Opioids are a highly addictive method of treating pain. Despite the known dangers of opioid addiction, they remain a popular treatment option.
One risk opioid use carries is the development of opioid-induced hyperalgesia (OIH). This condition increases the body’s sensitivity to pain. Pain that they may have previously been able to tolerate well feels more painful for patients with OIH. This may contribute to drug abuse.
“It was nurses who first noticed and reported that some patients using opioids had increased sensitivity to pain from needle sticks,” Professor Steven Kinsey in the School of Nursing says. “At first, it seemed like a paradox that pain-reducing opioid drugs could cause pain. Eventually, other clinicians and scientists also started paying attention to this surprising phenomenon.”
OIH happens when the opioid receptors in our brain and other parts of the body are repeatedly activated and hence desensitized, lowering a person’s overall pain threshold. Opioid use also activates inflammatory pathways when morphine binds to Toll-like receptors. Long-term opioid use causes these receptors to release a constant stream of inflammatory modulators, leading to opioid tolerance.
Kinsey is investigating if the human body’s cannabis-like compounds could mitigate the effects of OIH. This work is supported by a $442,000 grant from the National Institute on Drug Abuse.
Endocannabinoids are molecules produced by cells throughout the body. They help the body maintain homeostasis. Endocannabinoids help regulate sensations of hunger, thirst, pain perception, and many other processes that keep our bodies in balance.
Endocannabinoids have well-established anti-inflammatory effects with limited intoxicating effects, making them an attractive target for OIH treatment.
These molecules are similar to phytocannabinoids produced by plants. One example is THC, which comes from the cannabis plant. Our body responds to phytocannabinoids in a similar fashion to our own endocannabinoids. This is why cannabinoids like THC can help relieve pain.
Kinsey and his students will measure pain sensitivity in mice repeatedly exposed to morphine. He will also inhibit the enzyme responsible for the inactivation of endocannabinoids, known as monoacylglycerol lipase (MAGL). He predicts that this inactivation will decrease the pain and inflammation that repeated morphine exposure causes.
“Our idea is to tap into the body’s own, naturally produced cannabinoids to decrease pain caused by opioids,” Kinsey says. “MAGL inhibitors make it easier for our endocannabinoids to reach our cannabinoid receptors, thereby decreasing pain without the high associated with THC.”
Kinsey will use two approaches for inactivating MAGL. He will either use chemicals to inhibit the enzyme, or delete the gene that codes for MAGL. In the second approach he will test deleting this gene globally, from all cells, or in neurons only, to find out which parts of the body are most important in reducing OIH.
One critical and novel aspect of Kinsey’s study is that he will use both male and female mice. Previous studies have been largely constrained to males. This is a massive oversight given that women may be at an increased risk of developing OIH compared to men.
We now know that some drugs work differently in women than in men, and we are working to correct this historic inattention to women’s health. — Steven Kinsey
“For generations, scientific research has suffered from a sort of tunnel vision, focusing almost entirely on male animals,” Kinsey says. “Researchers assumed females were too complicated to study. We now know that some drugs work differently in women than in men, and we are working to correct this historic inattention to women’s health.”
This approach will allow Kinsey to study sex as a potential biological variable. This will make an important contribution to the basic understanding of how cannabinoids could provide relief for OIH patients and if that process looks different in male and female bodies.
This research will provide vital insights into the protective properties of the endocannabinoid system and whether this approach could be translated into new treatment options for people managing chronic pain.
Kinsey serves as the director of the Center for Advancement in Managing Pain. He holds a Ph.D. in behavioral neuroscience from The Ohio State University. His lab studies endocannabinoid and opioid systems with the goal of reducing pain and substance use disorders.
