Glutamate receptors and nociception: implications for the drug treatment of pain.

Evidence from the last several decades indicates that the excitatory amino acid glutamate plays a significant role in nociceptive processing. Glutamate and glutamate receptors are located in areas of the brain, spinal cord and periphery that are involved in pain sensation and transmission. Glutamate acts at several types of receptors, including ionotropic (directly coupled to ion channels) and metabotropic (directly coupled to intracellular second messengers). Ionotropic receptors include those selectively activated by N-methyl-D-aspartate, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid and kainate. Metabotropic glutamate receptors are classified into 3 groups based on sequence homology, signal transduction mechanisms and receptor pharmacology. Glutamate also interacts with the opioid system, and intrathecal or systemic coadministration of glutamate receptor antagonists with opioids may enhance analgesia while reducing the development of opioid tolerance and dependence. The actions of glutamate in the brain seem to be more complex. Activation of glutamate receptors in some brain areas seems to be pronociceptive (e.g. thalamus, trigeminal nucleus), although activation of glutamate receptors in other brain areas seems to be antinociceptive (e.g. periaqueductal grey, ventrolateral medulla). Application of glutamate, or agonists selective for one of the several types of glutamate receptor, to the spinal cord or periphery induces nociceptive behaviours. Inhibition of glutamate release, or of glutamate receptors, in the spinal cord or periphery attenuates both acute and chronic pain in animal models. Similar benefits have been seen in studies involving humans (both patients and volunteers); however, results have been inconsistent. More research is needed to clearly define the role of existing treatment options and explore the possibilities for future drug development.