Hindlimb paralytic effects of prodynorphin-derived peptides following spinal subarachnoid injection in rats.
Dynorphin A-(1-17) acts through non-opioid mechanisms to produce dose-related neurological deficits following injection into the lumbar spinal subarachnoid space in rats. Hindlimb motor function was examined following subarachnoid injection of dynorphin A fragments and other opioid peptides derived from prodynorphin to establish: (1) which portion(s) of the dynorphin A molecule cause hindlimb motor dysfunction, and (2) whether these paralytic actions are shared by other opioids (dynorphin B, alpha-neo-endorphin, and beta-neo-endorphin) derived from the same promolecule. To minimize the influence of enzymatic inactivation on relative bioactivities, peptides were coinjected with a combination of peptidase inhibitors previously shown to enhance the actions of dynorphin A fragments in vitro. Dynorphin A-(1-17) and -(2-17) produced dose-related neurological deficits with equal potencies and durations. Although without effect when injected alone, dynorphin A-(1-8), -(1-7) and -(3-8) caused transient motor dysfunction when co-injected with peptidase inhibitors. In contrast, dynorphin A-(1-6), -(1-5) and -(6-17) did not disrupt hindlimb motor function with or without peptidase inhibition. Dynorphin B, alpha-neo-endorphin and beta-neo-endorphin also caused hindlimb dysfunction which was potentiated by peptidase inhibition. These deficits appeared to result from non-opioid actions of these three peptides, since they were not blocked by the opioid antagonist naloxone. Thus, the paralytic effects of dynorphin A: (1) result from non-opioid actions involving the 3-7 or 3-8 positions of the molecule, and (2) are shared by other prodynorphin-derived opioid peptides.
Long
J B
JB
Department of Medical Neurosciences, Walter Reed Army Institute of Research, Washington, DC 20307-5100.
Martinez-Arizala
A
A
Echevarria
E E
EE
Tidwell
R E
RE
Holaday
J W
JW
D000818:Animals; D004399:Dynorphins / Q000008:administration & dosage / Q000633:toxicity*; D006614:Hindlimb / Q000187:drug effects; D007267:Injections; D008297:Male; D009270:Naloxone / Q000494:pharmacology; D010243:Paralysis / Q000139:chemically induced*; D051381:Rats; D011919:Rats, Inbred Strains; D013116:Spinal Cord; D013346:Subarachnoid Space
D009270:Naloxone; D004399:Dynorphins