The Delta Opioid Receptor – A Promising Drug Target for Inflammatory Pain Relief?

A research team has used nanoparticle drug delivery to target “DADLE” – a synthetic opioid peptide – to the delta opioid receptor. This approach could provide sustained relief from chronic inflammatory pain whilst causing fewer side effects, compared to other pain-relieving medications such as opioids. The study, published in the journal Proceedings of the National Academy of Sciences*, was conducted using cellular models of inflammatory bowel disease.

Opioids, receptors and pain relief

Opioid receptors are a specific type of G protein-coupled receptor (GPCR) that are primarily located in the central nervous system and gut. They can be activated by endogenously produced opioids as well as by exogenously administered opioid medications. Whilst opioid medications possess pain-relieving properties, they are highly addictive, and in recent years there has been mounting concern about their misuse. Whilst several different types of opioid receptor exist, most opioid drugs elicit their effects – including adverse effects – via the mu opioid receptor.

“The fundamental problem is that opioids not only inhibit pain, they also inhibit respiration – they stop your breathing. They also cause severe constipation. The difficulty is that with continued use, the effectiveness of opioids for treating pain diminishes and they also cause addiction,” explained Bunnett, in a recent interview with Technology Networks.

“However, the effects on respiratory depression and constipation remain. As a result, patients take higher and higher doses because they're addicted and because a larger dose is needed to treat the pain. At a high enough dose, opioids can stop your breathing and kill you,” 

Preventing pain – a different approach

In this study, the researchers homed in on a different opioid receptor – the delta opioid receptor – which, when activated, can inhibit pain. The researchers used biopsy samples obtained from the colons of patients and mice with ulcerative colitis to investigate the potential of this receptor as a therapeutic target for inflammatory pain. They found that the inflammatory cells within the colon trigger the release of opioids, which activate the delta opioid receptor. In its activated state, the receptor can inhibit neuronal activity in the gut, preventing the transmission of pain signals.

The study also revealed that the delta opioid receptors signal from within endosomes – membrane-bound compartments within the cell – as well as the cell surface. Until now, G protein-coupled receptors, such as the delta opioid receptor, were considered to predominantly function at the cell surface. Within the endosome, the receptors can signal for prolonged periods of time, meaning that when they are activated, they can relieve pain for longer.

"We've shown that the delta opioid receptor has a built-in mechanism of pain control and inhibits pain by signaling within an endosome. With this new knowledge, we thought the receptor would be a promising target for the treatment of chronic inflammatory pain," said Bunnett in a recent press release.

Delivering DADLE to the delta opioid receptor

To target the delta opioid receptor, the researchers exploited the delta opioid receptor agonist DADLE – incorporating DADLE into the core and liposome shell of the nanoparticle.

“If you have a conventional drug and you give it to a patient, the drug could distribute all over the body. In contrast, nanoparticles can be designed to deliver the drug to a specific cell or neuron type,” – Nigel Bunnett, Ph.D., New York University College of Dentistry.

The DADLE bound to the surface of the nanoparticle helps “guide” the nanoparticle, specifically targeting it to nerve cells that present the delta opioid receptor on their membrane. Shell-bound DADLE associates with the membrane bound receptor, resulting in endocytosis by the delta opioid receptor-expressing target cells. Once inside the cell, the nanoparticle is delivered to delta opioid receptor-positive early endosomes. The acidic and reducing environment within the endosome initiates the release of DADLE from the nanoparticle core. Unbound DADLE is then able to associate with the endosomal delta opioid receptor to prevent neuronal excitability and pain signaling.

"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.

Summary 

These findings demonstrate that endosomal delta opioid receptors are a key element in the underlying mechanism for pain control, and consequently, show promise as a therapeutic target for chronic inflammatory pain.

Related research

Previous research conducted by Bunnett and colleagues used nanoparticles to deliver a drug called aprepitant to substance P (SP) neurokinin 1 receptors (NK1), which are also implicated in pain signaling.

From their research so far, the team believes that, to successfully manage pain, multiple pain-transmitting pathways would need to be modulated simultaneously and precisely.

“Because pain is so important, there are many redundant pathways that transmit pain and many redundant messages. Because of this, you need to be able to antagonize more than one at the same time – you can do that with nanoparticles. If you have a conventional drug and you give it to a patient, the drug could distribute all over the body,” said Bunnett in a recent interview.

References

*Jimenez-Vargasa, et al. (2020). Endosomal signaling of delta opioid receptors is an endogenous mechanism and therapeutic target for relief from inflammatory pain. PNAS. DOI: 10.1073/pnas.2000500117/-/DCSupplemental.

Ramírez-García, et al. (2019). A pH-responsive nanoparticle targets the neurokinin 1 receptor in endosomes to prevent chronic pain. Nat. Nanotechnol. DOI: https://doi.org/10.1038/s41565-019-0568-x