World of Chronic Pain Suddenly Looks Different to Researchers

A nerve pathway responsible for a type of hypersensitivity that makes many people feel extreme pain in response to even light touch in the wake of inflammation, trauma or nerve injury has been identified by UCSF researchers.

Robert Edwards

Although pain and hypersensitivity after injury usually resolves, in some cases it can outlast the injury, creating a condition of chronic pain. Chronic pain due to this type of hypersensitivity is a common and often debilitating medical condition. It can be difficult to treat successfully. The new discovery suggests ideas for developing new drugs to target and block the transmission of pain through this pathway. Working with mice, a team led by UCSF neurologist Robert Edwards, MD, along with long-time pain researcher Allan Basbaum, PhD, professor and chair of the Department of Anatomy, identified a small subset of nerve cells – neurons -- responsible for this “mechanical” hypersensitivity. They report their findings in the November 15 online edition of the journal Nature. “These are oddball cells that had been known about for decades, but nobody was sure what they did,” Edwards says.

Allan Basbaum

The new study follows a report earlier this year by Basbaum in Cell, in which he described an exclusive role in quelling mechanical pain for just one of the different receptor molecules through which opioid drugs can act on neurons. Together the results strongly suggest that different types of pain are governed by distinct groups of neurons that use their own important signaling molecules. The type of neuron described in Nature is known to fire in response to a relatively weak mechanical stimulus, such as touch. Psychophysical studies in human subjects who have an unusual form of nerve damage in the extremities suggest that these cells convey the sensation of pleasant touch. But it was not really clear how they contributed to sensation until the UCSF researchers succeeded in selectively inactivating them. “We propose that the cells identified in this study initially convey signals that eventually come to be perceived as painful,” Edwards says. “It appears, moreover, that neurons in the spinal cord or brain that receive the information transmitted by these specialized cells somehow amplify it in conditions of injury.”

Taking Advantage of an Unanticipated Discovery

“These cells have been hard to study, and it was partly through coincidence that we made the discovery,” Basbaum says. Initially, Edwards was looking primarily in the brain for rare populations of neurons that use a particular “transporter” molecule. Edwards had previously shown that the transporter enables these neurons to release a certain type of signaling molecule, or neurotransmitter. Edwards studies the transmission of nerve signals across the gap, or synapse, between neurons. His lab focuses on the major “excitatory” signaling neurotransmitter, called glutamate. Glutamate signaling requires that supplies of the molecule be readied for release from compartments within the synapse, a task carried out by glutamate transporters. Edwards was the first to identify the genes for these transporters. He has a particular interest in the rarest and least well understood of the three known glutamate transporters, called VGLUT3. Neurons that release glutamate almost always use only one of the three types of VGLUT, it appears. Without VGLUT3, the neurons that normally would have it fire, but do not release any glutamate. This effectively inactivates the neurons. VGLUT3 is used by a small percentage of cells in the brain, and by the sound-detecting hair cells of cochlea. When it is absent, mice are deaf and have non-convulsive seizures. But the researchers did not expect to encounter VGLUT3 in nerve cells that communicate information about pain. These neurons are part of a cluster of cells called dorsal root ganglia, located just outside the spinal cord. Neurons within the dorsal root ganglia send projections toward the skin, where they can be activated by environmental stimuli such as touch or temperature. The same cells also send projections into the spinal cord, where they transmit signals to the brain. Rebecca Seal, a postdoctoral scholar from the Edwards’ lab, genetically engineered a strain of mice that no longer make VGLUT3.The mice were used to investigate pain behaviors. Xidao Wang, PhD, a postdoctoral scholar from Basbaum’s lab, performed many of the behavioral and anatomical studies. These studies demonstrated a loss of injury-induced mechanical hypersensitivity in animals lacking VGLUT3. Seal and Wang are the main authors of the Nature report. Seal then engineered a different strain of mice that produce VGLUT3 normally, but in which only cells with the VGLUT3 transporter emit an easily traced green light. These mice were useful in demonstrating that these cells do indeed normally respond to light touch. To show this, Seal traveled to the University of Wyoming lab of C. Jeffery Woodbury, PhD, one of the few people in the world expert in the techniques required to make such measurements. In the setting of injury, these same cells appear to generate pain in response to light touch. The bottom line is that this turn of events is pathological, Basbaum emphasizes. “Chronic pain is a disease of the nervous system; it’s not just a symptom of another illness.” “The notion that the nervous system has changed in the setting of injury and the idea that you have to prevent that or reverse that in order to treat the patient is a totally different perspective on the problem of pain,” he says.

Opioid Receptor in Pain Hypersensitivity

UCSF’s Basbaum also studies opioid receptors of two different types, called delta and mu. Neurons possessing these receptors send out signal-carrying projections from their cell bodies just outside the spinal cord, as do the neurons described in the Nature paper. When the opioid receptors encounter the body’s natural opioid-like molecules, they were thought to work together to inhibit neurons from firing in various circuits, including the nerve pathways responsible for pain. Morphine and synthetic opioids that are used clinically primarily act through the mu receptor. But the delta opioids that were developed have had intolerable side effects when administered systemically, by injection. “The delta and mu receptors were thought to coexist in the same cells and interact,” Basbaum says. “But it turns out that 20 years of assumptions were wrong.” Non-specific antibodies used to track the receptors led to faulty results and conclusions. Using mice and techniques similar to those reported in the Nature paper, Gregory Scherrer, PhD, a postdoctoral scholar in the Basbaum lab discovered that the two receptors are actually found in different neural pathways, serving distinct functions. This work is described in the June 12 issue of Cell. “The delta receptor is in a population of neurons that we predicted would be more important for the transmission of mechanical pain, which turned out to be true. Drugs administered to the spinal cord that block the delta receptor blocked mechanical pain.” Basbaum says it’s possible that the cells described in the Nature paper and the opioid-receptor-possessing cells described in the earlier Cell paper interact, or that the two populations might even overlap. It’s too soon to tell. In any case, the new findings make the delta opioid receptor a very attractive target for drugs delivered directly to the spinal cord, he says, which could block pain and minimize side effects. The VGLUT3 glutamate transporter that defines ultra-sensitive “light touch” cells might also be an attractive target for new, locally administered drugs, Basbaum suggests.

Injury-induced mechanical hypersensitivity requires C-low threshold mechanoreceptors

Rebecca P. Seal, Xidao Wang, Yun Guan, Srinivasa N. Raja, C. Jeffery Woodbury, Allan I. Basbaum & Robert H. Edwards

Nature (Published online November 15, 2009)


Dissociation of the opioid receptor mechanisms that control mechanical and heat pain

Grégory Scherrer, Noritaka Imamachi, Yu-Qing Cao, Candice Contet, Françoise Mennicken, Dajan O'Donnell, Brigitte L. Kieffer & Allan I. Basbaum

Cell (June 12, 2009)


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