So effective was the treatment in eight dogs severely affected by osteroarthritis, cancer-related pain, or both, all eventually became more active and later walked with slight or no limps. Just as importantly, none showed any adverse side effects from the treatment, their temperaments were improved, and their need for other pain-controlling medications was eliminated or greatly reduced.
The authors also reported selectively deleting the nerve cells, called C-fiber neurons, from among various human neurons cultured together in the laboratory, an indication the strategy might work in people. C-fibers convey to the central nervous system sensations of noxious heat and certain inflammatory signals. "Some have referred to the technique as using a 'molecular scalpel,'" said Dr. Michael J. Iadarola, a scientist at the NIH's National Institute of Dental and Craniofacial Research (NIDCR) and a senior author on the paper. "The technique selectively deletes certain neurons but leaves others untouched. As a result, the nervous system functions normally, it's just a certain spectrum of pain responsiveness that has been deleted."
Currently, doctors have no way of selectively eliminating nerve cells involved in chronic pain. Opioid-based analgesics, the mainstay of current treatments for moderate to severe chronic pain, cannot provide universal relief, and other treatments are nonselective and/or can cause serious side effects.
Iadarola said this month's paper stems from using the old drug resiniferatoxin, or RTX, in a new way. First isolated in the 1970s, RTX is often used as a laboratory tool because of its ability to bind to a much-studied protein called vanilloid receptor 1 (VR1), which is displayed on the surface of certain types of heat-pain-sensing neurons. As several laboratories have reported previously, RTX attaches to VR1, and, like opening a window, prompts a brief influx of calcium through a channel, or pore, but only in those cells that manufacture the ion channel.
Three years ago, Iadarola's group published data showing the RTX-induced flow of calcium can overdose, seriously disable, and ultimately kill these neurons. Because nerve cells in the peripheral nervous system first transmit their signals to the spine, where they then are processed and routed onward to the brain, their previous finding raised an intriguing therapeutic scenario: The cell bodies of these peripheral neurons bundle together in groups near the spine, called dorsal root ganglia. If RTX were applied directly to the ganglia, the scientists knew that they could selectively delete specific neurons, such as C-fibers, that express large amounts of the VR1 protein on their surface. By doing this, they wondered whether they could also permanently turn off their chronic pain signals, which are involved in severe arthritis, peripheral neuromas, trigeminal neuralgia, and advanced cancer?
"We realized that by focusing on RTX's ability to kill cells, we could apply it therapeutically," said Dr. Laszlo Karai, an NIDCR scientist and lead author on the paper. "That might seem like a radical departure from the standard paradigm of blocking protein receptors or desensitizing them to control pain, but our laboratory data, obtained from cells in a dish, was so compelling that we thought it just might work."
As reported this month, Karai et al. performed a series of experiments in rats that showed a single injection into the trigeminal ganglion (supplies sensation to the face), or into the cerebrospinal fluid that bathes the dorsal root ganglia, (supply sensation to the body), most likely deleted the C-fiber neurons permanently. The same held true when they injected the drug into multiple ganglia that connect to the tail and hind legs. In both experiments, rats maintained their normal motor function as well as their ability to respond to other sensory stimuli, such as warm and very hot thermal stimulation and a mechanical pinch, an indication that RTX had only affected C-fiber neurons.
"This showed us that the deficit in terms of overall pain sensation was probably minimal," said Dr. Zoltan Olah, an NIDCR scientist and one of the inventors of the technology. "What was lost were the C-fiber neurons, which confer that sense of aching, chronic pain."
The group then applied the technique to dogs, whose owners had brought them into nearby veterinary hospitals with severe pain from arthritis and cancer. "We were very encouraged to see a long-term therapeutic benefit that did not diminish with the progression of the disease," said Iadarola. "When a cancer progresses, you often have to increase the dose of conventional pain medications, such as opiate analgesics, which can produce alterations of consciousness, activity level, and other severe side effects that can impair overall quality of life."
Based on these data, Iadarola said the RTX technique has tremendous potential in veterinary care. But the group's ultimate goal is to move the treatment into early stage clinical trials in the near future for people with severe chronic pain. "One reason we were successful is we have a vertically integrated, multipdisciplinary group," said Iadarola. "There is a molecular/cell biologist, a pharmacologist, an anaesthesiologist, and a pathologist. We realized that permanently deleting cells wasn't a farfetched concept, and, if we applied this approach correctly, we could get it to work. And, that's what happened."
The study is titled, "hDeletion of vanilliod receptor 1-expressing primary afferent neurons for pain control." It is published in the May 2004 issue of The Journal of Clinical Investigation. The authors are: Laszlo Karai, Dorthothy Brown, Andrew J. Mannes, Stephan T. Connelly, Jacob Brown, Michael Gandal, Ofer W. Welisch, John K. Neubert, Zoltan Olah, and Michael J. Iadarola. All are affiliated with NIDCR, except Dr. Brown, who is in the School of Veterinary Medicine at the University of Pennsylvania.
Journal
Journal of Clinical Investigation