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|Research Shows Way To Boost Morphine's Pain-Killing Benefits|
|Flexible Pain Relief With Morphine-free Poppy|
Challenging a decades-old understanding of why morphine-like drugs lose effectiveness with increased use, UCSF scientists have demonstrated in animals how morphine’s potent painkilling powers can be easily sustained without increasing dosages. If confirmed in further studies, the discovery could lead directly to more effective relief using the powerful pain reliever. Morphine is prescribed to control severe, chronic pain, including pain from advanced cancers.
Researchers at UCSF’s Ernest Gallo Clinic and Research Center have shown that a natural cellular process known as endocytosis that had been thought to weaken the effect of most opiates actually serves a protective function. They showed that when boosted, the process can arrest the pattern whereby morphine’s pain-killing benefits tend to wear off unless dosages are increased.
The research is published in the January 25 issue of the journal Cell.
Morphine and other opioids affect the body first by docking with naturally occurring receptors on cell surfaces. Known as mu opioid receptors (MOR), they are part of a large family of receptors involved in the action of most neurotransmitters and hormones. These receptors are normally removed from service shortly after their contact with the opioid. They are drawn down into the cell in a process known as endocytosis. In the cell interior the receptors are either degraded or recycled back to the surface.
But, unusual among opioids, morphine does not promote endocytosis. The Gallo researchers showed, first in cell cultures and then in rats, that simply by pairing morphine with a harmless opioid that facilitates endocytosis, they could eliminate the tendency for morphine’s benefits to wear off – for the animals to become tolerant to its analgesic effects. The prevailing view had been that, far from being helpful, endocytosis was part of the cause of drug tolerance.
Many drugs are able to trigger endocytosis, so the discovery suggests a practical way to boost the duration of morphine’s pain-killing benefits without having to increase dosages continually, said Jennifer Whistler, PhD, UCSF assistant professor of neurology at the Gallo Center and senior author on the Cell paper.
“What I’d like to see from this work,” Whistler said, “is the development of new drugs – or new drug combinations -- to safely reduce tolerance to morphine for people suffering from severe chronic pain.”
A conventional test of analgesic effect is to test a laboratory rat’s heat sensitivity to a few-second exposure to a beam of non-burning laser light directed at the tail. Normally, rats actively flick their tails when they feel the heat. Rats given morphine showed much less sensitivity to the heat, but after four days, they became tolerant to morphine’s analgesic effect and flicked their tails, indicating they could feel the heat despite the morphine. But when rats were given both morphine and the opioid DAMGO, known to induce endocytosis of cell surface receptors, they felt no heat for the seven-day duration of the test.
To confirm their hypothesis that it was the increased endocytosis that blocked tolerance to the morphine, the researchers examined the cells of the spinal cord in both the experimental and control rats. Their focus was the mu opioid receptors (MOR) that morphine normally activates on the cell surface. In those rats that had been given only morphine, and who became tolerant to morphine in four days, the MOR receptors had remained predominantly on the cell surface.
But in those that had been administered morphine and also DAMGO to facilitate endocytosis, opioid receptors were detected throughout the cell, evidence that the receptors had been removed from the cell surface under the influence of DAMGO. These animals did not become tolerant to morphine at all.
“There may already be other opioid drugs that when used in conjunction with morphine would reduce the development of tolerance,” Whistler said. “Many of these drugs are not used for pain because of the side effects they produce at high doses. The key here is that our results predict that one could co-administer them at very low doses with morphine, avoiding side effects and enhancing the analgesic effects of morphine.”
Research is mounting that opioid cell surface receptors chemically interact with each other, or oligomerize. Whistler’s research group has evidence from the cell culture experiments that the MOR receptor oligomerizes, and this is the property that allows a MOR docked with DAMGO to latch on to a MOR docked with morphine and drag it down from the cell surface to be recycled.
In the Cell paper, the researchers suggest that morphine’s normal trait of failing to facilitate endocytosis, and therefore failing to recycle the receptors, is partially responsible for the cell’s inability to continue responding to the drug.
Whistler cautions that the development of tolerance is a complex, multi-step process which requires more study.
“It is important to remember,” she says, “that tolerance is likely mediated by multiple processes and that tolerance develops to many drugs, not just opiates. We hope our work will stimulate our colleagues to investigate the fate of their favorite receptors when they are bound to a drug.”
Lead author of the paper is Li He, MD, a UCSF postdoctoral fellow in Whistler’s lab. Co-authors are Jamie Fong, BA, a research associate in Whistler’s lab; and Mark von Zastrow, MD, PhD, UCSF associate professor of psychiatry.
The research was supported by the National Institutes of Health and by State
of California funds for medical research on alcohol and substance abuse through
UCSF’s Ernest Gallo Clinic and Research Center.
This story has been adapted from a news release issued by University Of California, San Francisco.
A handful of genes in a morphine free poppy could hold the key to producing improved pain management pharmaceuticals.
Norman, the 'no-morphine' poppy, is superior to morphine producing poppies as it produces thebaine and oripavine – compounds preferred by industry in the manufacture of alternative high value pain-killers.
CSIRO's Dr Phil Larkin, and The Australian National University's Anthony Millgate and Dr Barry Pogson have been working with Tasmanian Alkaloids to investigate Norman the morphine-free poppy.
"The genes we found behaved differently in Norman compared to standard morphine producing poppies and were consistently associated with the blockage in morphine synthesis and with the accumulation of thebaine and oripavine," Dr Larkin says.
"Understanding the genes responsible for the production of morphine, thebaine and oripavine is an important step in further developing poppies that are tailored to produce alternative pharmaceuticals."
The morphine free poppy variant, TOP1, was first discovered in 1995 by Tasmanian Alkaloids then released as Norman for commercial production in 1997 in Tasmania where it is now widely grown.
"Norman created substantial industry growth when there was a surplus of traditional products, such as morphine, allowing us to supply raw materials for the manufacture of other pharmaceutical ingredients," says Tasmanian Alkaloids' Manager of Agricultural Research, Dr Tony Fist.
Tasmania already grows over 40 per cent of the world's legal poppy crops and Norman will ensure Tasmania stays an international leader in pharmaceutical development from poppy compounds.
This research is supported by voluntary contributions from industry with matched funding for R&D from the Australian Government through HAL and is a collaboration between CSIRO Plant Industry, The Australian National University, Tasmanian Alkaloids, Institute for Plant Biochemistry (Germany) and the University Halle (Germany).
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