Tuesday, November 14, 2006
By Staff Reporter
15/11/2006 - Scientists, who have been studying the venoms of deadly, sea-dwelling cone snails, believe they have discovered a new target for painkillers, which could represent a new previously unrecognised mechanism for treating pain.
The hope of these new findings make it feasible to develop a painkiller that could be taken orally, although the researchers believe this would take at least 10 years.
The research is centred on neuropathic pain, a chronic compliant due to injury to the nerves, spinal cord or brain.
Such pain can result from diabetes damage to nerves in the feet or elsewhere, spinal injury, degenerative disc disease, spinal tumours, multiple sclerosis, shingles, nerve toxins and electrical or other damage to peripheral nerves.
Common pain medicines like aspirin, ibuprofen and acetaminophen often fail to relieve neuropathic pain. Morphine-like opiods such as oxycodone sometimes are used, but can cause constipation, nausea and a spaced-out feeling.
The study in rats used toxins that came from two cone snail species that eat worms, unlike relatives that eat fish or snails and occasionally deliver a fatal sting to a human fisherman.
The cone snail toxins, RgIA and Vc1.1, fit into alpha9alpha10 nicotinic acetylcholine receptors, which are found on nerve cells and are in the family of receptors activated by nicotine from cigarette smoking.
The study showed alpha9alpha10 nicotinic receptors provided a previously unknown route to pain relief.
For the study, the University of Utah researchers tied sutures loosely around one of each rat's two sciatic nerves to mimic nerve compression and injury from sciatica.
That made the rats overly sensitive to touch on one hind paw but not the other. Each rat's sensitivity was assessed by measuring how much pressure could be applied to a hind paw with a blunt Teflon tip before the rat pulled away the paw.
Normal rats could withstand 4.7 times more pressure before withdrawing their paws, compared with rats with sciatica. When cone snail toxin RgIA was injected, the rats with sciatica were able to tolerate a stronger touch from the tip – both four hours and 24 hours after the drug was given.
The highest dose completely reversed the hypersensitivity caused by sciatica, with no adverse effects. Daily injections "produced a sustained analgesic effect," the researchers wrote.
RgIA was such a potent pain reliever that "about 10 billionths of an ounce reversed the hypersensitivity to pain,” the scientists commented.
Vc1.1 had a similar effect – replicating studies by other researchers – allowing rats with sciatica to tolerate touch with greater pressure.
"We found a new way to treat a chronic and debilitating form of pain suffered by hundreds of millions of people on Earth," said Michael McIntosh, a University of Utah research professor of biology, and research director and professor in the Department of Psychiatry.
"Our findings not only suggest a previously unrecognised molecular mechanism for the treatment of neuropathic pain, but also demonstrate the involvement of alpha9alpha10 nicotinic receptors" in nerve injury,” McIntosh and colleagues wrote.
At the moment, anticonvulsant drugs for epilepsy are sometimes used to reduce the pain by decreasing nerve cell excitability, but have side effects such as lethargy, fatigue, clouding of mental state and weight gain.
Antidepressants and muscle relaxants have been used, but they can cause weight gain, nausea and sexual dysfunction.
Topical treatments include capsicum cream derived from chili peppers, but they usually are not very effective.
"There really is no highly effective treatment available for this kind of severe pain, so having a new way to treat it is exciting," McIntosh said.
"If the new discovery eventually leads to a new pain drug that is combined with existing treatments, you may be able to reduce the pain to a lower level than ever before."
McIntosh emphasised neither substance will be on the market soon. Vc1.1, also known as ACV1, is being developed by an Australian company, Metabolic, and is undergoing trials of its effectiveness in human patients.
While the drug targets nicotinic receptors, McIntosh said alpha9alpha10 nicotinic receptors had not been reported previously as a target for any kind of painkilling medication.
McIntosh added that Vc1.1 could be administered by subcutaneous (under the skin) injection.
The findings are being published the week of Nov. 13 in the online edition of the journal Proceedings of the National Academy of Sciences.