Long-term treatment with opioids, such as morphine, prior to trauma may increase the risk of post-traumatic stress disorder (PTSD), according to a study in mice.
The findings, published in the journal Neuropsychopharmacology, suggest a possible mechanism underlying the frequent co-occurrence of PTSD and opioid dependence.
PTSD and substance use disorders (SUDs) often occur together, with nearly 40 per cent of individuals with PTSD also having a SUD, explained the researchers from the University of California, Los Angeles in the US.
Understanding the relation may help explain the mechanisms by which these conditions develop, they said.
Previous research has shown that PTSD increases the risk of opioid dependence, but whether opioid dependence may also increase PTSD risk remained unclear, the researchers noted.
Using an established model of fear learning in mice, they assessed the potential impact of chronic opioid treatment on subsequent development of PTSD-like behaviours.
They found that mice that had been treated with opioids, and later experienced stress showed more pronounced post-stress reactions.
At the beginning of the study, mice were treated with morphine or saline for eight days, followed by a week of drug cessation.
Both groups of mice -- morphine-treated mice and saline-treated controls (22 and 24 mice, respectively) -- were then subdivided into trauma and non-trauma groups.
They were transferred to a chamber where animals in the trauma group received a series of mild foot shocks.
A day later, both groups of animals were returned to the chamber to assess their memory of the traumatic event.
"We have called this the trauma because the acute stressor, the foot shocks, is able to produce lasting fear and anxiety-like behaviours, such as freezing," said Michael Fanselow, the corresponding author of the study.
On the subsequent day, mice from both the trauma and non-trauma groups were transferred to a new environment and exposed to a mild stressor -- a milder foot shock -- before being returned to that environment for eight minutes on the fourth day of the experiment.
The researchers found no behavioural differences between morphine-treated and control mice following the initial trauma.
Neither group froze for longer when returned to the environment associated with the trauma, the researchers said.
However, morphine-treated mice showed more pronounced freezing when returned to the second environment after having been exposed to the mild stressor, they said.
Morphine-treated mice that had not experienced the trauma did not show signs of heightened fear levels.
"Our data are the first to show a possible effect of opioids on future fear learning, which may suggest that a person with a history of opioid use may become more susceptible to the negative effects of stress," said Michael Fanselow, corresponding author of the study.
"Also, this ability of opioids to increase PTSD-like symptoms far outlasted the direct effects of the drug or withdrawal from the drug, suggesting that the effect may continue even after opioid treatment has stopped," Fanselow said in a statement.
The researchers also tested treating mice with opioids after the initial trauma had occurred but before exposing them to the second, mild stressor.
They found that mice treated with morphine after the initial trauma did not show enhanced fear learning following exposure to the mild stressor.
The findings suggest that chronic exposure to opioids before -- but not after -- a traumatic event occurs, impacts fear learning during subsequent stressful events.
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