Difference between revisions of "Role of Metabotropic Glutamate Receptors in Pain"

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In addition to playing an essential role in various physiological activities, glutamate has been implicated in the pathogenesis of several pathological conditions affecting the CNS. This is due primarily to its widespread distribution in all brain areas, but also to its ability to activate receptor subtypes linked to the activation of calcium-permeable ion channels, whose accumulation is known to be harmful to neurons. Indeed, excessive stimulation of glutamate receptors results in neuronal death, a phenomenon termed "excitotoxicity," which has been proposed as a pathogenic mechanism for a variety of CNS disorders, such as cerebral ischemia <ref>Rothman SM, Olney JW. Glutamate and the pathophysiology of hypoxic--ischemic brain damage. Ann Neurol. 1986 Feb;19(2):105-11.</ref>. The concept of excitotoxicity has also been extended to epilepsy and chronic neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, and Huntington's chorea <ref>Albin RL, Greenamyre TJ. Alternative excitotoxic hypotheses. Neurology. 1992 Apr;42(4):733-8.</ref>. The exact role of glutamate in these pathological phenomena is not yet fully understood, whether it is a sufficient cause or a contributing factor to neuronal death. However, experimental evidence suggests that antagonists of glutamate receptors can exert neuroprotective actions.

The role of the periaqueductal gray (PAG) in nociceptive transmission is not fully understood. However, experimental evidence indicates that activation of Group I mGlu receptors in the PAG potentiates the antinociceptive activity of the descending pathway originating from this brain area. Indeed, recent studies indicate that intra-PAG administration of DHPG, a Group I mGlu agonist, reduces hyperalgesia induced by formalin injections <ref>Maione S, Oliva P, Marabese I, Palazzo E, Rossi F, Berrino L, Filippelli A. Periaqueductal gray matter metabotropic glutamate receptors modulate formalin-induced nociception. Pain. 2000 Mar;85(1-2):183-9.</ref>. This effect is thought to be linked to glutamate's ability, through mGlu activation, to prevent the establishment of the wind-up phenomenon.

The role of glutamate in the Peripheral Nervous System is still unclear. It has been shown that subcutaneous injection of glutamate in rats reduces the activation threshold for mechanical and thermal stimuli <ref>Jackson DL, Graff CB, Richardson JD, Hargreaves KM. Glutamate participates in the peripheral modulation of thermal hyperalgesia in rats. Eur J Pharmacol. 1995 Sep 25;284(3):321-5.</ref>. The application of antagonists for ionotropic glutamate receptors attenuates nociceptive levels in the formalin test, a model used to study inflammatory pain. Additionally, glutamate concentration increases in the cutaneous tissue after sciatic nerve stimulation and during the formalin test in rats <ref>de Groet M, van der Kooy D. Sensory neuron specific receptor activation reduces pain in rats. Nature. 2000.</ref>. Altogether, this data suggests that glutamate acts as an effective mediator of peripheral inflammation following tissue injury and that peripheral glutamate activates ionotropic receptors.