The role of kainic acid/AMPA and metabotropic glutamate receptors in the regulation of opioid mRNA expression and the onset of pain-related behavior following excitotoxic spinal cord injury

Intraspinal injection of quisqualic acid, a mixed kainic acid/2-amino-3(3-hydroxy-5-methylisoxazol-4-yl)propionic acid and metabotropic glutamate receptor agonist, produces an excitotoxic injury that leads to the onset of both spontaneous and evoked pain behavior as well as changes in spinal and cortical expression of opioid peptide mRNA, preprodynorphin and preproenkephalin. What characteristics of the quisqualic acid-induced injury are attributable to activation of each receptor subtype is unknown. This study attempted to define the role of activation of the kainic acid/2-amino-3(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) and metabotropic glutamate receptor subtypes in the regulation of opioid peptide expression and the onset of spontaneous and evoked pain-related behavior following excitotoxic spinal cord injury by comparing quisqualic acid-induced changes with those created by co-injection of quisqualic acid and the kainic acid/AMPA antagonist, 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f]quinoxaline, (NBQX) or the metabotropic antagonist, (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA). Therefore, 42 male Long-Evans adult rats were divided into seven treatment groups and received intraspinal microinjections of saline (sham), 0.5% dimethylsulphoxide (sham), quisqualic acid (1.2 microl, 125 mM), NBQX (1.2 microl, 60 microM), AIDA (1.2 microl, 250 microM), quisqualic acid/NBQX (1.2 microl, 125 mM/60 microM), or quisqualic acid/AIDA (1.2 microl, 125 mM/250 microM) directed at spinal levels thoracic 12-lumbar 2. Behavioral observations of spontaneous and evoked pain responses were completed following surgery. After a 10-day survival period, animals were killed and brain and spinal cord tissues were removed and processed for histologic analysis and in situ hybridization. Both AIDA and NBQX affected the quisqualic acid-induced total lesion volume but only AIDA caused a decrease in the percent tissue damage at the lesion epicenter. Preprodynorphin and preproenkephalin expression is increased in both spinal and cortical areas in quisqualic acid-injected animals versus sham-, NBQX or AIDA-injected animals. NBQX did not affect quisqualic acid-induced spinal or cortical expression of preprodynorphin or preproenkephalin except for a significant decrease in preproenkephalin expression in the spinal cord. In contrast, AIDA significantly decreases quisqualic acid-induced preprodynorphin and preproenkephalin expression within the spinal cord and cortex. AIDA, but not NBQX, significantly reduced the frequency of, and delayed the onset of, quisqualic acid-induced spontaneous pain-related behavior. From these data we suggest that both the kainic acid/AMPA and metabotropic glutamate receptor subtypes are involved in the induction of the excitotoxic cascade responsible for quisqualic acid-induced neuronal damage and changes in opioid peptide mRNA expression, while metabotropic glutamate receptors may play a more significant role in the onset of post-injury pain-related behavior.