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 d ependence, and enhances analgesia in morphine-tolerant animals. Its po tential use in humans is therefore of interest. Dynorphin A(1-13) has little toxicity when administered at modest doses IV but has been repo rted to cause hindlimb paralysis and necrosis of the spinal cord in ra ts, at the catheter tip, when administered intrathecally. To further e valuate its potential neurotoxicity, we administered dynorphin A(1-13) to rats at very high doses IV. Rats (n = 6-10 per group) received dyn orphin A(1-13) as bolus IV doses of 5 mg/kg, or as continuous IV infus ions of 40 mg/kg/day for 1 day, with saline controls. The appearance a nd behavior of all animals was normal. Tail flick latencies remained u nchanged (p > 0.5). There were no histologic abnormalities of the spin al cord or brain when examined by light microscopy. Two additional gro ups received bolus injections of dynorphin A(1-13) 50 or 100 mg/kg IV. Animals receiving 50 mg/kg showed cutaneous flushing, labored respira tions, and decreased spontaneous movement, which resolved within 10 mi n. Histology at 1 week was normal. Ah six animals receiving 100 mg/kg convulsed and died within minutes. Three animals that received dynorph in A(1-13) 40 mg/kg/day for 7 days had normal behavior and histology. We conclude that the previously observed neurotoxicity of intrathecall y 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.