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.