The opioid crisis has plagued the US and beyond for years, but researchers at the University of Michigan believe the key to turning the tide may lie within our own bodies, by enhancing our existing painkilling powers.
Fentanyl, oxycodone and morphine are a powerful double-edged sword when it comes to reducing patient suffering; on the one hand they provide powerful and effective pain relief but on the other, they can increasingly carve a path to painful death via addiction.
Rather than attempt to walk the tight rope and grapple with the delicate balancing act of managing potent pain relief while staving off powerful and often damaging side effects, John Traynor PhD and Andrew Alt PhD and their team at the University of Michigan Edward F. Domino Research Center examined the body’s existing ability to block pain.
Opioid drugs work on receptors in the brain and can often flood the patient’s system, leading to an almost euphoric state where once there was pain and misery.
The team sought a more precise solution within the body and examined the mu-opioid receptor, which binds to the body’s natural pain-killers, endogenous endorphins and enkephalins.
The pain-relief aspect of opioid medications which operate with these receptors comes at a cost, including but not limited to drowsiness, breathing difficulties, nausea and constipation which, as uncomfortable as they are, do not preclude addiction.
“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 hypothesized that substances called positive allosteric modulators could be deployed to enhance the body’s own natural painkillers and thereby reduce the need for more dramatic, widespread pain relief provided by opioids.
They found that one particular positive allosteric modulator, known as BMS-986122, can boost enkephalins’ ability to activate the mu-opioid receptor in a way more akin to a laser-guided missile of pain relief rather than the carpet bomb afforded by opioids, with their resultant side effects.
These modulators only function in the presence of endorphins or enkephalins, so they provide more on-demand pain relief rather than numbing the whole system over a continuous period.
They do not mimic the binding location used by opioids, binding elsewhere, thereby enhancing the overall pain relief in a more targeted way, allowing the human body to ‘paint the target’ rather than blasting the pain away and cause gastrointestinal problems such as nausea and constipation.
“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 tested the modulator by isolating a purified receptor and measuring the response to enkephalins, and found that lower levels of enkephalins were required to trigger the required response.
In tests on mice, monitored through numerous electrophysiology experiments, the researchers found that the opioid receptors were more strongly triggered but without the same impact on breathing, gastrointestinal function or the risk of crossing the threshold into addiction.
They will now assess the ability to enhance the pain relief effects of endogenous opioids but under a different set of conditions; stress and chronic pain, which are more prolonged and can often push patients into dependency and potentially addiction.
“While these molecules won’t solve the opioid crisis,” cautiomns Traynor, “they could slow it and prevent it from happening again because patients in pain could take this type of drug instead of a traditional opioid drug.”
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