By suppressing a key protein involved in pain control, scientists have potentially found a way to increase opioids’ effectiveness at lower doses, preventing addiction-related rewarding effects and delaying drug tolerance.
“Findings from this work point to novel intracellular pathways that can be targeted to optimize the actions of opioids for the treatment of chronic pain,” they said.
The study, “Suppression of RGSz1 function optimizes the actions of opioid analgesics by mechanisms that involve the Wnt/β-catenin pathway,” was published in Proceedings of the National Academy of Sciences. A team from the Icahn School of Medicine at Mount Sinai in New York led the work.
Opioids are commonly prescribed for the treatment of painful chronic conditions, including fibromyalgia; however there’s growing concern about the risk of opioid abuse, overdose, and death.
Painkillers reduce the intensity of pain signals that reach the brain, and also induce a sense of calm in patients. This calmness is the result of the opioids targeting the brain’s reward system, which can lead to addiction in prolonged use.
Researchers investigated if targeting a molecular pathway within the brain region involved in pain control could separate the drug’s pain-relieving action from its rewarding effect in mice.
RGSz1 is a protein that takes part in the pain-relieving molecular mechanism of opioids like morphine. Researchers found that suppressing RGSz1 decreased the risk of reward or dependence associated with opioid therapy.
When the RGSz1 function was suppressed, the effectiveness of the opioids also increased, meaning that mice required a lower dose of the medication to numb their pain.
The team also found that RGSz1 absence delayed the development of painkiller tolerance via another RGS protein known as Axin 2, promoting beta-catenin activation.
“Our discovery that RGSz1 and RGSz1 regulated pathways can be targeted to promote analgesia is very exciting because it enables us to develop strategies for the use of low opioid doses for pain relief,” Venetia Zachariou, PhD, said in a news release. Zachariou is an associate professor in the Fishberg Department of Neuroscience, the Department of Pharmacological Sciences, The Friedman Brain Institute, and The Addiction Institute, Icahn School of Medicine at Mount Sinai.
However, opioid actions on addiction-related pathways are dependent on different RGS family proteins. RGSz1 is only found in a subset of neurons involved in these mechanisms.
Therefore, researchers “are now screening currently prescribed opioids as well as new compounds to determine their abuse potential and analgesic efficacy based on the RGS protein they activate. That knowledge will be power in the fight against this deadly opioid epidemic,” Zachariou said.
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