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Studies by an international research team suggest that targeting the delta opioid receptor may represent an approach to treating chronic inflammatory pain that has fewer side effects than the use of traditional opioids that target the mu opioid receptor. The team’s research, in cells from humans and mice with inflammatory bowel disease, indicated that delta opioid receptors have a built-in mechanism for pain relief, and can be precisely targeted with drug-delivering nanoparticles.

“We’ve shown that the delta opioid receptor has a built-in mechanism of pain control and inhibits pain by signaling within an endosome,” said Nigel Bunnett, PhD, professor and chair of the department of molecular pathobiology at New York University (NYU) College of Dentistry. “With this new knowledge, we thought the receptor would be a promising target for the treatment of chronic inflammatory pain.” Bunnett is senior author of the team’s published report in Proceedings of the National Academy of Sciences (PNAS), which is titled, “Endosomal signaling of delta opioid receptors is an endogenous mechanism and therapeutic target for relief from inflammatory pain.”

G protein coupled receptors (GPCRs) control essential pathophysiological processes, the authors wrote. “One-third of FDA-approved drugs target GPCRs.” Opioid receptors are GPCRs that are located throughout the central nervous system and gut, and which can relieve pain when they are activated by opioids, which may include naturally occurring molecules that are produced by the body, as well as those that are taken as drugs. While there are several types of opioid receptors, the majority of opioid medications like oxycodone and morphine act on the mu opioid receptor. However, such drugs have significant side effects, including constipation and difficulty breathing. They are also addictive and their effectiveness diminishes over time, which means that people may require ever-increasing doses to manage their pain, leading to increased side effects and the risk of overdose.

In their newly reported study, Bunnett and colleagues focused on the delta opioid receptor (DOPr), which also inhibits pain when activated. Using biopsies from the colons of humans and mice with uncreative colitis, an inflammatory bowel disease, the researchers discovered that the delta opioid receptor provides a built-in mechanism to relieve inflammatory pain. The inflammatory cells from the colon were found to release their own opioids, which activated the delta opioid receptor and blocked the activity of neurons in the gut that transmitted painful signals.

To directly target the delta opioid receptor, the researchers encapsulated a painkiller called DADLE—which binds to the delta opioid receptor—inside nanoparticles. They then coated the nanoparticles with the same painkiller, which steered the nanoparticles specifically to nerve cells that control pain and away from other cell types, avoiding side effects. “Incorporating drugs into nanoparticles can enhance the stability and delivery of drugs, improving their effectiveness and often requiring smaller doses—and smaller, more targeted doses lower the risk of drugs causing unwanted side effects,” said Bunnett.

The researchers learned that the delta opioid receptor doesn’t just signal at the plasma membrane, as previously thought, but also signals from a compartment within the cell called the endosome. Their experiments showed that after binding to the receptors of nerve cells, the nanoparticles entered the cells to reach the endosome and then slowly released the painkiller to activate the delta opioid receptor. “Nanoparticles activated DOPr at the plasma membrane, were preferentially endocytosed by DOPr-expressing cells, and were delivered to DOPr-positive early endosomes,” the authors noted.

The studies indicated that in the endosome, receptors signal for prolonged periods, suggesting that delta opioid receptors can inhibit pain for longer stretches. The results found a sustained decrease in excitability (a measurement of pain) when the delta opioid receptors were activated in the inflammatory cells studied. This resulted in long-lasting receptor activation, suggesting a sustained ability to inhibit inflammatory pain. “Nanoparticles caused a long-lasting activation of DOPr in endosomes, which provided sustained inhibition of nociceptor excitability and relief from inflammatory pain,” the researchers noted. They concluded that their findings support the notion that DOPr in endosomes represents a key component of an endogenous mechanism of pain control. “The realization that GPCRs can signal from endosomes to mediate pain has revealed endosomal GPCRs as a viable therapeutic target.”

Bunnett added, “Our findings demonstrate that not only are delta opioid receptors in endosomes a built-in mechanism for pain control, but also a viable therapeutic target for relief from chronic inflammatory pain.” A previous study by Bunnett and colleagues used nanoparticles to deliver a drug that blocked a different type of receptor to relieve pain, while the newly reported study in PNAS focused on delivering a drug to activate the delta opioid receptor. The researchers hypothesize that effective pain control will involve blocking and activating multiple pain-transmitting pathways at the same time, which may lead to encapsulating a combination of drugs inside nanoparticles.

“Our results demonstrate the feasibility of using nanoparticles to target nociceptors with consequent reductions in dose,” the authors further suggested. “Nanoparticles might allow the simultaneous delivery to endosomes of agonists or antagonists of several endosomal GPCRs involved in pain. “Since multiple GPCRs control pain transmission, the ability to target multiple receptors in pain-transmitting neurons for prolonged periods might provide effective and long-lasting antinociception.”

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