Metabotropic glutamate receptors in spinal cord injury: Roles in neuroprotection, chronic central pain, and locomotor recovery.

摘要

Spinal cord injury (SCI) results not only in a loss of function, but also in chronic central pain (CCP) syndromes. In this study, the clinically relevant rodent contusion model of SCI was used to examine the roles of metabotropic glutamate receptors (mGluRs) in SCI. Group I mGluR antagonists and group II/III mGluR agonists were administered immediately after SCI and their effects on excitatory amino acid (EAA) release, locomotor recovery, development of CCP, and amount of spared tissue were examined. Since changes in mGluR expression may affect neuronal excitability leading to CCP, spatial and temporal expression of mGluRs was evaluated following SCI.; Intraspinal administration of a group I antagonist after SCI decreased the amount of EAAs released, improved initial locomotor recovery, attenuated the development of CCP, and was neuroprotective. However, administration of group I subtype specific antagonists revealed surprising results: (1) agents which did not affect EAA release were neuroprotective, (2) agents that reduced EAA release were not neuroprotective, and (3) subtypes within group I mGluRs mediate different aspects of CCP. Treatment with an mGluR1 antagonist did not affect EAA release, improved initial locomotor recovery, attenuated mechanical allodynia, potentiated thermal hyperalgesia, and was neuroprotective. However, treatment with an mGluR5 antagonist decreased EAA release, did not affect locomotor recovery or the development of mechanical allodynia, attenuated the development of thermal hyperalgesia, and had less neuroprotective properties compared to the mGluR1 antagonist. Agonists to both group II and III mGluRs attenuated the development of mechanical allodynia, but did not affect the development of thermal hyperalgesia or locomotor recovery. Surprisingly, antagonist treatment to group III mGluRs given immediately after injury (when endogenous ligand is the highest), decreased EAA release; however, neither group II nor III agonists produced significant tissue sparing after SCI.; Expression of mGluR1 was chronically increased in the peri-lesion area and on STT cells in the cervical enlargement; mGluR2/3 was chronically decreased, and mGluR5 remained unchanged in the peri-lesion area. The combination of the increase in mGluR1 and decrease in mGluR2/3 may act in concert to increase nociceptive responses, resulting in CCP syndromes. Interestingly, treatment with agonists to both group II and III results in an increase in mGluR2/3 expression at the epicenter of injury without an increase in amount of spared tissue. These results suggest that mGluRs play important roles in EAA-induced cell death and in the development of CCP following SCI.