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National Institute on Drug Abuse -  NIDA NOTES
Research Advances
Volume 11, Number 1
January/February 1996

Hibernation-Triggering Opioid Extends Life of Organs for Transplantation


By Neil Swan, NIDA NOTES Staff Writer


Using an opiate-like compound to mimic a blood chemical that triggers hibernation in animals, a researcher at NIDA's Division of Intramural Research (DIR) has collaborated with scientists at the University of Kentucky to dramatically extend the time that animal hearts, livers, and other organs can remain viable for transplantation.

This finding suggests the compound may also have potential for increasing organ survival time in severely injured persons, thus helping battlefield casualties and accident victims live longer while waiting for emergency medical care, according to the U.S. Army. The finding also shows how drug abuse research can contribute to advances in other areas of medical science.

Although modern technology now permits the transfusion or transplantation of human tissues such as blood cells or corneas after months or years of cold storage, large organs such as the heart, lungs, and liver can be kept viable for only a few hours outside the body. This means that transplantation of these organs must be performed within hours of the death of a donor. A human pancreas must be transplanted within 4 to 6 hours after removal from the donor, a liver within 8 hours, and a heart in less than 6 hours.


Ground

The natural blood chemical that induces animals such
as these ground squirrels to hibernate also has been
shown to lengthen the time that animal organs remain
viable for transplantation. A synthetic opioid that mimics
this natural compound can extend the organ survival time
even further.


Scientists are now able to increase the time animal organs can survive in the laboratory from 8 hours to 46 hours by using an opiate-like compound in combination with a preservation method that keeps a number of organs from the same donor animal linked with connecting veins. The research holds great promise for making the life-saving transplantation of human organs more readily available, manageable, and routine, according to Dr. Tsung-Ping Su, a biochemist at NIDA's Addiction Research Center in Baltimore.

During earlier studies, researchers at the University of Kentucky Medical Center had found a blood compound that induces certain animals to hibernate in winter by slowing life functions so that the animals exist in a state between sleep and death. The compound - found in the plasma of deeply hibernating woodchucks, ground squirrels, bats, and black bears - is called hibernation induction trigger (HIT).

Dr. Su explains that hibernation slows the heart rate to 1 or 2 beats a minute and breathing to less than 12 breaths a minute. "These physiological changes during hibernation show certain resemblance to the effects of opiates like morphine and heroin in animals," he says.

The scientists determined that a synthetic opioid called DADLE (D-Ala2-D-Leu5 enkephalin), a delta opioid ligand, induced hibernation in animals by mimicking the action of HIT. However, mu and kappa opioid ligands did not induce hibernation; researchers speculated that these ligands may actually trigger arousal from hibernation.

DADLE (pronounced DAY-dul), a synthetic product of amino acids that is familiar to drug-abuse researchers, is a modified form of a naturally occurring opiate substance called an enkephalin, which is found in the brains of mammals. Because DADLE is synthetic and is metabolically stable, it can be created in the laboratory and used to preserve transplant tissues.

In their quest to preserve organs longer for transplantation, the Kentucky researchers had already developed a multiorgan preservation method. The method preserves the heart, lungs, liver, spleen, duodenum, kidneys, abdominal aorta, and portions of connecting veins of research animals as a whole unit submerged in a tissue preservation bath. This procedure keeps organs viable for about 14 hours compared to about 8 hours using single-organ conservation.

Dr. Su, who was closely following the Kentucky studies, and Dr. Peter R. Oeltgen, leader of the Kentucky researchers, quickly recognized that there was potential for using HIT and DADLE to further enhance animal organ survival time, and Dr. Su became a collaborator in subsequent organ preservation studies.

In tests, adding HIT to the bath increased multiorgan survival time from 14 to 44 hours while adding DADLE instead of HIT increased it even more - from 14 to 46 hours.

Dr. Su collaborated with Dr. Oeltgen, Dr. Sufen Chien, and Dr. David Bruce of the University of Kentucky and Wheaten College in Illinois. The DIR and Kentucky researchers are now seeking to learn specifically how DADLE works to increase organ survival time. They report that DADLE may boost tissue survival time in three possible ways: inhibiting tissue metabolism, reducing or eliminating liver congestion, or reducing hemolysis, the destruction of red blood cells.

The researchers are also working with a leading organ transplant surgeon, Dr. Steven F. Bolling of the University of Michigan, who is interested in potential clinical applications of their organ-preservation findings.

While the Kentucky researchers collaborate with Dr. Su of NIDA's DIR, their studies are supported by grants from the U.S. Army Medical Research and Materiel Command. "The Army is interested in this research because of its potential for developing therapies to increase the survival time of combat casualties - soldiers suffering battlefield shock and blood loss," says Dr. Oeltgen. Any potential new advances in prolonging tissue and organ survival time in living persons is of great interest to Army emergency treatment physicians because response time is critical.

Sources

Chien, S.; Oeltgen, P.R.; Diana, J.N.; Salley, R.K.; and Su, T.-P. Extension of tissue survival time in multiorgan block preparation with a delta opioid DADLE. Journal of Thoracic and Cardiovascular Surgery 107:965-67, 1994.

Oeltgen, P.R.; Horton, N.D.; Bolling, S.F.; and Su, T.-P. Extended lung preservation with the use of hibernation trigger factors. Annals of Thoracic Surgery, in press.

Oeltgen, P.R.; Nuchols, P.A.; Nilekani, S.P.; Spurrier, W.A.; and Su, T.-P. Further studies on opioids and hibernation: Delta opioid receptor ligand selectively induced hibernation in summer-active ground squirrels. Life Sciences 43:1565-1574, 1988.

From NIDA NOTES, January/February, 1996


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