A Step Forward In Targeted Pain Therapy

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A Step Forward In Targeted Pain Therapy

http://www.sciencedaily.com/releases/2008/01/080121120828.htm

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 activates 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, however, 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.

Journal reference: " Reversal of pathological pain through specific

spinal GABAA receptor subtypes " , Knabl, Witschi,

Katharina Hösl, Heiko Reinold, Ulrike B. Zeilhofer, Seifollah

Ahmadi, Johannes Brockhaus, Marina Sergejeva, s Hess, Kay

Brune, Jean-Marc Fritschy, Uwe Rudolph, Hanns Möhler & Hanns Ulrich

Zeilhofer, Nature, Vol 451, 17 January 2008

Adapted from materials provided by Swiss Federal Institute of

Technology Zurich, via AlphaGalileo.