Hindlimb paralytic effects of prodynorphin-derived peptides following spinal subarachnoid injection in rats

Abstract

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, α-neo-endorphin, and β-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, α-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.