MILWAUKEE -- Blocking kappa opioid receptors may lead to new pain treatment approaches that are less addictive than current opioids, researchers said here.
Inhibiting the dynorphin-kappa opioid receptor system in the mesolimbic pathway of rats appeared to dampen their negative emotions and restore their motivation even when they were in pain, reported Jose Morón-Concepcion, PhD, of Washington University in St. Louis, in a plenary session at the 2019 .
"We're in the midst of an opioid epidemic and the euphoria associated with opioids is a major driver of opioid dependence," Morón-Concepcion said in a statement. "By targeting the emotional aspects of pain, we hope to make pain less debilitating so that patients won't crave the emotional high they get from opioids."
Current pharmacological treatments focus mainly on the nociceptive component of pain, leaving its emotional disturbances understudied and poorly treated, he added.
Existing opioid medications such as morphine, oxycodone, and fentanyl target mu opioid receptors. In , Morón-Concepcion and colleagues studied kappa opioid receptors, exploring whether chemically blocking them could improve emotional states during pain.
Most people in the field are working on sensory components of pain, noted Ted Price, PhD, of the University of Texas at Dallas, who was not involved with the study. "This research group is focused on trying to understand its affective components," he said.
"Anhedonia that arises with persistent pain is an important feature of this," Price told 鶹ý. "This group has given us the first basic insight into what drives that anhedonia."
To identify the role of kappa opioid receptors, the researchers injected the paws of rats with an agent that caused persistent inflammation. They used a task the animals could perform for sucrose rewards to measure the emotional effects of pain. In the experiment, rats had to push the lever progressively more each time they wanted sugar.
As expected, persistent pain decreased the rodents' motivation. "When the animals experienced pain, they were less likely to seek a reward," Morón-Concepcion said. "This is analogous to humans, because people in pain don't get as much pleasure from daily activities they normally enjoy."
When only low efforts were required to get a sugar pellet, however, the inflamed rats pushed the lever. This demonstrated that the pain did not affect the rats' ability to interact with the lever, but rather impaired their motivation when high efforts were needed, Morón-Concepcion observed.
When the researchers chemically blocked the ability of dynorphin to bind to kappa opioid receptors, the animals recovered their motivation to get sugar, and pushed the lever as frequently as normal control rats. "Motivation was restored, even though the animals' sensory component of pain was not eliminated," Morón-Concepcion noted.
Using small-animal positron emission tomography (PET) imaging, the researchers observed that when the rats were in pain, kappa opioid receptors were very active in the nucleus accumbens compared with baseline.
"The data demonstrate that the dynorphin-kappa opioid receptor system in the brain represents an important target for new therapeutic approaches for treating pain-induced negative affect," Morón-Concepcion said.
"By attacking the emotional aspects of pain, it could be possible to improve quality of life for pain patients without relying on as many addiction-prone opioid medications," he added.
Morón-Concepcion and his team currently are reviewing PET data in people to study human kappa opioid receptors.
Disclosures
The work in this presentation was supported by the National Institute on Drug Abuse, the National Institute on Neurological Disorders and Stroke, and the National Institute on Alcohol Abuse and Alcoholism of the NIH, with additional funding from a NARSAD Independent Investigator Award, the Philippe Foundation, the Spanish Ministerio de Edonomia y Competitividad MINECO, and the Mallinckrodt Institute of Radiology. The researchers declared no competing interests.
Primary Source
American Pain Society
Morón-Concepcion J "Opioid-Induced Plasticity and the Interaction with Pain" APS 2019.