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.