Hyperalgesia is the result of plasticity in the pain pathway. A well-known example of synaptic plasticity is long-term potentiation, whereby brief, conditioning stimuli evoke enhancement of responses to subsequent stimuli by a mechanism that involves trafficking of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subclass of glutamate receptors from the cytosol to the membrane (86). Glutamate is the main fast excitatory neurotransmitter in the spinal dorsal horn and it has been suggested that synaptic potentiation of spinal neurons is associated with the insertion of AMPA-R subunits into synapses (87). Recently it has been shown, using a model of referred visceral hyperalgesia in the mouse, that glutamate receptor trafficking mediates the synaptic plasticity in the spinal cord that leads to pain hypersensitivity (79).
Induction of visceral pain and hyperalgesia by intracolonic application of capsaicin was associated with a pronounced increase in the abundance of the AMPA-R subunit GluR1 in the membrane fraction with a peak 3.7-fold increase 180 minutes after treatment and a corresponding decrease in the levels in the cytosolic fraction. In contrast to the pronounced effects of the painful visceral stimulus on GluR1 distribution, capsaicin treatment had no effect on the intracellular distribution of GluR2/3 in spinal tissue (Fig. 4B). This is consistent with observations in other brain areas and with the proposal that GluR1 insertion into the membrane is an inducible and tightly regulated process, whereas GluR2/3 subunits are constitutively cycled in and out of the membrane to maintain normal transmission (86). The trafficking of GluR1 to the membrane of spinal neurons induced by the painful visceral stimulus was also shown to be dependent on the activation of calcium-calmodulin kinase II (CaMKII) showing that the process shared cellular properties with other forms of synaptic plasticity such as long-term potentiation. Interestingly, inhibition of the functional exocytotic machinery of the neurons prevented the GluR1 accumulation in the neuronal membrane and inhibited the referred visceral hyperalgesia induced by intracolonic capsaicin (79). These results suggest that synaptic incorporation of GluR1 plays an important role in the development and expression of visceral hyperalgesia.
These observations show that natural activation of the visceral pain pathway in intact adult animals in vivo provokes trafficking of GluR1 subunits in the spinal cord and reveals an association between GluR1 trafficking and the development of hyperalgesia in a model of visceral pain. They also confirm that the molecular mechanisms of synaptic plasticity that mediate process such as learning or memory is shared by the visceral pain pathway.
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