Natural protein provokes chronic pain

Research reported this week in The EMBO Journal has uncovered evidence that a protein which occurs naturally in the body is involved in the mechanisms behind chronic pain in rats.

Varying definitions of chronic pain classify it as pain that has lasted more than six months or for more than 12 months, but either way the condition is persistent and usually difficult to treat. The new study has sparked hopes for the development of potential therapies to mitigate the symptoms.

"We are fortunate to have a wide range of technologies that allow us to look more precisely at the molecular events that lead to the onset of chronic pain in animals," said lead author Professor Marc Landry, of the University of Bordeaux.

Chronic pain is at least partially caused by irregularities in molecular signalling between neurons which alters nervous system interactions between the brain and the spinal cord.

"Our results show that the levels of the naturally occurring protein 14-3-3 zeta are higher in the spinal cord of rats that have chronic pain," Professor Landry explained. "Moreover, we have been able to demonstrate how 14-3-3 zeta triggers changes in the signalling pathway that leads to the symptoms of chronic pain."

The GABA_B receptor is a protein complex that is found on the surface of nerve cells. They are a type of G-protein coupled receptor; these are often targeted in drug development as they are responsible for the regulation of many physiological processes.

Using antibody labelling and microscopy techniques, the scientists from France and Sweden were able to explore the interactions between proteins involved in signalling on a molecular level. They found that 14-3-3 zeta (pictured) disrupts the pain-relieving activity of GABA_B receptors by interacting directly with their B1 sub-units.

This effect was demonstrated both in living animals and in cells. The researchers were also able to inhibit the symptoms of chronic pain by interfering with the 14-3-3 zeta protein using small interfering RNA (siRNA) and other competing molecules.

"The impairment of the GABA_B receptor by 14-3-3 zeta is a novel mechanism for the modulation of chronic pain," Professor Landry added. "We see potential in combining the use of inhibitors that interfere with the action of 14-3-3 zeta together with existing drug treatments like Baclofen for chronic pain. Targeting the GABA_B dissociation process may be of therapeutic interest since it may allow classical pain killers to be more effective."