Opioids are the most commonly used pain medication, and they work by attaching to and activating opioid receptors, which are proteins that sit on the surface of cells. Drugs that activate the kappa opioid receptor (KOR), one of four types of opioid receptors, relieve pain and itch, but unlike drugs like morphine that attach to different opioid receptors, they do not seem to be addictive or rewarding. However, KOR drugs often cause sedation and dysphoria—extreme discomfort or aversion—which limit their use in patients.
But now, new research suggests that it may be possible to achieve pain relief while avoiding these side effects. Researchers show that triazole 1.1, a new kind of opioid that activates KOR, relieves pain and itch in mice—but without the sedation and dysphoria seen with traditional opioids like morphine.
The study “is really exciting for us because [triazole 1.1] was from a whole series of compounds that we’ve been studying…it’s encouraging because we know they are doing something fundamentally different,” says Laura Bohn of Scripps Research Institute and one of the senior authors of the new research.
The study was published online November 29 in the journal Science Signaling, and led by Bohn and colleagues at Scripps Research Institute, Wake Forest School of Medicine, and the University of North Carolina at Chapel Hill.
Discovering a new drug
After drugs attach to the KOR, molecular signals are produced within cells, ultimately leading to both the beneficial and negative effects of the drugs. But the researchers knew that the beneficial effects depend on one signaling pathway that uses its own unique set of molecules, while the detrimental effects rely on another signaling pathway involving a whole different set of molecules.
The authors of the new study took advantage of this knowledge and asked: could we develop a drug that, when it attaches to the KOR, only activates the “good” pathway, while leaving the “bad” pathway untouched?
This concept of a drug that promotes a favorable signaling pathway over a less favorable one is known as biased agonism. This led the investigators to test whether triazole 1.1, a biased agonist that binds to and activates the KOR, could preferentially activate the pathway leading to pain and itch relief, without affecting the other pathway leading to sedation and dysphoria.
One order of pain relief—hold the side effects
The study found that, in mice, triazole 1.1 relieved pain similarly to a more traditional drug called U50,488H that activates both the beneficial and detrimental signaling pathways that come into play after the KOR is activated. (To measure pain relief, the researchers used the tail-flick assay. This is a widely used test in pain research that measures the amount of time it takes an animal to remove its tail from a painful stimulus, such as hot water).
To test if triazole 1.1 could also prevent itch, mice were injected at the back of the neck with a drug that causes the animals to scratch. Triazole 1.1 and U50,488H similarly blocked scratching behaviors at all doses tested.
Traditional drugs like U50,488H that activate KOR decrease the effects of dopamine, a neurotransmitter in the brain. This causes sedation and dysphoria. However, because triazole 1.1 did not appear to affect dopamine, the researchers thought this new drug might avoid those side effects. Indeed, this was the case: triazole 1.1 did not affect how much the animals moved, indicating that the drug did not sedate the animals, nor did it cause dysphoria.
Drugs that activate the KOR have never been used in the US for pain treatment. “They’re really nice analgesics [pain relievers] and they work well, but they have always caused dysphoria and even hallucinations,” says Bohn. However, avoiding such side effects may one day become a reality with biased agonists like triazole 1.1, though more work in animal studies is first needed to fully understand the potential.
Still, “this is a really important step forward,” says Thomas Kash, University of North Carolina School of Medicine, who was not involved with the current study. –Hillary Doyle
To read about the research in more detail, see the related Pain Research Forum news story here.
Hillary Doyle is a PhD candidate and science writer studying pain and analgesia at Georgia State University in Atlanta.
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