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Opiate drugs increase vulnerability to stress

August 29, 2005

Rats given morphine show bigger biological and behavioral signs of stress-induced anxiety even after going off the drug

Washington - A new study has found that opiate drugs such as morphine leave animals more vulnerable to stress. This means that stress and opiates are in a vicious cycle: Not only does stress trigger drug use, but in return the drug leaves animals more vulnerable to stress. The study, conducted at the University of New South Wales, helps to explain why people who use opiates such as heroin have very high rates of anxiety problems, including post-traumatic stress disorder, even after they stop using. That emotional fragility can also make them more likely to start using again.

The study appears in the current issue of the journal Behavioral Neuroscience, which is published by the American Psychological Association (APA). Understanding how opiate users respond to and cope with stress may lead to better treatment and help prevent relapses. Co-author Gavan McNally, PhD, notes that heroin is the most commonly used illicit opiate, followed perhaps by morphine. In medical settings, pethidine, fentanyl, morphine and codeine are typically used.

McNally and his colleagues conducted four experiments with rats, injecting them with either morphine or saline solution every day for 10 days. Then, either one or seven days after the final injection, they gently restrained each rat for 30 minutes as a form of stress.

The team then measured the rats' biological responses to the restraint stress. They also studied behaviors that reflect anxiety, checking the rats' levels of social interaction and general activity. The researchers tested anxiety responses for three different dose levels and different durations of exposure (0, 1, 5 or 10 days).

In the absence of stress, the opiate-treated rats were exactly the same as the control rats. Only when the animals were exposed to a stressor were there marked differences in nervous-system and behavioral responses. For example, in terms of anxiety, the impact of stress was twice as great for the morphine-treated rats as for the saline-treated rats. Whereas stress reduced social interaction by about 31 percent in the saline-treated animals, it reduced social interaction by 68 percent in the morphine-treated animals.

Thus, exposure to morphine left those rats significantly more anxious in response to stress. This effect was sensitive to both dose and duration: The longer the duration or the higher the dose of morphine, the greater the difference in anxiety between morphine- and saline-treated rats.

The authors say this is the first important evidence that opiate use increases subsequent vulnerability to stress - a tough knot to untie given that stress leads to drug use. The results also were first to show that the vulnerability could last at least a week, evidence that the altered response was independent of any recent effect of the opiate or of opiate withdrawal.

McNally points out that brief exposure to opiates, of five or fewer days, was not enough to change vulnerability to stress. He says, "It appears the development of opiate dependence is the critical variable, and there are marked individual differences in humans in the development of dependence. A few days of codeine to relieve post-operative pain are unlikely to lead to the development of dependence."

Because rodent nervous systems are so like ours, animal models allow neuroscientists to study the behavioral and brain mechanisms for drug addiction. McNally says, "Our goal is the translation of these findings in the clinical domain. Our data suggest that implementing treatments that are designed to reduce vulnerability to stress - such as cognitive-behavioral therapy, pharmacological approaches, or both - in opiate addicts may be therapeutically useful."

As for why opiate exposure raises vulnerability to stress, the authors speculate that opiates may, by altering the expression of specific anxiety-related genes, prime the nervous system in a lasting way to be more vulnerable to stress. McNally notes the paradox that drugs used to escape from stress instead may heighten its impact.

American Psychological Association