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National Institute on Drug Abuse -  NIDA NOTES
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Volume 12, Number 6
November/December 1997

NIDA Researchers Developing Problem-Free Pain Relievers

By Steven Stocker, NIDA NOTES Contributing Writer

New compounds for treating pain may soon be available for use with patients. Some appear to reduce pain with only minimal side effects, whereas others might be administered in combination with existing analgesics to enhance their pain-relieving properties or eliminate their side effects.

The most effective analgesics currently available are the opioids, including morphine and related synthetic compounds. Although they are highly potent pain relievers, current opioid analgesics cause side effects, including constipation and reduced breathing.

Dr.

Dr. Victor Hruby of the University of Arizona synthesized a promising analgesic from one of the body's natural pain-relieving compounds.

Further, if currently available opioids are used regularly for longer than several weeks, most people develop some tolerance to the medications, meaning that they need to use more to get the same pain relief. Patients may also experience some degree of physical dependence, meaning that they have mild withdrawal symptoms - such as insomnia, irritability, and mild anxiety - when they stop taking the medications.

When patients use these medications over prolonged periods, a few develop a craving for their euphoric effects. Although addiction to analgesics among pain patients is rare, physicians sometimes underprescribe these analgesics because the physicians or their patients are concerned about the possibility of addiction.

These drawbacks associated with current analgesics have prompted researchers to look for new compounds that are as potent as the current medications but do not cause increased tolerance, addiction, or other side effects. This search gathered momentum in the 1970s when NIDA-funded scientists found that opioid analgesics reduced pain by acting as agonists. Agonists stimulate molecules called receptors - in this case, opioid receptors - on the surface of nerve cells. Three classes of opioid receptors were eventually identified - mu, kappa, and delta. The scientists determined that it was the mu receptor that was primarily responsible for the analgesic effects of morphine and the other opioid analgesics as well as their addictive properties and other side effects.

The researchers knew that agonists stimulate cell receptors by mimicking the effects of naturally occurring chemicals in the body, but at that point, they did not know which body chemicals the opioid analgesics were mimicking. They reasoned that perhaps the nervous system contained chemicals that reduced pain by stimulating the opioid receptors just as morphine and the other opioid analgesics did. Subsequently, other NIDA-funded researchers discovered these natural, or endogenous, opioid analgesics in the nervous system. Scientists speculated that if they were to produce derivatives of the endogenous opioids, particularly derivatives that were delta or kappa agonists, they might be able to create medications that produced analgesia without causing addiction or other side effects.

Researchers around the country, including many at pharmaceutical firms, started producing derivatives of endogenous opioids, but despite synthesizing several thousand compounds, they failed to produce one that was superior to existing medications. Interest in this area rapidly declined, and pharmaceutical firms turned to other approaches for developing analgesics.

DPDPE: The Parent Compound

Research in this field might have died off entirely, except for continued funding from the National Institutes of Health. In 1983, this support was rewarded when Dr. Victor Hruby at the University of Arizona in Tucson and Dr. Henry Mosberg - then in Dr. Hruby's lab and now at the University of Michigan at Ann Arbor - and their colleagues produced a promising compound by chemically modifying an endogenous opioid. This compound, called DPDPE, selectively stimulated the delta receptor and effectively reduced pain in rats and mice. This showed for the first time that a compound does not have to be a mu agonist to produce analgesia but that a delta agonist can also be effective. Furthermore, DPDPE produced fewer side effects than morphine and the other mu agonists did - it did not produce constipation, and it caused less physical dependence.

DPDPE is not without its drawbacks, however. It is not as potent as morphine or as long lasting, but its major problem is that it has difficulty getting into the central nervous system, or brain and spinal cord, which is where analgesics exert most of their effects. When DPDPE is injected into a vein or a muscle, very little of the compound is able to cross the blood-brain barrier that prevents potentially damaging cells and large molecules from leaving the blood and entering the brain. As a fairly large molecule, DPDPE has difficulty navigating this barrier.

Dr. Frank Porreca of the University of Arizona discovered that certain compounds can enhance morphine's analgesic effect without increasing morphine's side effects.

Dr.

To enhance the permeability of DPDPE and other delta agonists, Dr. Hruby and his colleagues have been chemically modifying them. A few of the new compounds cross the blood-brain barrier with greater efficiency than their parent compounds, and at least one produces a greater analgesic effect than DPDPE does.

NIDA-supported researchers at the University of Arizona, New England Medical Center in Boston, and University of California at San Diego are preparing to conduct a clinical trial of DPDPE in patients with cancer pain and patients who are recovering from prostate surgery. In both groups, DPDPE will be injected intrathecally, or into the fluid surrounding the spinal cord, which solves the problem of how to get DPDPE past the blood-brain barrier.

"We chose DPDPE for a clinical trial because it is the most studied of our delta agonists," says Dr. Frank Porreca, Dr. Hruby's colleague at the University of Arizona, who tests the potential analgesics in animals. "DPDPE is important for establishing whether delta agonists can produce analgesia in humans, but it would probably not make a lot of money for drug companies because it would have to be given by the intrathecal route. Some patients routinely receive intrathecal administration of analgesics, but not many."

Biphalin: The 2-for-1 Stimulator

A compound that may have more potential for widespread use is biphalin. Synthesized by Dr. Andrzej Lipkowski of the Polish Academy of Sciences in Warsaw and his colleagues, biphalin has been tested extensively by Dr. Porreca, Dr. Hruby, and others at the University of Arizona.

Dr.

Dr. Philip Portoghese of the University of Minnesota found that some compounds can block the development of morphine dependence without blocking morphine's analgesic effect.

