potential generation. There may also be a decrease in potassium channels which would normally oppose action potential generation. Each of these changes appears to support an increase in excitability, which may allow endogenous stimuli to cause spontaneous pain. Central Central mechanisms of neuropathic pain involve a number of major pathways. Nociception is ordinarily transduced by a polysynaptic pathway through the spinal cord, and up the spinothalamic tract to the thalamus and then the cortex. Broadly speaking in neuropathic pain, neurons are hypersensitized, glia become activated and there is a loss of inhibitory tone. Pain gates A major hypothesis in the theory of pain perception is the gate control theory of pain, proposed by Wall and Melzack in 1965. The theory predicts that the activation of central pain inhibitory neurons by non-pain sensing neurons prevents the transmission of non-harmful stimuli to pain centers in the brain. A loss of inhibitory neurons, GAD65/67 expression (the enzymes that synthesise GABA; the predominant inhibitory transmitter in the adult brain), has been observed in some systems following peripheral neuropathy such as in rats, and mice. However, these observations remain controversial with some investigators unable to detect a change. The loss of inhibitory inputs may allow fibers to transmit messages via the spinothalamic tract thus causing pain in normally painless stimuli. This loss of inhibition may not be limited to the spinal cord and a loss of GABA has also been observed in chronic pain patients in the thalamus. Glia During neuropathic pain, glia become "activated" leading to the release of proteins that modulate neural activity. The activation of glia remains an area of intense interest for researchers. Microglia, the brain and spinal cord resident immune cells, respond to extrinsic cues. The source of these cues may include neurons secreting chemokines such as CCL21 and surface immobilized chemokines such as CX3CL1. Other glia such as astrocytes and oligodendrocytes may also release these extrinsic cues for microglia and microglia themselves may produce proteins that amplify the response. The effect of microglia on neurons that leads to the neurons being sensitized is controversial. Brain derived neurotrophic factor, prostaglandins, TNF and IL-1β may be produced by microglia and cause changes in neurons that lead to hyperexcitability. Central sensitization Central sensitization is a potential component of neuropathic pain. It refers to a change in synaptic plasticity, efficacy, and intrinsic disinhibition that leads to an uncoupling of noxious inputs. In the