Animal Studies Show Promise for Safer Opioids

By Pat Anson, Editor

Animal studies currently underway could hold the key to developing new opioid therapies that relieve pain without the risk of addiction, overdose and other harmful side effects.

Researchers at Wake Forest Baptist Medical Center in North Carolina have developed a pain killing compound -- called BU08028 – that relieves pain in monkeys without causing physical dependence. BU08028 is similar to buprenorphine, an opioid currently used to treat both pain and addiction.

"Based on our research, this compound has almost zero abuse potential and provides safe and effective pain relief," said Mei-Chuan Ko, Ph.D., professor of physiology and pharmacology at Wake Forest Baptist and lead author of the study published in the Proceedings of the National Academy of Sciences.

"This is a breakthrough for opioid medicinal chemistry that we hope in the future will translate into new and safer, non-addictive pain medications."

This study, which was conducted on 12 monkeys, targeted a combination of mu opioid receptors in the brain – the same receptors targeted in humans by existing opioid pain medication.

The Wake Forest researchers examined behavioral, physiological and pharmacologic factors and found that BU08028 blocked pain signals without the side effects of respiratory depression, itching or adverse cardiovascular events. In addition, the study showed pain relief lasted up to 30 hours in the monkeys and repeated administration did not appear to cause physical dependence.

"To our knowledge, this is the only opioid-related analgesic with such a long duration of action in non-human primates," said Ko. “Given the decades-long effort aimed at developing abuse-free opioid analgesics, BU08028 represents a major breakthrough for opioid medicinal chemistry.”

Ko plans further animal studies on related compounds to see if they have the same safety profiles as BU08028. If those studies are successful, he hopes to begin studies on humans with the ultimate goal of getting FDA approval for a new class of opioid medication.

The research is funded by the National Institutes of Health and National Institute on Drug Abuse.

Rat Study Targets Peripheral Nerves

Another animal study is taking a different approach to pain relief – by targeting nerves in peripheral tissue – not the mu opioid receptors in the brain and spinal cord.

In findings published in Cell Reports, researchers at the University of Texas found that targeting delta opioid receptors on sensory neurons in the peripheral tissue of laboratory rats produces fewer side effects and with much lower abuse potential.

"Being able to increase the responsiveness of peripheral opioid receptor systems could lead to a reduction in systemic opioid administration, thereby reducing the incidence of side effects," says senior study author Nathaniel Jeske of the University of Texas Health Science Center at San Antonio.

One complication is that delta opioid receptors in peripheral tissues only become activated in the presence of inflammation. Because it has not been clear how to overcome this need for an inflammation trigger, the development of drugs that target peripheral nerves has been limited.

Jeske and his colleagues discovered a protein called GRK2 that binds to and prevents delta opioid receptors on rat sensory neurons from responding normally to opioids. But when those peripheral nerves were exposed to a natural inflammatory molecule called bradykinin, GRK2 moved away from the delta opioid receptors, setting off a biochemical reaction that restored the functioning of these receptors.

In addition, rats with reduced GRK2 levels in peripheral sensory neurons regained sensitivity to the pain-relieving effects of a drug that activates delta opioid receptors, and without the need for an inflammatory trigger.

The researchers hope to replicate the same findings using human tissues.

"By shedding light on how inflammation activates delta opioid receptors, this research could potentially lead to the development of safer, more effective opioids for the treatment of pain," said Jeske, whose work is funded by the National Institutes of Health.