Competitive and non-competitive NMDA antagonists limit dynorphin A-induced rat hindlimb paralysis.
It has been proposed that the endogenous opioid dynorphin A (Dyn A) contributes to the pathogenesis of posttraumatic spinal cord injury (SCI). Dyn A-related peptides given intrathecally (i.t.) produce hindlimb paralysis. These include Dyn A(1-17), Dyn A(1-13), Dyn A(2-17), and Dyn A(3-13). Because Dyn A(2-17) and Dyn A(3-13) are inactive at opiate receptors, Dyn A-induced paralysis may include a non-opioid component. Recently, it has been reported that competitive N-methyl-D-aspartate (NMDA) antagonists block the loss of tail-flick reflex caused by i.t. administration of Dyn A(1-13). In the present studies we examined whether competitive [(4-[3-phosphonopropyl]-2-piperazine-carboxylic acid (CPP)] or non-competitive (dextrorphan) NMDA antagonists could attenuate paralysis induced by Dyn A(1-17) or Dyn A(2-17). CPP or dextrorphan each significantly attenuated the neurologic dysfunction and mortality associated with Dyn A(1-17) administration. In addition, CPP and dextrorphan significantly reduced the neurologic dysfunction caused by Dyn A(2-17)(all P less than 0.05). From these data we suggest that the non-opioid component of Dyn A-induced paralysis is mediated in part by the NMDA receptor.
Bakshi
R
R
Department of Neurology, University of California, San Francisco 94143.
Faden
A I
AI
D000818:Animals; D001667:Binding, Competitive; D003917:Dextrorphan / Q000494:pharmacology*; D004399:Dynorphins / Q000494:pharmacology* / Q000502:physiology; D006614:Hindlimb / Q000503:physiopathology; D008297:Male; D009019:Morphinans / Q000494:pharmacology*; D010243:Paralysis / Q000139:chemically induced* / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000502:physiology*
D009019:Morphinans; D010446:Peptide Fragments; D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D003917:Dextrorphan; D004399:Dynorphins; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid