Effects of high intravenous doses of dynorphin A(1-13) on tail flick latency and central nervous system histology in rats.
Dynorphin A(1-13) blocks opiate withdrawal in rats without producing dependence, and enhances analgesia in morphine-tolerant animals. Its potential use in humans is therefore of interest. Dynorphin A(1-13) has little toxicity when administered at modest doses IV but has been reported to cause hindlimb paralysis and necrosis of the spinal cord in rats, at the catheter tip, when administered intrathecally. To further evaluate its potential neurotoxicity, we administered dynorphin A(1-13) to rats at very high doses IV. Rats (n = 6-10 per group) received dynorphin A(1-13) as bolus IV doses of 5 mg/kg, or as continuous IV infusions of 40 mg/kg/day for 1 day, with saline controls. The appearance and behavior of all animals was normal. Tail flick latencies remained unchanged (p > 0.5). There were no histologic abnormalities of the spinal cord or brain when examined by light microscopy. Two additional groups received bolus injections of dynorphin A(1-13) 50 or 100 mg/kg IV. Animals receiving 50 mg/kg showed cutaneous flushing, labored respirations, and decreased spontaneous movement, which resolved within 10 min. Histology at 1 week was normal. All six animals receiving 100 mg/kg convulsed and died within minutes. Three animals that received dynorphin A(1-13) 40 mg/kg/day for 7 days had normal behavior and histology. We conclude that the previously observed neurotoxicity of intrathecally administered dynorphin A(1-13) is a local effect that does not occur when dynorphin A(1-13) is administered IV, even at very high doses.
Pentel
P R
PR
Department of Medicine, University of Minnesota Medical School, Hennepin County Medical Center, Minneapolis 55415, USA.
Wananukul
W
W
Hooke
L P
LP
Jones
C R
CR
Hatsukami
D
D
Anderson
W R
WR
Lee
N M
NM
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects / Q000473:pathology*; D004399:Dynorphins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D007262:Infusions, Intravenous; D010147:Pain Measurement / Q000187:drug effects*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects
D000701:Analgesics, Opioid; D010446:Peptide Fragments; C026843:dynorphin (1-13); D004399:Dynorphins