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<h2 class="element-invisible">You are here</h2><div class="breadcrumb"><a href="/">Home</a> » <a href="/news-events">News & Events</a> » <a href="/news-events/nih-research-matters">NIH Research Matters</a></div> <div class="l-region l-region--section-header">
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<p class="publishdate"><span property="dc:date" datatype="xsd:dateTime" content="2022-10-18T00:00:00-04:00" class="date-display-single">October 18, 2022</span></p><div class='syndicate'><h1>Compounds block pain without sedation in mice</h1><div class="callout callout-with-border"><h3>At a Glance</h3>
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<ul>
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<li>Researchers identified several compounds that activate a specific pain-blunting receptor on cells.</li>
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<li>In studies in mice, the compounds blocked pain without causing the sedation seen with other drugs that target this receptor.</li>
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</ul></div><div class="media-float-right"><div class="ds-1col file file-image file-image-jpeg view-mode-floated_media clearfix">
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<picture title="3D representation of pain signals being transmitted by nerve cells">
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<!--[if IE 9]><video style="display: none;"><![endif]-->
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<source srcset="https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-large/public/news-events/research-matters/2022/20221014-pain.jpg?itok=xEwTV6oE&timestamp=1666033645 1x" media="screen and (min-width: 960px)" />
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<source srcset="https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-medium/public/news-events/research-matters/2022/20221014-pain.jpg?itok=cU4ExP3W&timestamp=1666033645 1x" media="screen and (min-width: 800px)" />
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<source srcset="https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-medium-small/public/news-events/research-matters/2022/20221014-pain.jpg?itok=_sz_T4ix&timestamp=1666033645 1x" media="screen and (min-width: 600px)" />
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<source srcset="https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-small/public/news-events/research-matters/2022/20221014-pain.jpg?itok=6f3DQCFO&timestamp=1666033645 1x" media="screen and (min-width: 480px)" />
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<source srcset="https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-tiny/public/news-events/research-matters/2022/20221014-pain.jpg?itok=Iu4pQRxm&timestamp=1666033645 1x" media="screen and (min-width: 0)" />
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<!--[if IE 9]></video><![endif]-->
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<img src="https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-medium/public/news-events/research-matters/2022/20221014-pain.jpg?itok=cU4ExP3W&timestamp=1666033645" alt="3D representation of pain signals being transmitted by nerve cells" title="3D representation of pain signals being transmitted by nerve cells" />
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||
</picture><span class="caption">Researchers developed compounds that retained the pain killing effects of an established drug without its sedative effects. </span><span class="credit">Trzmiel / Shutterstock</span></div>
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||
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</div><p>Drugs to better treat pain, both acute and chronic, are desperately needed. Many available drugs don’t work well for some pain conditions, or in some people. Opioids, a mainstay of pain treatment, can lead to dependency, and also addiction when misused.</p>
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||
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||
<p>Drugs that target a receptor found on cells called the α<sub>2A</sub>AR receptor can provide potent pain relief. However, these drugs also cause very strong sedation. This makes them impractical for use outside of a hospital.</p>
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||
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||
<p>An international team of researchers, funded in part by NIH, has been looking for ways to harness the painkilling effects of α<sub>2A</sub>AR activation without causing sedation. Current drugs are thought to turn on many cell-signaling pathways controlled by α<sub>2A</sub>AR. The unwanted side effects like sedation may result from the activation of these multiple pathways.</p>
|
||
|
||
<p>In a new study, the team used powerful computers to screen the structures of more than 300 million diverse molecules for their potential to interact with the α<sub>2A</sub>AR receptor. The researchers then synthesized and tested the most promising candidates in cells and mice. The results were published on September 30, 2022, in <em>Science</em>.</p>
