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-h ydroxy-5-methylisonazol-4-yl) pionic acid and metabotropic glutamate recept or agonist, produces an excitotoxic injury that leads to the onset of both spontaneous and evoked pain behavior as well as changes in spinal and corti cal expression of opioid peptide mRNA, preprodynorphin and preproenkephalin . What characteristics of the quisqualic acid-induced injury are attributab le 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-m ethylisoxazol-4-yl) acid (AMPA) and metabotropic glutamate receptor subtype s in the regulation of opioid peptide expression and the onset of spontaneo us and evoked pain-related behavior following excitotoxic spinal cord injur y by comparing quisqualic acid-induced changes with those created by co-inj ection of quisqualic acid and the kainic acid/AMPA antagonist, 2,3-dihydrox y-6-nitro-7-sulfamoylbenzo[f]quinoxaline, (NBQX) or the metabotropic antago nist, IRS)-1-aminoindan-1,5-dicarboxylic acid (AIDA). Therefore, 42 male Lo ng Evans adult rats were divided into seven treatment groups and received i ntraspinal microinjections of saline (sham). 0.5% dimethylsulphoxide (sham) , quisqualic acid (1.2 mul, 125 mM), NBQX (1.2 mul. 60 muM). AIDA (1.2 mul. 250 muM), quisqualic acid/ NBQX (1.2 mul. 125 mM/60 muM), or quisqualic ac id/AIDA (1.2 mul, 125 mM/250 muM) directed at spinal levels thoracic 12-lum bar 2. Behavioral observations of spontaneous and evoked pain responses wer e completed following surgery. After a 10-day survival period, animals were killed and brain and spinal cord tissues were removed and processed for hi stologic analysis and in situ hybridization. Both AIDA and NBQX affected th e quisqualic acid-induced total lesion volume but only AIDA caused a decrea se in the percent tissue damage at the lesion epicenter. Preprodynorphin an d preproenkephalin expression is increased in both spinal and cortical area s in quisqualic acid-injected animals versus sham-, NBQX or AIDA-injected a nimals. NBQX did not affect quisqualic acid-induced spinal or cortical expr ession of preprodynorphin or preproenkephalin except for a significant decr ease in preproenkephalin expression in the spinal cord. In contrast, AIDA s ignificantly decreases quisqualic acid-induced preprodynorphin and preproen kephalin expression within the spinal cord and cortex. AIDA. but not NBQX, significantly reduced the frequency of, and delayed the onset of, quisquali c 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 excitotoxi c cascade responsible for quisqualic acid-induced neuronal damage and chang es in opioid peptide mRNA expression, while metabotropic glutamate receptor s may play a more significant role in the onset of post-injury pain-related behavior. (C) 2001 IBRO. Published by Elsevier Science Ltd. All rights res erved.