In the not-too-distant future, patients in pain may be better treated with fewer side effects using lower morphine doses combined with new painkillers already under development, according to a new study reported by researchers from the University of California San Francisco in the March 26 issue of the scientific journal Nature.
We may perceive pain as a continuum ranging from irritating to unbearable, but a UCSF research team led by Allan Basbaum, PhD, now has made the striking discovery that -- biologically -- mild pain and more intense pain are distinct and governed by different signaling molecules. Effective management of intense pain should take these distinctions into account, Basbaum says.
"Pain is not a single phenomenon that can always be attacked with one type of analgesic drug," according to Basbaum, chairman of anatomy and research scientist with the W.M. Keck Foundation Center for Integrative Neuroscience at UCSF.
Yu Qing Cao, a graduate student in Basbaum's lab, conducted key experiments on mice which revealed that two different types of signaling molecules, called neurotransmitters, are involved in mild pain and more intense pain.
For several years researchers have known that the neurotransmitter glutamate is important in signaling pain. But Cao, along with researchers in the lab of Charles Epstein, MD, UCSF professor of pediatrics, developed a "knockout" strain of mice lacking a gene for substance P and neurokinin A, two members of a different class of neurotransmitters called the tachykinins.
By measuring how long it took mice to move away from applied mechanical pressure, or how many seconds they licked skin where hot pepper extract had been applied, Cao determined that the knockout mice were as sensitive to mild pain as normal mice, but that they were much less sensitive to moderate or more intense pain.
The research team concluded that substance P or neurokinin A -- or both -- are needed to transmit moderate or more intense pain signals in a variety of painful conditions. Although the mutant and normal mice needed the same amount of morphine to relieve mild pain, the mutant mice, which lacked the tachykinins, needed less morphine to experience pain relief under more intense pain conditions.
Pharmaceutical companies have been developing prototype painkillers to block the action of substance P and neurokinin A on receptors located on the surfaces of pain-transmitting nerve cells. The recent rodent studies by Basbaum and others are defining and refining scientific understanding of the roles played by these and other molecules in specific pain syndromes. Their findings point to strategies that might be adopted to design more effective drugs to individually target these various molecules.
"Drug candidates need to be evaluated in the context of a particular pain syndrome," Basbaum says. "Pain relief often may depend on the particular medical condition and on the quality and intensity of the pain."
The undertreatment of pain is a severe challenge to the quality of life for millions of seriously ailing people worldwide, Basbaum points out. Morphine, the strongest painkiller that may be legally prescribed in the United States, appears to act across the pain spectrum by inhibiting the pain signals transmitted by glutamate, Basbaum says. Morphine is not used as much as it should be, according to Basbaum, often because of misplaced worries about its addiction potential in pain patients.
Physicians need to better understand how to most effectively administer painkillers, including morphine, Basbaum says. But the new knowledge emerging from rodent studies about how neurokinin A, substance P and other neurotransmitters act on different receptors could lead to new drugs that could provide good pain relief when combined with lower, less problematic doses of morphine, he adds. This could significantly reduce the negative side effects that occur when higher doses of morphine are required.
The Nature study was funded by the National Institutes of Health and the Howard Hughes Medical Institute.
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Nature