Fentanyl, oxycodone, morphine -- these substances are familiar to many as a
source of both pain relief and the cause of a painful epidemic of addiction
and death.
Scientists have attempted for years to balance the potent pain-relieving
properties of opioids with their numerous negative side effects -- with
mostly mixed results.
Work by John Traynor, Ph.D., and Andrew Alt, Ph.D., and their team at the
University of Michigan Edward F. Domino Research Center, funded by the
National Institute on Drug Abuse, seeks to side-step these problems by
harnessing the body's own ability to block pain.
All opioid drugs -- from poppy-derived opium to heroin -- work on receptors
that are naturally present in the brain and elsewhere in the body. One such
receptor, the mu-opioid receptor, binds to natural pain-killers in the body
called endogenous endorphins and enkephalins. Drugs acting on the mu-opioid
receptor can cause addiction as well as unwanted side effects like
drowsiness, problems with breathing, constipation and nausea.
"Normally, when you are in pain, you are releasing endogenous opioids, but
they're just not strong enough or long lasting enough," says Traynor. The
team had long hypothesized that substances called positive allosteric
modulators could be used to enhance the body's own endorphins and
enkephalins. In a new paper published in PNAS, they demonstrate that a
positive allosteric modulator known as BMS-986122 can boost enkephalins'
ability to activate the mu-opioid receptor.
What's more, unlike opioid drugs, positive allosteric modulators only work
in the presence of endorphins or enkephalins, meaning they would only kick
in when needed for pain relief. They do not bind to the receptor in the way
that opioids do instead binding in a different location that enhances its
ability to respond to the body's pain-relieving compounds.
"When you need enkephalins, you release them in a pulsatile fashion in
specific regions of the body, then they are metabolized quickly," explains
Traynor. "In contrast, a drug like morphine floods the body and brain and
sticks around for several hours."
The team demonstrated the modulator's ability to stimulate the mu-opioid
receptor by isolating the purified receptor and measuring how it responds to
enkephalins. "If you add the positive allosteric modulator, you need a lot
less enkephalin to get the response."
Additional electrophysiology and mouse experiments confirmed that the opioid
receptor was more strongly activated by the body's pain-relieving molecules
leading to pain relief. In contrast the modulator showed much reduced side
effects of depression of breathing, constipation and addiction liability.
Their next goal is to measure their ability to enhance activation of
endogenous opioids under conditions of stress or chronic pain, explains
Traynor, to ensure that they are effective but don't lead to more dangerous
responses like depression of breathing.
"While these molecules won't solve the opioid crisis," says Traynor, "they
could slow it and prevent it from happening again because patients in pain
could take this type of a drug instead of a traditional opioid drug."
Reference:
Ram Kandasamy, Todd M. Hillhouse, Kathryn E. Livingston, Kelsey E. Kochan,
Claire Meurice, Shainnel O. Eans, Ming-Hua Li, Andrew D. White, Bernard P.
Roques, Jay P. McLaughlin, Susan L. Ingram, Neil T. Burford, Andrew Alt,
John R. Traynor. Positive allosteric modulation of the mu-opioid receptor
produces analgesia with reduced side effects. Proceedings of the National
Academy of Sciences, 2021; 118 (16): e2000017118 DOI:
10.1073/pnas.2000017118