Morphine-Like Painkiller Appears to be Less Addictive

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Move over, morphine: Researchers at the University of Arizona and the University of New England have developed a new narcotic based on a natural painkiller found in the body that appears in animal studies to be more potent but less addictive.

Although researchers have developed many narcotic-type painkillers that rival morphine in strength, few have had the ability to avoid its potential side effects, until now. These side effects include severe constipation, reduced blood pressure and breathing, and addiction.

"This represents one of the most promising morphine-like painkillers to date in terms of avoiding its side effects, particularly addiction," says Robin Polt, Ph.D., a professor of chemistry at the University of Arizona in Tucson and a chief researcher on the project. He presented details of the research today at the 225th national meeting of the American Chemical Society, the world's largest scientific society.

Called a glycosylated enkephalin, the compound appears promising in studies using mice. If it works in humans, it could be a safer alternative for people who are allergic to morphine or cannot take the drug because of concern for its side effects, the researchers say.

These improved features make it particularly appealing to the military, which hopes that the safer, less-addictive drugs can be self-administered by soldiers who are severely wounded during battle without depending on the assistance of a medic.

"Our hope is that glycosylated enkephalins can be used to block pain in severe trauma injuries, in victims who could not normally receive narcotics," says Polt, who is currently servings as a visiting scientist at the National Science Foundation in Arlington, Va.

Morphine, one of the most potent pain relievers available, is beneficial to both cancer and trauma patients. However, its potential side effects have limited its use.

For years, researchers have sought to find a drug that could block pain the same way that morphine does without its negative side effects. In the 1970s, scientists discovered enkephalins, small proteins that are naturally produced by the body to reduce pain.

Synthetic analogs of enkephalins seemed to fit the bill, but they soon ran into a major problem that rendered them ineffective: the blood-brain barrier, a biological membrane that blocks toxins from entering the brain.

"Unfortunately, the blood-brain barrier stops most small peptides, including the enkephalins, from entering the brain," Polt says.

After years of experimentation, Polt and his associates recently discovered that attaching a glucose molecule to the enkephalins permits them to penetrate the blood-brain barrier, allowing them to attach to pain receptors in the brain and reduce pain in a manner similar to morphine.

Although other peptides have been developed that can cross the blood brain barrier, few have done so with the ease the new drug, Polt says.

One of Polt's associates, Edward J. Bilsky, Ph.D., of the University of New England, recently conducted tests in which mice were injected with the experimental compound. It had two to three times the potency of morphine, Polt and Bilsky say. Further studies in mice indicate that the drug had significantly fewer side effects and was less toxic than morphine and related narcotics. The drug triggered behavior that was consistent with less addiction, the researchers say.

The researchers have also gained new insights into how the drugs work. It has been known for some time that morphine binds to certain receptors on the brain, called "mu" receptors, to achieve its analgesic effect. Much focus has recently been placed on a newly discovered type of pain receptor, the "delta" receptor, which is also found in abundance in the brain.

Polt and his associates now believe that the synthetic enkephalins interact with both receptors simultaneously. Interactions between the two receptors appear to increase analgesic strength while limiting the narcotic side effects.

"Mu and delta receptors are the two knobs that control pain. Morphine only twists one of them," Polt explains. "A glucose-bound enkephalin twists both knobs, maximizing pain reduction while simultaneously reducing side effects."

Polt believes that this research opens up the door to a whole new class of compounds that are based on brain peptides. Newer synthetic analogues of the naturally occurring peptides can be created that can similarly be linked to carbohydrate molecules in order to pass through the blood- brain barrier and reach their specific targets in the brain. These drugs may hold promise for problems related to memory, attention and even depression, he says.

These glycosylated neuropeptides, as they are called, have two main advantages. First, they are easily degraded into amino acids and sugars in the body, which reduces their risk of toxicity. In addition, they are more specific in their action with the brain's receptors, which means fewer side effects.

For now, researchers continue to work on reducing any possible side effects associated with this new class of drugs. More work is needed before the drugs can be used in humans; additional animal studies are now planned. If all goes well, an actual drug could be available in five to 10 years, says Polt.

Although it will likely be initially administered by injection, developing the drug as an oral pill is now under consideration, he says.

The Office of Naval Research and the National Science Foundation funded this study.

The paper on this research, ORGN 256, will be presented at 3:00 p.m., Monday, March 24, at the Morial Convention Center during the symposium "Proteins, Peptides, Amino Acids, and Nucleotides."

Robin Polt, Ph.D., is a professor of chemistry at the University of Arizona in Tucson. He is currently serving as a visiting scientist at the National Science Foundation in Arlington, Va.

