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Allan Basbaum takes the pain away

Basbaum produced a landmark study showing how opiates reduce pain by inhibiting certain nerve cells in the spinal cord. (Photo: Susan Merrell/UCSF))

Shortly after Allan Basbaum published a study about a new method for alleviating neuropathic pain, letters asking for help began arriving.

At his lab at the University of California, San Francisco (UCSF), where he chairs the department of anatomy, Basbaum reads aloud one letter:

"The dermatologist in my local hospital told me my only hope was the embryonic stem cells. If you push ahead with human trials, will you consider me? I would be more than willing to come and see you."

For millions of people with neuropathic pain—common in cancer patients undergoing chemotherapy, diabetics, and shingles sufferers—the most powerful opiates such as morphine are often ineffective. Neuropathic pain is characterized by extremely painful responses to innocuous stimuli, such as heat or touch, or else an increased sensitivity to pain. It can be a chronic condition.

"There are a lot of desperate people out there, because the drugs, even when they work are not good enough by any means," said Basbaum, an AAAS Fellow and one of the world's leading experts on pain control. "Even the best drugs only reduce pain by about 30 percent in about 30 percent of people." Some estimates report that up to two percent of people with chronic unrelieved neuropathic pain commit suicide, he added; many more can't hold down a job.

Basbaum's recent work may provide a therapeutic breakthrough for such patients, and is so far the high point of a long career diligently spent mapping and understanding the extensive biological circuitry of pain control—from nerve fibers to individual neurotransmitters.

He first became interested in neuropathic pain in the 1970s, as a postdoc in London, where he saw patients with postherpetic neuralgia—a neuropathic pain that occurs in about 20 percent of patients who develop shingles.

"There was really no treatment at all," Basbaum said. Surgeons used to try cutting nerves that innervated the part of the body affected, or even cutting the spinal cord—a procedure called cordotomy—"which was horrific."

Basbaum produced a landmark study with UCSF colleague Howard Fields showing how opiates reduce pain by inhibiting certain nerve cells in the spinal cord. He also has helped identify the location and function of neurotransmitters responsible for pain control, such as those he discovered during his collaborations with David Julius at UCSF on the function and the location of the TRPV-1 receptor—known as the capsaicin receptor, as it is sensitive to capsaicin, the pain-producing substance found in chili peppers or topical ointments.

Basbaum's most recent study, published in the May 24 issue of Neuron with lead author João M. Brázas, involved a transplant of brain cells from embryonic mice into the spinal cords of mice with a condition that models neuropathic pain. The embryonic cells, from the medial ganglionic eminence (MGE), are responsible for producing GABA, the chief inhibitory neurotransmitter in the brain. Basbaum wanted to try the transplant approach, reasoning that neuropathic pain entails a loss of the inhibition that GABA normally provides, but colleagues had been skeptical of the approach, warning that MGE cells may not integrate well in the spinal cord, as they are destined to become interneurons in the cortex.

The cells "look different from normal spinal cord GABA cells and they have a different origin," Basbaum said. "And in the cortex they disperse dramatically. You put them in one small place and they move all over the place."

Basbaum was surprised with the results. The study showed that transplanted MGE cells integrated smoothly with the nerve circuitry in the spinal cord, making connections with neurons.    

"Four weeks later the animals were completely normal; the mechanical hypersensitivity that characterized the neuropathic pain condition had disappeared," Basbaum said.

Basbaum's colleagues credit his success to his enthusiasm for teaching as much as his groundbreaking research. He is a member of the American Academy of Arts and Sciences, the Institute of Medicine, and the Academy of Medical Sciences (Britain). He is also a fellow of the Royal Society in the United Kingdom and the editor-in-chief of Pain, the official journal of the International Association for the Study of Pain.

 \"He's somebody who can juggle a lot of balls in the air at the same time, do a lot of different things and do them all well," said colleague Howard Fields.

Colleagues also note his sense of humor, which includes impressions of French-Canadian accents and a sly joke every now and then.

"Everyone says, 'How long will it take'" for human trials, Basbaum said of the mouse transplant study. "There's a great sign. I don't know if it was even a joke or if it was real. It said: 'Meeting of the Psychic Conference is Cancelled.' And then somebody wrote: 'for unforeseen circumstances.'"

"I don't have a crystal ball," Basbaum said. "But if the human cells work in animals—and we'll know that within six months—then I would think we would be on a track to consider going to trials."

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Basbaum produced a landmark study showing how opiates reduce pain by inhibiting certain nerve cells in the spinal cord. (Photo: Susan Merrell/UCSF))
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Chris Raphael

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