Experimental Opioid Modulator Shows Antidepressant Properties
BU10119, a combination of buprenorphine and naltrexone, appears to reduce symptoms of depression in an animal model without activating mu receptors.
An experimental drug that combines the properties of buprenorphine and naltrexone in one compound may one day offer relief to patients with stress-related illnesses. A study published in the British Journal of Pharmacology found this drug, known as BU10119, alleviated depressive-like behaviors in mice without producing any of the negative effects associated with opioid drugs.
Sarah Bailey, Ph.D. (center), and her lab developed a novel compound that combines the properties of buprenorphine and naltrexone, allowing them to selectively modulate the opioid receptors that react to stress and not those involved in the pain response.
University of Bath
While BU10119 is in the preclinical stages, the early results are promising, noted study author Sarah Bailey, Ph.D., a senior lecturer in the Department of Pharmacy and Pharmacology at the University of Bath in the United Kingdom.
Most available antidepressants target serotonin and/or dopamine receptors. BU10119, like buprenorphine, instead targets kappa opioid receptors.
“These receptors are part of the body’s response to stress, which is a major risk factor for depression,” Bailey said. Following a stressful event, the body releases molecules called dynorphins, which activate kappa receptors and contribute to a depressed-like state. Drugs that block these receptors could help to alleviate depressive symptoms, she explained.
“Such drugs might even be useful at preventing the incidence of depression or anxiety in situations where we know someone will be stressed, such as soldiers going into combat or emergency workers responding to a disaster,” Bailey added.
The obstacle in using drugs that target kappa opioid receptors such as buprenorphine is that these agents also affect mu opioid receptors, which when activated produce euphoria. These receptors are the primary targets of pain-relieving opioids.
Bailey’s research group had previously shown that mice administered buprenorphine and naltrexone—a medication that shuts down mu receptors—had lower depressive-like behaviors than mice that did not receive the drug combination. Bailey’s group wanted to know if combining these two medications into one—BU10119—would have similar effects.
The researchers assessed BU10119 in mice using a variety of tests that simulate depressive and anxious behaviors. The researchers found that BU10119 was as effective as fluoxetine in two measures of depressive states; however, it was not as effective as diazepam at reducing fear in the mice in two measures of anxiety.
Bailey noted that it is possible the anxiety tests used in the study may have not been stress-inducing enough to trigger kappa opioid activity. She said she remains hopeful BU10119 may reduce symptoms of some types of anxiety disorders.
Importantly, BU10119 did not induce any responses to suggest it activates mu opioid receptors. Unlike mice treated with buprenorphine only, mice treated with BU10119 did not show any reduced pain sensitivity; likewise, mice did not show any strong preference for BU10119-treated water compared with saline.
“Of course, we can only speculate based on what we see in mice, and studies in higher order animals are needed,” she said. Her group is now taking a closer look at the role of gender in kappa opioid responses, as depression and anxiety are much more commonly reported in women than men (this current study was conducted using all male mice).
This study was funded by a grant from the Royal Society, with additional support from the National Institute of Drug Abuse and a scholarship from the Government of Saudi Arabia. ■
An abstract of “Antidepressant-like Effects of BU10119, a Novel Buprenorphine Analogue With Mixed κ/μ Receptor Antagonist Properties, in Mice” can be accessed here.
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Psychiatrics News
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Published online: 31 January 2018
Published in print: January 20, 2018 – February 2, 2018
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