A strychnine-sensitive site is involved in dynorphin-induced paralysis and loss of the tail-flick reflex.
Dynorphin A(1-13) administered intrathecally to rats induces a reversible hindlimb paralysis and permanent loss of the tail-flick reflex in a dose-dependent and all-or-none manner. The loss of the tail-flick reflex has been determined to result from neurotoxicity linked to the N-methyl-D-aspartate (NMDA) receptor. Recently, it has been reported that NMDA antagonists attenuate irreversible paralysis induced by dynorphin A(1-17) and dynorphin A(2-17). In the present studies, we examined whether repeated injections of dynorphin A(1-13) acetate salt could change the characteristics of the reversible paralysis. Injections repeated every 48 h resulted in hindlimb paralysis upon each injection which was not different in terms of magnitude or duration (P greater than 0.60). Injections repeated at 2 h intervals resulted in desensitization of the paralytic effects (P less than 0.05). We also examined if strychnine sulfate, a glycine antagonist would alter the paralytic response to dynorphin. Strychnine protected rats from paralysis (P less than 0.01) and loss of the tail-flick reflex with an ED50 of 7 nmol. We conclude that the reversible paralysis induced by dynorphin A(1-13) is repeatable which suggests that the paralysis results from nontoxic or subtoxic actions of dynorphin. Desensitization to the paralytic effects occurs with closely spaced injections by some unknown mechanism. In addition, we conclude that the spinal glycinergic inhibitory system may participate in the induction of the paralysis because strychnine antagonizes dynorphin-induced paralysis.(ABSTRACT TRUNCATED AT 250 WORDS)
Stewart
P
P
Department of Pharmacology, University of Illinois College of Medicine, Chicago.
Isaac
L
L
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004399:Dynorphins / Q000494:pharmacology*; D008297:Male; D009294:Narcotics / Q000494:pharmacology; D010243:Paralysis / Q000139:chemically induced* / Q000503:physiopathology; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011930:Reaction Time / Q000187:drug effects; D012018:Reflex / Q000187:drug effects*; D013331:Strychnine / Q000494:pharmacology*
D009294:Narcotics; D010446:Peptide Fragments; C026843:dynorphin (1-13); D004399:Dynorphins; D013331:Strychnine