Avoiding the severe pain, nausea, agitation, sweats and other symptoms of opiate withdrawal are among the many reasons addicts are motivated to continue taking drugs. Now, researchers have found that disrupting the brain's stress-response mechanism exacerbates behavioral withdrawal symptoms in mice, and that giving the mice the hormone corticosterone alleviates those symptoms. The researchers said their findings suggest new approaches to reduce withdrawal symptoms.
Angelo Contarino of Université Victor Segalen Bordeaux 2 and colleagues published their findings in the February 15, 2007 issue of the journal Neuron, published by Cell Press.
In their studies, the researchers mimicked the pattern of opiate addiction and withdrawal in mice that were genetically deficient in a receptor called CRF1. Receptors are proteins on the cell surface that trigger reactions in the cell when activated. CRF1 is a trigger for the corticotrophin-releasing factor system in the brain and is an essential protein for coping with stressful events. In mimicking addiction and withdrawal, the researchers gave the mice increasing doses of morphine and then stopped morphine administration to induce withdrawal symptoms.
The researchers found that the CRF1-deficient mice showed more severe and prolonged behavioral symptoms of withdrawal—such as jumping and "wet dog shaking"—when compared with normal mice as had been shown previously. Similarly, when the researchers administered a drug that blocks the receptor in normal mice, they saw the same aggravating effects.
The researchers also detected genetic changes in the brains of the mice, which indicated that the stress-response circuitry in the brain was impaired.
However, Contarino and colleagues found that giving the mice the steroid hormone corticosterone abolished the difference in withdrawal symptoms between the CRF1-deficient and normal mice. The hormone also restored the normal stress-response-related genetic activity in the brain, they found.
"The findings of the present study demonstrate that, like hyperactive stress systems, severe deficiencies in major components of the stress-responsive system may worsen the somatic reactions to drug withdrawal," the researchers concluded.
The researchers include Francesco Papaleo, Université Victor Segalen Bordeaux 2 and Unité INSERM 588 in Bordeaux, France and University of Padova in Padova, Italy; Pierre Kitchener of Unité INSERM 588 in Bordeaux, France; Angelo Contarino of Université Victor Segalen Bordeaux 2 and Unité INSERM 588 in Bordeaux, France and University of Padova in Padova, Italy.
A.C. was supported by a research grant from the University of Padova and the European Union Grant MCIF HPMF-CT-2001-01327. F.P. was supported by a Ph.D. Fellowship grant from the University of Padova, Italy. P.K. was supported by a Ph.D. Fellowship grant from the University Victor Segalen Bordeaux 2, Bordeaux, France.
Papaleo et al.: "Disruption of the CRF/CRF1 Receptor Stress System Exacerbates the Somatic Signs of Opiate Withdrawal." Neuron 53, 577–589, February 15, 2007. DOI 10.1016/j.neuron.2007.01.022. www.neuron.org.
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Neuron