Edward J. Bilsky, Ph.D., is an assistant professor at the University of New England in Biddeford, Maine.

-- Mark T. Sampson

EMBARGOED FOR RELEASE: Monday, March 24, 3:00 p.m., Central Time

ORGN 256 Glycosylated enkephalins penetrate the blood-brain barrier adsorptive endocytosis: Analgesia superior to morphine

Robin Polt1, Michael M Palian1, Edward J. Bilsky2, Henry I. Yamamura3, Frank Porreca4, Victor J. Hruby1, and Richard D. Egleton3. (1) Department of Chemistry, University of Arizona, Old Chemistry Building, 1306 E. Univerisity Dr, Tucson, AZ 85721, [email protected], (2) Department of Pharmacology, University of New England College of Medicine, (3) Department of Pharmacology, College of Medicine, University of Arizona, (4) Department of Pharmacology, University of Arizona

Enkephalin analogs (Tyr-D-Thr-Gly-Phe-Leu-Ser-amide (1), and related O-linked glycopeptides bearing glucose (2), maltose (3), and maltotriose, (4) were synthesized, and their interactions with membrane model systems was characterized by CD, NMR and Monte Carlo studies. Glycosylation did not significantly perturb the peptide backbone in aqueous solution, but all four compounds strongly associated with 5-30 mM SDS or DPC micelles, and underwent profound membrane-induced conformational changes. The peptide backbones all possessed random coil structures in water, and all formed a nearly identical pair of ensembles, all with a stable b-turn motif at the C-terminus in the presence of micelles. Use of spin labels (Mn++ and DOXYL-stearic acid) allowed for the determination of the position and orientation of the compounds relative to the surface of the micelle, which is consistent with adsorptive endocytosis as a means of penetrating the blood-brain barrier. Glycopeptide 2 produced potent analgesia in mice following s.c. administration.

EMBARGOED FOR RELEASE: Monday, March 24, 3:00 p.m., Central Time

ORGN 256 Glycosylated enkephalins penetrate the blood-brain barrier adsorptive endocytosis: Analgesia superior to morphine

*Briefly explain in lay language what you have done, why it is significant and its implications, particularly to the general public.

The brain produces small peptides called enkephalins [en-kef'-lins] to control pain by binding to the same receptor that is bound by morphine. In the early 1970's when the enkephalins were first discovered there was great excitement in the chemistry community, because it was believed that these peptides could be used to block pain in the same way that morphine does. Unfortunately, the blood-brain barrier stops small peptides, including the enkephalins, from entering the brain. Our research group at The University of Arizona has discovered that enkephalins with a sugar attached to them will penetrate the blood-brain barrier and produce analgesia in much the same way that morphine does. One glycosylated enkephalin that we have produced has been tested on mice and rats, and has two to three times the potency of morphine.

The drugs were designed and synthesized in the Polt Group Laboratory in the Chemistry Department at The University of Arizona, and tested at the Department of Pharmacology there, and in the laboratory of Dr. Edward J. Bilsky at the University of New England College of Medicine in Biddeford, Maine.

Dr. Bilsky's studies with mice indicate that the drug lacks many of the side effects associated with morphine, and is significantly less toxic than morphine or related narcotics. Many patients suffering from pain cannot take morphine because they are allergic to narcotics, or because morphine reduces blood pressure and respiration.

Our hope is that the glycosylated enkephalins can be used to block pain in severe trauma injuries, in victims who could not normally receive narcotics. The Office of Naval Research has funded more work to see if these drugs can be used as a safer alternative to morphine for use on the battlefield or at sea for wounded military personnel. Often, wounded soldiers must be transported and wait for surgery without pain medication, or else run significant risks with the use of narcotics in combination with blood loss. More work is needed before these drugs can be tested in humans.

* How new is this work and how does it differ from that of others who may be doing similar research?

Our first attempts at this began in the early 1990's, but these attempts were hampered by the type of peptide we were using at that time. Collaboration with other research groups have taught us how the presence of the sugar allows the peptide to enter the brain, and how to preserve the potency of the peptide in producing analgesia. Following up on our earlier work, there are now chemists in Italy who are using the same strategy in order to produce analgesics from glycosylated peptides. The Italian scientists have used peptides derived from frog skin (dermorphins) as the basis for analgesia. Our work focuses on "delta selective opiates," which are predicted to be free of many of the side effects associated with the "muselective opiates" being explored by the Italian scientists.

*Corresponding author's name and business title or position:

Dr. Robin PoltProfessor of Chemistry

*Work department:

Department of ChemistryThe University of Arizona

*Business address including organization:

1306 East University DriveDepartment of ChemistryThe University of ArizonaTucson, AZ 85721