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Transporter offers reliable clues for safer pain medicine

Researchers have zeroed in on a transporter that actually quietens the body’s natural pain killers. This discovery will show the way for potent and non-habit //forming pain killers and will help perceive the pain threshold of AIDS patients.

Opioid peptides are natural pain relievers with receptors – first identified because they react to opium – throughout the body, says Dr. Vadivel Ganapathy, chair of the Department of Biochemistry and Molecular Biology at the Medical College of Georgia. Studies have shown, for example, opioid peptide levels increase during childbirth.

Many potent pain killers, such as morphine and codeine, override this natural pain control system by directly activating opioid peptide receptors. While pain control is effective, it comes at a price: potential addiction, immune suppression and constipation.

Now researchers want to know whether safer pain killers can be developed that augment the body’s natural pain-killing ability by targeting instead the opioid peptide transport system that terminates pain-control communication, says Dr. Ganapathy. 'This has the potential for non-addictive pain killers that are effective, but by a different mechanism.'

Many popular antidepressants work in a similar fashion to keep the body’s natural chemical messengers, called neurotransmitters, working longer by keeping them from being taken back up into the neuron by transport systems. Chemical messengers are supposed to have limited action, he says. But depressed patients have insufficient levels of chemicals for adequate communication between neurons. Antidepressants provide more mileage from existing neurotransmitters.

Dr. Ganapathy hopes to do the same with endogenous pain killers. Armed with a two-year, $286,000 grant from the National Institute on Drug Abuse, he is working to clone the opioid peptide transporter he identified three years ago and identify the responsible gene and protein.

Interestingly he also has found mice expressing one of the HIV proteins have increased activity of this transporter, a finding that might help explain why HIV patients have increased pain perception. 'That means the normal endogenous activity of this transport system is higher in HIV patients, so natural pain mechanisms are not working that well,' says Dr. Ganapathy.

The National Institute on Drug Abuse asked him to apply for the Cutting Edge Basic Research Grant – which enables quick review for funding of novel ideas – to pursue this hypothesis as well as the molecular analysis of the transporter.

The idea that a transport system is involved is itself a novel concept. Conventional wisdom was that an enzyme was responsible for hydrolyzing, or decomposing, opioid peptide, Dr. Ganapathy says. This is the case for at least one neurotransmitter – acetylcholine, implicated in Alzheimer’s - which is inactivated by an enzyme, rather than being transported back into the neuron like other neurotransmitters, such as serotonin, which has a role in depression.

But when he watched the activity of opioid peptides, he saw it actively taken back up into the neuronal cells.

Cloning the transporter and dissecting its molecular profile will ultimately provide a model for studying whether naturally occurring or designer drugs block this re-uptake. In fact, the National Institute on Drug Abuse will provide Dr. Ganapathy with a number of synthetic opioid peptides to see whether they are substrates, or blockers, of this transport system.

'We know this recognizes peptides. Therefore, any chemical compound that will block the transport function must have some resemblance to its natural substrate. Otherwise, it might not do the job,' Dr. Ganapathy says.

He’s already testing naturally occurring amino acids and peptides and found one – lysine, an essential amino acid vital to good growth and found in high concentrations in red meat, cheeses, poultry, sardines, nuts, eggs and soybeans – that’s a pretty good fit.

'We may be able to take this compound as a starting point, then add a few things to make it more effective. You could have a lysine-based drug for the treatment of pain, maybe even a nutritional supplement to prevent pain,' says Dr. Ganapathy. 'You could use such a treatment to block this transport activity for HIV patients as well as other patients to control pain.'


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