated sodium channels, Nav1.8.
Nav1.8 properties are:
- Predominately found in small diameter neurones - Nociceptive C &
A Fibres
- Resistant to TTX
- High Threshold of activation
- Inactivation: Short refractory period, allowing a higher frequency of APs.
Nav1.9 is a second type of TTX-resistant sodium channel, which has a hyperpolarized activation voltage and a depolarised resting potential. The increased threshold of these voltage-gated sodium channels is a result of an increase in the steady-state inactivation of TTX-sensitive neurones that results in a decrease in neuronal excitability. This lowered excitability results in the increased threshold by depolarising the resting membrane potential. Nociceptive neurones contain both TTX-sensitive and TTX-resistant neurones but it is the inactivation state of the TTX-sensitive channels that set the neurones’ resting potential. [32, 40, 46, 49]
