Key Trigger Of Opioid Withdrawal Symptoms Found

They believe that drugs to inhibit the chemical--called a transporter--could relieve some of the early physical symptoms of withdrawal, such as teeth-chattering, uncontrolled shaking, and jumpiness. Such drugs could become part of the arsenal of medicines and behavioral techniques aimed at helping addicts kick their habits.

To zero in on the machinery underlying withdrawal symptoms, researchers led by Elena Bagley and Macdonald Christie of the Pain Management Research Institute at Royal North Shore Hospital (a division of the University of Sydney) performed biochemical studies on brain slices from mice that had been treated with morphine. Their objective was to understand what happens to a particular region of the midbrain--called the periaqueductal gray (PAG)--known to be involved in such withdrawal symptoms. Opiate addiction inhibits neuron activity in this region, which alters the neuronal machinery to compensate for this inhibition. Upon opiate withdrawal, the neurons rebound, becoming hyperactive.

The scientists' analysis revealed that a transporter molecule for the neurotransmitter GABA was responsible for the electrical abnormalities that produce a hyperexcitability in the neurons. Neurotransmitters are the molecular ammunition that one neuron fires at its neighbor to trigger a nerve impulse in the neighbor. Propagation of such nerve impulses through the networks of neurons in the brain is the basis of all neural activity. Transporter molecules are the proteins that retrieve neurotransmitter molecules from the spaces between neurons after they trigger nerve impulse, to reload the neuron for its next signaling burst.

Bagley and her colleagues also discovered that a molecular switch called protein kinase A was part of the triggering machinery involved in activating the abnormal GABA transporter activity.

Importantly, the researchers found that drugs that inhibit either the GABA transporter activity or protein kinase A eliminate the hyperexcitability of the PAG neurons in the mouse brain slices.

The researchers cited other studies showing that treatment with opioids also altered levels of the transporter for the neurotransmitter glutamate, "suggesting that neurotransmitter transporters may prove to be useful targets for management of opioid dependence," they wrote. The researchers also wrote that, since GABA is a neurotransmitter that inhibits nerve impulses, drugs to inhibit the GABA transporter "could produce their therapeutic effect through altering extracellular GABA concentrations as well as directly altering the excitability of GABAergic neurons."

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Elena E. Bagley, Michelle B. Gerke, Christopher W. Vaughan, Stephen P. Hack, and MacDonald J. Christie: "GABA Transporter Currents Activated by Protein Kinase A Excite Midbrain Neurons during Opioid Withdrawal"

The other members of the research team include Michelle B. Gerke, Christopher W. Vaughan, Stephen P. Hack of the Pain Management Research Institute at Royal North Shore Hospital, a division of the University of Sydney. This work was supported by National Institute on Drug Abuse, National Health and Medical Research Council of Australia; C.J. Martin Fellowship and project grants.

Publishing in Neuron, Volume 45, Number 3, February 3, 2005, pages 433–445. http://www.neuron.org