Selective potentiation of NMDA-induced activity and release of excitatory amino acids by dynorphin: possible roles in paralysis and neurotoxicity.
Selective antagonists of N-methyl-D-aspartate (NMDA) excitatory amino acid (EAA) receptors have been shown to protect against dynorphin-A (DYN)-induced paralysis and neurotoxicity in the spinal cord. To test the hypothesis that either DYN-induced paralysis or neurotoxicity involves an enhanced release of EAAs, we used microdialysis to monitor aspartate (Asp) and glutamate (Glu) release in both the lumbar spinal cord extracellular fluid (ECF) and the spinal cord cerebral spinal fluid (CSF) of conscious rats in response to DYN (1-13). Injection of 5 nmol of DYN produced temporary paralysis in 8 of 10 animals, but did not significantly change Asp or Glu release in either the ECF or the CSF. Injection of 20 nmol of DYN caused permanent paralysis and neuronal cell loss in all animals tested as well as a significant increase of Asp and Glu in both the ECF and the CSF, and a decrease in glutamine (Gln) release only in the ECF. Pretreatment with 1 mg/kg of the NMDA antagonist MK-801 blocked both paralysis and amino acid changes in the ECF. Pretreatment of animals with 5 mg/kg naloxone inhibited glutamate release in the ECF, but did not block paralysis, Asp release or inhibition of Gln release. As MK-801 sensitive paralysis by DYN was not mediated through enhanced EAA release, we examined whether DYN could act through postsynaptic facilitation of NMDA receptors by testing the ability of DYN to alter the magnitude of a behavioral response produced by intrathecal injection of NMDA in mice.(ABSTRACT TRUNCATED AT 250 WORDS)
Skilling
S R
SR
Department of Veterinary Biology, University of Minnesota, St. Paul 55108.
Sun
X
X
Kurtz
H J
HJ
Larson
A A
AA
D000818:Animals; D001224:Aspartic Acid / Q000134:cerebrospinal fluid / Q000378:metabolism*; D001522:Behavior, Animal / Q000187:drug effects; D016923:Cell Death; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004399:Dynorphins / Q000494:pharmacology*; D005971:Glutamates / Q000134:cerebrospinal fluid / Q000378:metabolism*; D018698:Glutamic Acid; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology*; D009474:Neurons / Q000473:pathology; D010243:Paralysis / Q000139:chemically induced / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*
D005971:Glutamates; D001224:Aspartic Acid; D018698:Glutamic Acid; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D004399:Dynorphins