Neurologic deficits and neuronal injury in rats resulting from nonopioid actions of the delta opioid receptor antagonist ICI 174864.
The delta opioid receptor antagonist ICI 174864 produces postural abnormalities and barrel rolling after i.c.v. injection and hindlimb and tail flaccidity after spinal subarachnoid injection in rats. These effects appear to result from nonopioid characteristics of ICI 174864 because they are neither shared nor blocked by other opioid antagonists (naloxone, ICI 154129 and WIN 44,441-3) and are produced by two compounds (ICI 174644 and ICI 178173) that are structurally related to ICI 174864 but lack its delta antagonist properties. Barrel rolling and hindlimb paralysis are also produced by dynorphin A-related peptides; however, rats failed to demonstrate tolerance or cross-tolerance to the hindlimb paralytic actions of ICI 174864 or dynorphin A (1-13) after 7 days of continuous spinal intrathecal infusion of either of these compounds. Whereas hindlimb responses to low doses of ICI 174864 (1.6-6.2 nmol intrathecally) were usually transient, higher doses (6.2-25 nmol intrathecally) produced persistent hindlimb motor dysfunction, altered nociception, priapism, hindlimb edema, bladder infarction and atony and urinary incontinence. Neuronal and axonal changes in the lumbosacral spinal cords of rats with persistent and transient neurologic deficits provided direct evidence of the neuropathologic actions of ICI 174864 (3.1 and 6.2 nmol) and ICI 174644 (25 nmol). These results indicate that 1) use of ICI 174864 as a selective delta opioid receptor antagonist is potentially compromised by its nonopioid neuropathologic actions and 2) ICI 174864 and dynorphin A-related peptides are unique among opioid agonists and antagonists in sharing barrel rolling and hindlimb paralytic effects. A similar mechanism of action may underlie the shared nonopioid actions of these peptides.
Long
J B
JB
Department of Medical Neurosciences, Walter Reed Army Institute of Research, Washington, D.C.
Petras
J M
JM
Holaday
J W
JW
D000818:Animals; D004361:Drug Tolerance; D004399:Dynorphins / Q000633:toxicity; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives* / Q000633:toxicity; D008297:Male; D009292:Narcotic Antagonists / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects*; D010243:Paralysis / Q000139:chemically induced*; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000187:drug effects*; D017465:Receptors, Opioid, delta; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology
D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D004743:Enkephalin, Leucine; D004399:Dynorphins; C040643:N,N-diallyl-tyrosyl-alpha-aminoisobutyric acid-phenylalanyl-leucine