Researchers Develop Targeted Approach To Pain Management

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Researchers Develop Targeted Approach To Pain Management

Imagine an epidural or a shot of Novocain that doesn't paralyze your

legs or make you numb, yet totally blocks your pain. This type of

pain management is now within reach. As a result, childbirth,

surgery and trips to the dentist might be less traumatic in the

future, thanks to researchers at Massachusetts General Hospital

(MGH) and Harvard Medical School, who have succeeded in selectively

blocking pain-sensing neurons in rats without interfering with other

types of neurons.

The pint-sized subjects received injections near their sciatic

nerves, which run down their hind limbs, and subsequently lost the

ability to feel pain in their paws. But they continued to move

normally and react to touch. The injections contained QX-314, a

normally inactive derivative of the local anesthetic lidocaine, and

capsaicin, the active ingredient in hot peppers. In combination,

these chemicals targeted only pain-sensing neurons, preventing them

from sending signals to the brain.

" We've introduced a local anesthetic selectively into specific

populations of neurons, " explains Harvard Medical School Professor

Bruce Bean, an author on the paper, which appears in Nature on Oct.

4. " Now we can block the activity of pain-sensing neurons without

disrupting other kinds of neurons that control movements or non-

painful sensations. "

" We're optimistic that this method will eventually be applied to

humans and change our experience during procedures ranging from knee

surgery to tooth extractions, " adds Professor Clifford Woolf of

Massachusetts General Hospital, who is senior author on the study.

Despite enormous investments by industry, surgical pain management

has changed little since the first successful demonstration of ether

general anesthesia at MGH in 1846. General and local anesthetics

work by interfering with the excitability of all neurons, not just

pain-sensing ones. Thus, these drugs produce dramatic side effects,

such as loss of consciousness in the case of general anesthetics or

temporary paralysis for local anesthetics.

" We're offering a targeted approach to pain management that avoids

these problems, " says Woolf.

The new work builds on research done since the 1970's showing how

electrical signaling in the nervous system depends on the properties

of ion channels, that is, proteins that make pores in the membranes

of neurons.

" This project is a perfect illustration of how research trying to

understand very basic biological principles can have practical

applications, " says Bean.

The new method exploits a membrane-spanning protein called TRPV1,

which is unique to pain-sensing neurons. TRPV1 forms a large

channel, where molecules can enter and exit the cell. But a " gate "

typically blocks this opening. The gate opens when cells are exposed

to heat or the chili-pepper ingredient capsaicin. Thus, bathing pain-

sensing neurons in capsaicin leaves these channels open, but non-

pain sensing neurons are unaffected because they do not possess

TRPV1.

The new method then takes advantage of a special property of the

lidocaine derivative QX-314. Unlike most local anesthetics, QX-314

can't penetrate cell membranes to block the excitability of the

cell, so it typically lingers outside neurons where it can't affect

them. For this reason it is not used clinically.

When pain-sensing neurons are exposed to capsaicin, however, and the

gates guarding the TRPV1 channels disappear, QX-314 can enter the

cells and shut them down. But the drug remains outside other types

of neurons that do not contain these channels. As a result, these

cells fully retain their ability to send and receive signals.

The team first tested their method in the Petri dish.

Binshtok, a postdoctoral researcher in Woolf's lab, applied

capsaicin and QX-314 (separately and in combination) to isolated

pain-sensing and other neurons and measured their responses. Indeed,

the combination of capsaicin and QX-314 selectively blocked the

excitability of pain-sensing neurons, leaving the others unaffected.

Next, Binshtok injected these chemicals into the paws of rats and

measured their ability to sense pain by placing them on an

uncomfortable heat source. The critters tolerated much more heat

than usual. He then injected the chemicals near the sciatic nerve of

the animals and pricked their paws with stiff nylon probes. The

animals ignored the provocation. Although the rats seemed immune to

pain, they continued to move normally and respond to other stimuli,

indicating that QX-314 failed to penetrate their motor neurons.

The team must overcome several hurdles before this method can be

applied to humans. They must figure out how to open the TRPV1

channels without producing even a transient burning pain before QX-

314 enters and blocks the neurons, and they must tinker with the

formulation to prolong the effects of the drugs. Both Bean and Woolf

are confident they'll succeed.

" Eventually this method could completely transform surgical and post-

surgical analgesia, allowing patients to remain fully alert without

experiencing pain or paralysis, " says Woolf. " In fact, the

possibilities seem endless. I could even imagine using this method

to treat itch, as itch-sensitive neurons fall into the same group as

pain-sensing ones. "

Research in the Woolf lab is supported by the National Institute of

Neurological Disorders and Stroke (NINDS) and the National Institute

of Dental and Craniofacial Research. Research in the Bean lab is

supported by NINDS and the National Institute of General Medical

Sciences.

Harvard and MGH have filed patents on this technology platform.

Principal Investigators:

Bruce Bean, Harvard Medical School, Department of Neurobiology

Clifford Woolf, Harvard Medical School, Department of Anesthesia and

Critical Care at Massachusetts General Hospital

http://www.medicalnewstoday.com/articles/84599.php