"Biphalin has incredible efficacy," says Dr. Porreca. "It is one of the most potent analgesic compounds we know of." Studies with animals have shown that, when injected directly into the fluid that bathes the brain, biphalin is 257 times more potent than morphine for reducing pain. When injected into the abdomen of animals, biphalin is as potent as morphine without causing constipation or significant physical dependence. Like DPDPE, biphalin has difficulty crossing the blood-brain barrier when injected into the abdomen, but the small amount that crosses is potent enough to produce considerable analgesia, Dr. Porreca says. A NIDA-funded clinical trial with biphalin is being planned by the same researchers who will be conducting the DPDPE clinical trial. Biphalin will be administered intravenously.

Studies show that biphalin acts by stimulating both mu and delta receptors in the central nervous system. When delta receptors are activated at the same time as mu receptors, the analgesia produced by the mu receptors is greatly enhanced, but the side effects associated with mu receptors, such as constipation and physical dependence, are not.

This mu-delta interaction effect may be useful for treating painful conditions that do not respond well to morphine and other standard pain treatments, Dr. Porreca suggests. An example is neuropathic pain, which occurs when nerves outside the spinal cord are damaged from, for example, trauma or a tumor.

SNC 80: The Small Compound

Like DPDPE and biphalin, many delta agonists that have been developed have trouble crossing the blood-brain barrier. One way that scientists are attempting to solve this problem is by producing smaller delta agonists. A big step in this direction was the synthesis of a compound called SNC 80 by investigators at the National Institute of Diabetes and Digestive and Kidney Diseases' and NIDA's intramural research programs, the University of Arizona, and Burroughs Wellcome Company. Tests show that SNC 80 is a highly selective delta agonist that produces analgesia when injected into the brain, spinal cord, or abdomen of laboratory animals. It is even somewhat effective when given orally.

"SNC 80 is the compound that has really lit the fire again in the delta agonist field," says Dr. Porreca. "It has been the stimulus to synthesize a variety of compounds that can cross the blood-brain barrier. I don't think that SNC 80 itself is the right compound for testing in humans, but other compounds based on SNC 80 may be."

DIPP[psi]-amide: The Stimulating Inhibitor

In other research, scientists have found that interesting effects can also be obtained by blocking the delta receptor rather than stimulating it. Dr. Philip Portoghese, Dr. Akira Takemori, and others at the University of Minnesota in Minneapolis have tested the effects of combining morphine with a delta antagonist, a compound that prevents chemicals from binding to the delta receptor, thereby blocking their action. "We knew that if you give a delta agonist, you enhance the analgesic effect of morphine, so we wondered what would happen if you give a delta antagonist," explains Dr. Portoghese. "We were surprised to find that delta antagonists block the development of both morphine dependence and tolerance without blocking morphine analgesia."

Dr. Peter Schiller of the Clinical Research Institute of Montreal has produced a promising analgesic compound that does not cause dependence. The computer screen shows a model of a type of "receptor" molecule found on the surface of nerve cells. Many of the potential new analgesics act at these molecules..

Dr.

Dr. Peter Schiller of the Clinical Research Institute of Montreal has developed a compound called DIPP[psi]-amide that is both a mu agonist and a delta antagonist. The mu agonist component produces analgesia by stimulating the mu receptor, just as morphine does, and the delta antagonist component prevents the development of tolerance and dependence. "Preliminary tests with rats have shown that this compound is about 50 percent more potent than morphine when administered into the brain," says Dr. Schiller. "When we gave high doses of it to rats for a relatively long period, it did not produce any physical dependence, and it produced less tolerance than morphine." Dr. Schiller is continuing to develop other mu agonist-delta antagonist compounds, as is Dr. Portoghese.

Dr. Rao Rapaka of NIDA's Division of Basic Research thinks that the more analgesics of different types developed, the better. "You want as many compounds as possible so that you can switch medications if there is a need," says Dr. Rapaka. "If one medication doesn't work with a particular patient, then you can try another."

Sources

Bilsky, E.J.; Calderon, S.N.; Wang, T.; Bernstein, R.N.; Davis, P.; Hruby, V.J.; McNutt, R.W.; Rothman, R.B.; Rice, K.C.; and Porreca, F. SNC 80, a selective, nonpeptidic, and systemically active opioid delta agonist. The Journal of Pharmacology and Experimental Therapeutics 273(1):359-366, 1995.

Horan, P.J.; Mattia, A.; Bilsky, E.J.; Weber, S.; Davis, T.P.; Yamamura, H.I.; Malatynska, E.; Appleyard, S.M.; Slaninova, J.; Misicka, A.; Lipkowski, A.W.; Hruby, V.J.; and Porreca, F. Antinociceptive profile of biphalin, a dimeric enkephalin analog. The Journal of Pharmacology and Experimental Therapeutics 265(3):1446-1454, 1993.

Miyamoto, Y.; Portoghese, P.S.; and Takemori, A.E. Involvement of delta2 opioid receptors in the development of morphine dependence in mice. The Journal of Pharmacology and Experimental Therapeutics 264(3):1141-1145, 1993.

Rapaka, R.S.; and Porreca, F. Development of delta opioid peptides as nonaddicting analgesics. Pharmaceutical Research 8(1):1-8, 1991.

Schiller, P.W.; Weltrowska, G.; Schmidt, R.; Nguyen, T.M.-D.; Berezowska, I.; Lemieux, C.; Chung, N.N.; Carpenter, K.A.; and Wilkes, B.C. Four different types of opioid peptides with mixed mu agonist/delta antagonist properties. Analgesia 1:703-706, 1995.

NIDA NOTES - November/December 1997

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