Peripheral sensitization
Peripheral sensitization is a reduction in threshold and an increase in responsiveness of the peripheral ends of nociceptors, the high-threshold peripheral sensory neurons that transfer input from peripheral targets (skin, muscle, joints and the viscera) though peripheral nerves to the central nervous system (spinal cord and brainstem).

Peripheral sensitization contributes to the pain hypersensitivity found at the site of tissue damage and inflammation. A good example of this is the change in heat sensitivity after sunburn, when a normally warm stimulus such as a shower feels burning hot in the sunburned areas.

Sensitization arises due to the action of inflammatory chemicals or mediators released around the site of tissue damage or inflammation. Some of these, such as ATP, can directly activate the ends of the peripheral nociceptors, signalling the presence of inflamed tissue and producing pain. Other chemical mediators are produced by activated inflammatory cells, such as neutrophils (a type of white blood cell). When activated, these cells begin making an enzyme known as Cox-2, which leads to the production and secretion of prostaglandin PGE2. This mediator act as a sensitizer, altering pain sensitivity by increasing the responsiveness of peripheral nociceptors. Aspirin-like pain-killing drugs act by inhibiting Cox-2 and prostaglandin production.

Central sensitization
Central sensitization is an increase in the excitability of neurons within the central nervous system, so that normal inputs begin to produce abnormal responses.

The increased excitability is typically triggered by a burst of activity in nociceptors (such as that evoked by an injury), which alter the strength of synaptic connections between the nociceptor and the neurons of the spinal cord (so-called activity-dependent synaptic plasticity).

Low-threshold sensory fibres activated by very light touch of the skin, for example, begin to activate neurons in the spinal cord (for inputs from the body) or in the brainstem (for inputs from the head) that normally only respond to noxious stimuli. As a result, an input that would normally evoke an innocuous sensation now produces pain. In effect, the synaptic changes increase the 'gain' of the system.

Although the pain feels as if it originates in the periphery, it is actually a manifestation of abnormal sensory processing within the central nervous system.

Central sensitization is responsible for tactile allodynia (pain in response to light brushing of the skin) and for the spread of pain hypersensitivity beyond an area of tissue damage so that adjacent non-damaged tissue is tender. Central sensitization can also occur after surgery, contributing to pain on movement or touch, in migraine attacks where brushing hair is often painful, and in some patients with nerve damage where even blowing on the skin produces excruciating burning pain.

More recently, it has been suggested that diseases such as fibromyalgia (a condition associated with a tender painful muscular pain) or irritable bowel syndrome may be manifestations not of peripheral pathology but of altered function of the nervous system (functional pain).

What are the mechanisms responsible for peripheral and central sensitization? At a cellular level they are quite different, but at a molecular level they share several similarities.

Mechanisms: peripheral sensitization
Peripheral sensitization is the result of changes in key proteins and ion channels (known as transduction proteins) that determine the excitability of the nociceptor terminal. The transduction proteins are the means by which a noxious stimulus, for example excessive heat, is converted into electrical activity. Normally for heat this only occurs at around 42°C, the heat pain threshold. After peripheral inflammation, though, the threshold falls considerably.

Two processes have been implicated in this increase in sensitivity:

• changes to existing nociceptor proteins (post-translational processing)
  
  
• changes to the proteins being made by the nociceptor (altered gene expression).

Post-translational changes usually involve the addition of phosphate groups to some of the protein's amino acids, by enzymes known as kinases. This phosphorylation can dramatically alter the properties of a protein, for example reducing the temperature required to open an ion channel. Sodium ion channels that determine the excitability of the nociceptor terminal can also be phosphorylated. As well as lowering the threshold at which they open, phosphorylation also makes the channel open for longer, so that any stimulus to the terminal will evoke a greater response.

The kinases are activated by a cascade of intracellular signals initiated by inflammatory mediators (such as prostaglandins) acting on receptors present on the peripheral ends of the nociceptor. Most of these signals act locally in the terminal to change the properties of proteins present on the membrane.

Some signals, however, are transported from the terminal along the axon or nerve fibre to the cell body of the sensory neurons in the dorsal root ganglion. Here they either change transcription (increase expression of particular genes) or increase translation (ensure more protein is produced from messenger RNA). The increased protein is then shipped back down to the terminal where it contributes to an increased responsiveness of the terminal to peripheral stimuli. One example is the TRPV1 protein, an ion channel that responds to heat stimuli. Activation of kinases takes minutes, changes in protein levels a day or so.

Central mechanisms
Central sensitization also has two phases:

• an immediate but relatively transient phase; and
  
  
• a slower onset but longer-lasting phase.

Again, the first phase depends on changes to existing proteins while the second phase relies on new gene expression.

The early phase reflects changes in synaptic connections within the spinal cord, after a signal has been received from nociceptors. The central terminals of the nociceptor release a host of signal molecules, including the excitatory amino acid synaptic transmitter glutamate, neuropeptides (substance P and CGRP) and synaptic modulators including BDNF.

These transmitters/modulators act on specific receptors on the spinal cord neurons, activating intracellular signaling pathways that lead to the phosphorylation of membrane receptors and channels, particularly the NMDA and AMPA receptors for the glutamate neurotransmitter. These post-translational changes lower the threshold and opening characteristics of these channels, thereby increasing the excitability of the neurons.

A later transcription-dependent phase of central sensitization is mediated by increased levels of protein production. The net effect of these changes is that normally subliminal inputs begin to activate the neurons and pain sensibility is drastically altered.

Among the proteins mediating this effect are dynorphin, an endogenous opioid that increases neuronal excitability, and Cox-2, the enzyme that produces prostaglandin E2. As well as being involved in peripheral sensitization, prostaglandins also affect central neurons, contributing to central sensitization. Indeed, the analgesic action of aspirin-like drugs may derive more from their central than peripheral actions on Cox-2.