Neurological dysfunction after intrathecal injection of dynorphin A (1-13) in the rat. II. Nonopioid mechanisms mediate loss of motor, sensory and autonomic function.
The kappa opioid agonist dynorphin A (Dyn A) (1-13) produced dose-related neurological deficits after subarachnoid injection in the lumbar spinal cords of rats. Whereas the neurological dysfunctions produced by low doses of Dyn A (1-13) were transient, higher doses caused persistent deficits, characterized by motor and nociceptive impairment in hindlimbs and tail, hindlimb edema, priapism, bladder infarction and atony and urinary incontinence. These deficits appeared to result from nonopioid actions of Dyn A (1-13), as they were: 1) not blocked by the opioid antagonists naloxone or WIN 44,441-3; 2) shared by Dyn A (3-13), which lacks opioid activity; and 3) not produced or altered by the selective kappa opioid agonist U 50,488. Coinjection of a combination of peptidase inhibitors, shown previously to enhance the actions of Dyn A fragments in vitro, significantly increased the paralytic actions of Dyn A (1-13). The peptidase inhibitors did not by themselves cause neurological dysfunction, and they did not alter the paralytic potency of the peptidase-resistant delta opioid antagonist ICI 174864. These findings indicate that Dyn A effects were: 1) limited appreciably by its rapid enzymatic degradation after injection and 2) most likely the result of actions of the intact peptide rather than proteolytic products generated after injection. Neuroanatomical evaluations revealed extensive neuronal and axonal injury in the lumbosacral spinal cords of rats injected with 25 nmol of Dyn A (1-13). Collectively, these results indicate that Dyn A (1-13) acts through nonopioid mechanisms to cause the injury and death of neurons involved in diverse spinal cord functions.
D000818:Animals; D001341:Autonomic Nervous System / Q000187:drug effects; D004399:Dynorphins / Q000008:administration & dosage / Q000494:pharmacology*; D007278:Injections, Spinal; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009619:Nociceptors / Q000187:drug effects; D010243:Paralysis / Q000139:chemically induced; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013116:Spinal Cord / Q000187:drug effects*
D010446:Peptide Fragments; C026843:dynorphin (1-13); D004399:Dynorphins