黑料不打烊

For almost as long as we鈥檝e known about the powerful spell opium can cast on a user, scientists have been trying to learn precisely how the drug operates in the body, particularly in the brain. According to recent Wednesday Afternoon Lecture Series guest Dr. Brigitte Kieffer, researchers are closer than ever to understanding, witnessing, mimicking and perhaps predicting opioids鈥� work within the gray matter.聽

鈥淥pium is kind of a magical substance that seems to relieve any kind of pain鈥攑hysical pain, mental pain, social pain鈥攁nd produces euphoria,鈥� said Kieffer, who began her lecture, 鈥淥pioid Receptors and Brain Function,鈥� by briefly tracing the drug back to its botanical origins thousands of years ago.

A large portion of opium鈥檚 mystery was revealed about 200 years ago, Kieffer continued, when a German chemist discovered its active ingredient. Morphine, she said, was shown to produce a 鈥渉ighly efficient analgesia, was a strong painkiller鈥攁nd is still the strongest painkiller today鈥攂ut also had strong addictive liability鈥�So the holy grail in the field since then has been to find as good a painkiller as morphine, but one that would be devoid of the addictive liability.鈥�

Kieffer, a long-time NIH grantee and professor in the department of psychiatry at 黑料不打烊 University, was making her second visit to NIH in recent months. She had presented a shorter talk as part of a multi-institute-sponsored symposium, 鈥淭he Opioid Crisis and the Future of Addiction and Pain Therapeutics: Opportunities, Tools and Technologies鈥� in February.

NIH director Dr. Francis Collins introduced the French molecular neurobiologist as 鈥渁 giant in the study of the opioid system in the brain, a topic of considerable current interest and importance given the crisis we face in this country of opioid overuse and addiction and opioid overdose deaths.鈥�

The Brain on Opioids

鈥淭his is your brain,鈥� declared the speaker, holding an egg up to the camera. 鈥淭his is your brain on drugs,鈥� he went on, cracking the egg into a sizzling skillet. 鈥淎ny questions?鈥� he deadpanned.聽

To people of a certain age, that 1980s-era public service announcement by the Partnership for a Drug-Free America offered a lasting image of the damaging effects of drug use.

To scientists鈥攁nd perhaps neuroscientists in particular鈥攊t could easily have been throwing down a gauntlet: What does the brain really look like on opioids?

Opium has been a societal challenge for decades, Kieffer recounted, describing the Opium Wars in the mid-19th century and today鈥檚 opioid crisis. Since 2000, she said, opioid over-prescription for pain relief has led 鈥渕any, many people to become addicted to opioids and to transition to heroin or fentanyl use and this alarming increase in overdose.

In her lecture, 鈥淥pioid Receptors and Brain Function,鈥� Kieffer traces the drug back to its botanical origins thousands of years ago.

"During all these years,鈥� Kieffer noted, 鈥渘euroscience has dramatically evolved and we have discovered a fascinating opioid neuronal system.鈥�

Morphine acts by binding on the brain. In 1973, researchers identified opioid binding sites, then known as 鈥渙pioid receptors.鈥� It took about 40 years, from the identification of binding sites, through the isolation of the first opioid receptor gene, to crystallography of the encoded receptor protein and the resolution of receptor structure.

Kieffer, Collins noted, 鈥渨as the first to isolate a gene encoding an opioid receptor, research that led to much of what the field now understands about how opioids work at the molecular level鈥�Her work has been transformative.鈥�

Familiar Family

鈥淲e know a lot about this protein,鈥� Kieffer said. 鈥淲e know it atom by atom. These receptors belong to the big G-protein-coupled receptor family. They are extremely important as biomedical targets. Half of the drugs used to treat people are agonists or antagonists of G-protein-coupled receptors. We can think of the opioid system as a system that exists in our brain to teach us beneficial behaviors and help us cope with stress. This system is important to regulate reward and aversion processes. It鈥檚 also a system that is extremely important to reduce pain and cope with stress.鈥�

Kieffer鈥檚 talk covered opioid receptor physiology, in both mood state and drug abuse, homing in on the mu opioid receptor (MOR) in brain circuits. She showed studies identifying MOR as a 鈥渟ingle target that mediates both analgesic and adverse [addictive] effects of opioids used in the clinic or abused in the streets.

鈥淢OR is a target to kill pain and many strategies are underway to try to reduce adverse effects mediated by activated mu receptors,鈥� Kieffer said. She recommended more organism-level studies for drug development.

Using knockout mice, 鈥渨e demonstrated that there is an important role for the mu opioid receptor鈥攂eyond drug abuse鈥攖hat has to do with natural reward,鈥� such as mother-child bonding, Kieffer said.

MOR Complex

Her group also has learned more about two other opioid receptors, and how the three each 鈥渃ontribute very differently to all facets of addiction鈥� and have 鈥渄istinct roles in hedonic homeostasis and emotional control.鈥�

In addition, Kieffer suggested more study of opioid peptides produced by our brain,聽 which naturally bind and activate the receptors. 鈥淲e know much less about the peptides compared to what we know about the receptors,鈥� she said.

Kieffer covered opioid receptor physiology, in both mood state and drug abuse, homing in on the mu opioid receptor in brain circuits.

Kieffer explained that scientists had hoped to find that receptors had one designated job, but MOR鈥檚 role proved to be more complicated.聽

鈥淢ORs facilitate drug-seeking and taking in reward circuits,鈥� she said. 鈥淢OR function and adaptation to opioids in aversion centers is key to 鈥榯he problem.鈥欌��

Concluding her talk, Kieffer mentioned her group鈥檚 new approach, translational neuroimaging, to view receptor function and brain connectivity.

鈥淕ene-to-connectome mapping is feasible in the mouse,鈥� she said. 鈥淏rain network analysis is at the crossroads of mechanistic and biomarker research.鈥澛�

Currently researchers are examining how morphine, fentanyl and buprenorphine affect the brain. In the long term, Kieffer said, 鈥渢his work will help scientists better understand opioid effects on the brain and predict behavioral effects of a drug.鈥澛犅