Morphine Regulator May Reduce Pain-Kill Abuse Risk

Researchers appear to have identified a specific molecule that controls morphine receptor signaling in a small group of brain cells. The particular regulator of G protein signaling (RGS) protein is called RGS7 and has been identified as a novel regulator of the μ-opioid receptor (MOR), which morphine acts upon to mediate its euphoric and analgesic effects. The study shows that RGS7 regulates MOR signaling by dissecting its circuit-specific actions and pinpointing its role in regulating morphine reward by controlling the activity of nucleus accumbens neurons.

Led by Kirill Martemyanov, PhD, associate professor of neuroscience at the Florida campus of The Scripps Research Institute, and published in Biological Psychiatry, the study could lead to a new drug target for less-addictive pain medications and perhaps offer some insight into the genetic predisposition of some patients to addiction before treatment.

For the study, Martemyanov and colleagues used genetically modified animal models lacking RGS7 to show that eliminating the protein enhanced reward, increased pain relief, delayed tolerance, and heightened withdrawal in response to self-administered morphine doses. “We used genetic approaches to ablate [RGS7] both globally and in specific neuronal populations,” they write. “We used conditioned place preference and self-administration paradigms to examine reward-related behavior and a battery of tests to assess analgesia, tolerance, and physical dependence to morphine. Electrophysiology approaches were applied to investigate the impact of RGS7 on morphine-induced alterations in neuronal excitability and plasticity of glutamatergic synapses. At least three animals were used for each assessment.”

“The μ-opioid receptor acts as a conductor of the drug’s effects, while RGS7 acts as a brake on the signal,” said Martemyanov. “The animals could press a lever to receive an infusion of morphine. We looked at the number of lever presses to determine how much they liked it and, judging from this test, mice lacking RGS7 craved the drug much more than their normal siblings.”

The researchers suggest that RGS7 works by regulating morphine-induced changes in excitability of neurons and plasticity of synapses.

“This study reveals a unique modulatory role of RGS7 in a brain-region-specific action to morphine use and indicates RGS7 as a potential drug target,” said lead author Laurie P. Sutton, PhD, a research associate at The Scripps Research Institute. “Pharmacological intervention at the level of RGS7 may reduce some of the detrimental side-effects associated with opiates.”

The finding could also have an impact on the future screening of patients who may be at risk for drug abuse, according to Martemyanov. “If our findings hold true for human patients, you could look specifically for RGS7 levels for any disabling mutation with a simple blood test,” he said. “Mutations could indicate a strong reaction to a drug such as morphine--people carrying a deficient copy of the RGS7 gene might need much lower doses of opioids and could be cautioned to be extra careful with these substances.”