National rates of opioid use and overdose are still on the rise despite ongoing efforts to improve access to treatment and support of cutting-edge research on chronic pain and addiction. A critical issue contributing to opioid dependence and overdose center around a lack of medication options available to individuals seeking treatment. Preclinical researchers are working hard to help remedy this problem. The laboratories of Drs. David Siderovski and Vincent Setola at West Virginia University are researching the pharmacology of opioids and their receptors in the brain, in hopes of contributing to the discovery of new and promising treatment options for opioid use disorder. A recent, groundbreaking project from their group, led by former graduate student Dr. Joshua Gross, sheds light on how one specific type of opioid receptor, the kappa opioid receptor (KOR), plays an important role in pain and reward.
Opioids produce their effects by attaching to opioid receptors that are found on nerve cells. When opioids interact with these receptors, messages are sent throughout the brain and body to block pain. However, activation of these receptors in areas of the brain like the striatum, which plays key roles in regulating motivation and reward, produces euphoric effects that can lead to misuse of and development of dependence on opioid drugs. In hopes of creating medications that are effective in treating pain but have lower risk of abuse, early studies looked at KORs as a potential target. This research revealed that KORs played a central role in controlling motivation and reward, among other behaviors, which are often disrupted in substance use disorders and other neuropsychiatric diseases like depression. However, activating KORs also produced unpleasant side effects, such as dysphoria, which would limit their potential as medications. Therefore, it has become essential to better understand how KORs produce their signals in the brain, in order to develop improved medications that minimize these side effects.
Using cutting-edge molecular and genetic approaches, the Siderovski and Setola group has made large advances in tackling this important question. Their group takes a unique approach to studying receptor signaling by focusing on a family of small, powerful intracellular proteins called Regulators of G protein Signaling (RGS) proteins that act like a brake pedal on receptor signaling. Of the many subtypes of RGS proteins, each of which play unique roles in the brain and the rest of the body, the Siderovski group has paid particular attention to one subtype, RGS12, characterizing its structure and function for over 20 years. Ongoing work in their lab revealed that RGS12 can control KOR signaling, making it an ideal tool to better understand aspects of KOR function in the brain that have yet to be explored.
Dr. Gross explains that “one of the current shortcom-ings of being able to study KOR function in the brain is crosstalk with other opioid receptor subtypes”. Their recent paper makes advances in addressing this issue by showing that RGS12 inhibits KOR better than the other opioid receptor subtypes, highlighting RGS12 as a strong tool to study KOR signaling with greater specificity than many previous approaches. Capitalizing on this new strategy to intricately control KOR function, their recent project distinguishes precisely which components of KOR signaling in the ventral striatum are associated with pain relieving therapeutic benefits and adverse side effects that are observed with medications that activate KORs. These findings not only move the field of opioid receptor pharmacology forward but importantly, showcase RGS proteins as a versatile and powerful experimental tool that could be used to greatly expand our understanding of how many receptors work in the brain.
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