Smart painkillers target damaged tissue

• 31 May 2007
• NewScientist.com news service
• Roxanne Khamsi

Imagine a painkiller that only switches on in injured tissue, leaving the rest of the body unaffected. That is the idea behind a new class of pH-dependent drugs that interfere with nerve signals to the brain and spinal cord - but only where the tissue is slightly acidic due to injury.

Normal tissue has a pH of around 7.4, but this drops to around 7.0 in injured tissue, largely because the blood supply is disrupted, resulting in the accumulation of waste products such as carbon dioxide and a switch to anaerobic respiration, which produces lactic acid.

The new drugs act by blocking NMDA receptors, which are found on cells throughout the brain and central nervous system and are implicated in a variety of nerve functions, including pain sensitisation. Earlier generations of drugs, such as ketamine, also targeted NMDA receptors, but these often have unwanted side effects such as impaired movement or hallucinations, because they act on undamaged nerve tissue as well.

“The drugs act by blocking NMDA receptors, which are found on cells throughout the brain and central nervous system”

Ray Dingledine of the Emory University School of Medicine in Atlanta, Georgia, and his colleagues have now developed a compound called NP-A, that binds to the base of NMDA receptors and stops glutamate and a related neurotransmitter called NMDA from binding. A slight drop in pH can cause a significant boost in NP-A's ability to block the receptor - for example, a drop in pH from 7.6 to 6.9 causes the compound's activity to increase 62 fold.

This means that NP-A gets switched on only where it's most needed, says Dingledine, who has now set up a company called NeurOp to develop the drug further. "It's a context-dependent blocking of pain, which is a new strategy for these receptors," he says.

He showed that rats were significantly less sensitive to pain in an injured paw when they were injected with NP-A. Usually, rats will flinch when their paw is touched using a force greater than 15 grams. When they have injured paws, however, they pull their leg back when the force is only 2 g. Forty-five minutes after an NP-A injection, the rats did not move their injured paws away until the force was about 12 g.

The pain stayed away for about 3 hours, and the animals showed no signs of side effects. The results were presented at the annual meeting of the Biotechnology Industry Organization in Boston, Massachusetts, last month.

Dingledine believes that a compound like NP-A could one day provide pain relief for people with agonising peripheral nerve damage, or neuropathy. Doctors often prescribe drugs such as gabapentin, which boost a pathway in the brain that inhibits pain through a neurotransmitter called GABA. However, these drugs don't work for everyone - possibly because GABA misfiring is not necessarily the cause of the pain.

Min Zhuo of the University of Toronto in Canada, who studies NMDA receptors and pain, says that a drug targeting NMDA receptors might help a different subset of patients who experience pain because of NMDA overactivation. "GABA inhibition and NMDA firing are like yin and yang," he says.

From issue 2606 of New Scientist magazine, 31 May 2007, page 11

http://www.newscientist.com/article/mg19426064.400?DCMP=NLC-nletter&nsref=mg19426064.400