A step forward in targeted pain therapy

Jan 22, 2008

Our bodies sense painful stimuli through certain receptors located in the skin, in joints and many internal organs. Specialized nerve fibers relay these signals coming from the periphery to the brain, where pain becomes conscious. “The spinal cord is placed between these structures as kind of a pain filter”, says Hanns Ulrich Zeilhofer, Professor at the Institute of Pharmaceutical Sciences at ETH Zurich and at the Institute of Pharmacology and Toxicology of the University of Zurich.

That filter assures that pain is not evoked by everyday stimuli like light touch. This is accomplished by inhibitory nerve cells located in the spinal dorsal horn that release the messenger molecule -amino butyric acid (GABA) at specialized contacts between neighboring nerve cells, so-called synapses. GABA then acti-vates chloride channels on those neighboring cells which relay the pain signals to the brain.

Activating pain inhibiting factors

In patients with chronic inflammatory diseases, such as rheumatoid arthritis or after nerve damage, for example following injuries, the pain inhibiting action of GABA becomes severely compromised. Pain signals are then conducted to the brain nearly unfiltered. Benzodiazepines, such as the sedative drug Valium®, which enhance the action of GABA, alleviate chronic pain when they are applied directly to the spinal cord via an injection into the spinal canal. In practice, how-ever, such injections can only be done in very selected cases.

More often benzodiazepines are administered systemically, such as with tablets. In this instance, the benzodiazepines not only act in the spinal cord but also in the brain where they can have undesired, sometimes deleterious, effects on pain patients. The drugs cause sedation, impair memory, and can even lead to addiction. In addition, during prolonged treatment their effect often fades with time. Classic benzodiazepines should therefore be avoided in chronic pain patients.

GABAA receptors as pain targets

It had been acknowledged for some time that GABA serves important functions in pain control. That benzodiazepines act on at least four different subtypes of GABA receptors was also known. Nonetheless, these receptors were largely neglected as potential targets for pain treatment.

The research team led by Ulrich Zeilhofer used genetically altered mice in experiments to target the GABA receptors that control spinal pain relay. They first induced a slight inflammation in one hind paw or irritated the sciatic nerve to induce pain. A few days later the mice received an injection of a benzodiazepine close to the spinal cord. Experiments with the mice allowed the researchers to identify two subtypes of GABAA receptors which mediate spinal pain control.

A challenge for drug design

For experiments with animals, drugs with the proposed receptor specificity are already available. Such experiments have confirmed that the pharmacological enhancement of spinal GABA receptor function inhibits the relay of pain signals to the brain. Further studies have also shown that these compounds did not lose their analgesic effects during prolonged treatment and did not lead to addiction.

Successful design of a drug that targets only those two subtypes of GABA receptors would be a big step forward in pain therapy. Chronic pain could be treated specifically and with fewer side effects. “The challenge is now for pharmaceutical companies to develop drugs that specifically target these receptors in humans”, says Zeilhofer.

Source: Swiss Federal Institute of Technology

Explore further: Three-people IVF debate process on the move in UK

add to favorites email to friend print save as pdf

Related Stories

North Atlantic right whale's prospects tied to climate

29 minutes ago

A pleasant scientific surprise: The North Atlantic right whale population – once projected for extinction – exhibited an unexpected increase in calf production and population size during the past decade.

Finding the 'heart' of an obstacle to superconductivity

39 minutes ago

A team at Cornell and Brookhaven National Laboratory has discovered that previously observed density waves that seem to suppress superconductivity are linked to an electronic "broken symmetry," offering an ...

Heat testing the miniature Aausat 4 satellite

39 minutes ago

The miniature Aausat satellite undergoes repeated temperature variations in a vacuum chamber, cooling the CubeSat to –10°C and heating it to +45°C for more than two weeks. This harsh baptism will make ...

Recommended for you

Intestinal parasites are 'old friends,' researchers argue

1 hour ago

Intestinal parasites such as tapeworms, hookworms and a protist called Blastocystis can be beneficial to human health, according to a new paper that argues we should rethink our views of organisms that live off the human ...

Researchers unlock the protein puzzle

1 hour ago

By using brightly hued dyes, George Mason University researchers discovered an innovative way to reveal where proteins touch each other, possibly leading to new treatments for cancer, arthritis, heart disease and even lung ...

User comments : 0