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New Targets Found for Drug Development in Neuropathic Pain

For release: Thursday, February 22, 2007

New studies reveal that two proteins in the body play a role in neuropathic pain – pain and sensitivity from a nerve injury that persist long after the nerve has healed.  By zeroing in on these proteins, scientists hope to develop better drugs for the condition.

Both proteins regulate how cells utilize neurotransmitters – the chemical signals sent between nerve cells.  One protein appears to be important for how pain is perceived in the brain; the other appears to be important for sensing pain at the site of nerve injury. 

Blocking the action of neurotransmitters is how most of the current drugs for neuropathic pain work, but it’s also the reason they cause many side effects – including sedation, weight gain, nausea, sexual dysfunction, and cognitive impairment.

“The trick is to get a drug with enough specificity so that you don’t interfere with the normal function of the nervous system but you prevent neuropathic pain,” said Christian Rosenmund, Ph.D., a professor of genetics and neuroscience at Baylor College of Medicine in Houston.  Dr. Rosenmund was a contributor to one of the studies, published in the Journal of Neuroscience.*

Dr. Rosenmund, who is supported in part by the National Institute of Neurological Disorders and Stroke (NINDS), has spent much of his career studying how nerve cells release and respond to glutamate – one of the predominant neurotransmitters in the brain.  His latest research shows that a protein called VGLUT2 helps trigger neuropathic pain.

VGLUT2 is a subtype of vesicular glutamate transporter, a protein essential for packing glutamate into tiny parcels (vesicles) that are stored inside brain cells.  Without glutamate transporters, millions of brain cells would be silenced, with devastating effects.  Indeed, Dr. Rosenmund and his collaborators found that mice lacking the gene for VGLUT2 died at, or soon after, birth.

On the other hand, mice bred to produce about half the normal level of VGLUT2 were normal in most respects – except that they exhibited less neuropathic pain after nerve injury.  That “completely unexpected” result, said Dr. Rosenmund, suggests that drugs designed to knock down VGLUT2 activity could be effective against neuropathic pain, without causing adverse complications.

The second study, published in the Proceedings of the National Academy of Sciences,** shows that a protein called the alpha-9alpha-10 nicotinic acetylcholine receptor (a9a10 nicotinic AChR) is another culprit in neuropathic pain.

Acetylcholine receptors enable nerve cells to detect and respond to acetylcholine, a neurotransmitter that is essential for voluntary muscle contraction and is linked to many brain functions as well.  There are a wide variety of acetylcholine receptors, and the a9a10 nicotinic AChR appears to be found mainly in the body’s periphery – near muscles and sensory organs – and possibly in non-nervous tissue.

A team led by J. Michael McIntosh, M.D., a professor of psychiatry at the University of Utah in Salt Lake City, tested two toxins found in cone snail venom – one known to attach to the a9a10 nicotinic AChR, and one known to produce pain relief – to determine if they could alleviate neuropathic pain.  When given to rats by intramuscular injection, both toxins relieved pain caused by a prior nerve injury, and both turned out to be highly specific for the a9a10 nicotinic AChR.

The fact that the toxins act on acetylcholine receptors in the periphery, rather than in the brain, could make them useful for developing analgesic (painkilling) drugs without neurological side effects, said Dr. McIntosh, whose study was supported in part by NINDS.

The toxins themselves could be modified for use as drugs, most likely in an injectable form, or further studies on their mechanism of action could lead to other similar-acting medications, possibly in oral form.  One cone snail toxin, omega-conotoxin (MVIIA), is already on the market for neuropathic pain under the trade name Prialt.  It has to be pumped into the spinal fluid via a surgically implanted device.

The idea of a painkilling animal toxin might seem counterintuitive since the venoms people are most familiar with – from snakes, spiders, and the like – actually cause pain so that prey can be easily debilitated and eaten.  But Dr. McIntosh said that a toxin that soothes its prey makes sense for the cone snail, which feasts on marine worms and small fish by first harpooning them.

“It may be beneficial for the snail to have toxins that are analgesic so that its prey doesn’t thrash around and try to get away,” he explained.

*Moechars D et al.  “Vesicular Glutamate Transporter VGLUT2 Expression Levels Control Quantal Size and Neuropathic Pain.”  Journal of Neuroscience, November 15, 2006, Vol. 26(46), pp. 12055-12066.

**Vincler, M et al.  “Molecular Mechanism for Analgesia Involving Specific Antagonism of a9a10 Nicotinic Acetylcholine Receptors.”  Proceedings of the National Academy of Sciences, November 21, 2006, Vol. 103(47), pp. 17880-17884.

-By Daniel Stimson, Ph.D.

Last Modified February 23, 2007