|
||
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||
<p>The researchers focused on 48 of the top candidates that had structures unlike those of available drugs that activate α<sub>2A</sub>AR. Of these, 30 bound to the receptor in the laboratory. Seventeen bound at levels that would make them potentially useful as a drug.</p>
|
||
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||
<p>The most potent of these 17 compounds all activated α<sub>2A</sub>AR differently than the currently available drugs. In cells, they turned on a more selective set of cell-signaling pathways.</p>
|
||
|
||
<p>Using cryo-electron microscopy, the researchers examined the structure of two of these compounds bound to the receptor. They then used information about their interactions to optimize the strongest of the compounds, called ‘9087.</p>
|
||
|
||
<p>The team created and tested several new compounds based on ‘9087 for their ability to bind to and activate α<sub>2A</sub>AR. They tested the most potent of these, called PS75, along with ‘9087, in mice. Both accumulated successfully in the brain after either intravenous or oral administration.</p>
|
||
|
||
<p>Both compounds reduced the sensitivity of mice to pricking, heat, inflammation, and pain. When the team gave the mice another compound that blocked the activity of α<sub>2A</sub>AR, the pain-killing effects were largely lost. This showed that the compounds worked primarily as expected, by activating α<sub>2A</sub>AR.</p>
|
||
|
||
<p>The compounds didn’t affect appetite or cause constipation. And importantly, neither reduced the ability of mice to navigate a rotating cylinder, showing that balance, coordination, and awareness remained intact. This confirmed that the compounds didn’t have a sedative effect.</p>
|
||
|
||
<p>“We showed that it’s possible to separate the [pain killing] and sedative effects related to this receptor,” says Dr. Brian Shoichet from the University of California, San Francisco, who helped lead the study. “That makes it a very promising target for drug development.”</p>
|
||
|
||
<p>Further testing of these compounds for multiple pain conditions, as well as for side effects, including those potentially affecting the heart, are needed before the compounds could be tested in people.</p>
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||
<p>—by Sharon Reynolds</p></div><h2 class="label-above">Related Links</h2><ul class="spaced print-urls"><li><a href="https://www.nih.gov/news-events/nih-research-matters/understanding-how-sound-suppresses-pain" target="_top">Understanding How Sound Suppresses Pain</a></li><li><a href="https://www.nih.gov/news-events/nih-research-matters/retraining-brain-treat-chronic-pain" target="_top">Retraining the Brain to Treat Chronic Pain</a></li><li><a href="https://www.nih.gov/news-events/nih-research-matters/study-finds-link-between-red-hair-pain-threshold" target="_top">Study Finds Link Between Red Hair and Pain Threshold</a></li><li><a href="https://www.nih.gov/news-events/nih-research-matters/gene-therapy-chronic-pain-relief" target="_top">Gene Therapy for Chronic Pain Relief</a></li><li><a href="https://www.nih.gov/news-events/nih-research-matters/scientists-find-new-pain-suppression-center-brain" target="_top">Scientists Find New Pain-Suppression Center in the Brain</a></li><li><a href="https://www.nih.gov/news-events/nih-research-matters/how-gentle-touch-can-turn-painful-after-injury" target="_top">How Gentle Touch Can Turn Painful After Injury</a></li><li><a href="https://www.nih.gov/news-events/nih-research-matters/designing-more-effective-opioids" target="_top">Designing More Effective Opioids</a></li><li><a href="https://newsinhealth.nih.gov/2018/10/managing-pain" target="_top">Managing Pain: Moving Beyond Opioids</a></li><li><a href="https://www.ninds.nih.gov/health-information/disorders/chronic-pain" target="_top">Chronic Pain</a></li></ul><p class="footnote"><strong class="label-inline">References: </strong><a href="https://pubmed.ncbi.nlm.nih.gov/36173843/">Structure-based discovery of nonopioid analgesics acting through the α2A-adrenergic receptor.</a> Fink EA, Xu J, Hübner H, Braz JM, Seemann P, Avet C, Craik V, Weikert D, Schmidt MF, Webb CM, Tolmachova NA, Moroz YS, Huang XP, Kalyanaraman C, Gahbauer S, Chen G, Liu Z, Jacobson MP, Irwin JJ, Bouvier M, Du Y, Shoichet BK, Basbaum AI, Gmeiner P. <em>Science</em>. 2022 Sep 30;377(6614):eabn7065. doi: 10.1126/science.abn7065. Epub 2022 Sep 30. PMID: 36173843.</p><p class="footnote"><strong class="label-inline">Funding: </strong>NIH’s National Institute of General Medical Sciences (NIGMS), National Institute of Neurological Disorders and Stroke (NINDS), and National Institute of Mental Health (NIMH); Defense Advanced Research Projects Agency; Deutsche Forschungsgemeinschaft; Open Philanthropy; Facial Pain Research Foundation; CIHR Foundation; National Science Foundation; Science, Technology and Innovation Commission of Shenzhen Municipality; Kobilka Institute of Innovative Drug Discovery; Shenzhen Key Lab.</p>
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