morphinans and 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.

Topics: Animals; Binding, Competitive; Dextrorphan; Dynorphins; Hindlimb; Male; Morphinans; Paralysis; Peptide Fragments; Piperazines; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter

Topics: Alcohols; Amobarbital; Animals; Antipyrine; Benzazepines; Blood Coagulation; Chloral Hydrate; Chlordiazepoxide; Enzyme Induction; Ethanol; Fluorometry; Half-Life; Humans; Hydrocortisone; Hypnotics and Sedatives; Ketones; Kinetics; Male; Metabolism; Microsomes, Liver; Morphinans; Nitro Compounds; Paralysis; Phenobarbital; Rats; Rheumatic Heart Disease; Secobarbital; Sleep; Time Factors; Warfarin