The National Institute of Dental and Craniofacial Research has awarded New York University (NYU) College of Dentistry researchers Nigel Bunnett, PhD, and Brian Schmidt, DDS, MD, PhD, a $3.9 million grant to study the targeting of endosomal receptors to treat chronic pain.
The five year grant will support the researchers’ work, which aims to ultimately yield improved pain management without the need for opioids.
The grant is funded through the National Institutes of Health Helping to End Addiction Long-Term Initiative (NIH HEAL), an effort to speed scientific research that enhances pain management and offers solutions for the national opioid crisis.
Although opioids are widely used to treat chronic pain, their efficacy is limited, and their side effects often include misuse and addiction, the researchers said. Approximately 500,000 Americans have died on opioid overdose over the past two decades.
While many of these deaths are caused by opiates such as heroin, the researchers said, the cycle of addiction and death often is initiated by the use of prescription drugs that were diverted from their intended purpose.
Bunnett, who is the chair of the Department of Molecular Pathobilogy at NYU Dentistry, and Schmidt, who directs the NYU Bluestone Center for Clinical Research, have collaborated since 2009, when they were colleagues at the University of California, San Francisco.
Recently, they have jointly received three NIH grants and one grant from the Department of Defense to fund their research on pain. The current NIH HEAL grant is the first time that they have secured collaborative funding as colleagues at NYU.
Their research explores signaling mechanisms related to a family of proteins called G protein-coupled receptors (GPCRs), which control most disordered physiological processes, including pain, and are the target of a third of clinically used drugs.
While GPCRs are thought to function at the surface of the cell, they can be subsumed within cellular organelles called endosomes. Once a GCPR enters an endosome, it is called an endosomal GPCR (eGPCR), which may be a critical mediator of sustained neuronal excitability in the context of chronic pain.
Accordingly, Bunnett and Schmidt seek to validate eGPCRs as therapeutic targets for chronic inflammatory, neurpathic, and cancer pain. As part of this work, they will test the hypothesis that eGPCRs generate signals in subcellular compartments of neurons that are responsible for persistent excitation and chronic pain.
“Our hypothesis, that signaling continues after a GCPR enters an endosome, breaks with the currently accepted interpretation that this process squelches signaling,” said Bunnett. “Many GPCR-targeted drugs have failed clinical trials, but perhaps this is because drugs should be targeting eGPCRs inside the endosome instead.”
To test this hypothesis, the researchers will design nanoparticles that deliver antagonists and agonists of GPCRs into endosomes within neurons. The nanoparticles will selectively target neurons, promote GPCRs entering endosomes, and release eGPCR antagonist and agonists in the acidic environment within an endosome.
In this way, the nanoparticles will be used to experimentally probe the mechanisms by which eGPCRs generate signals that control neuronal excitation and pain. This nanoparticle delivery method will also enable the investigators to validate that eGPCRs are a viable and superior target for the treatment of chronic pain.
If their hypothesis is correct, the researchers said, eGPCRs may be suitable targets for the treatment of chronic pain, generating a pathway for new pathways without the side effects and addiction potential of opioids.
“Our aim is to lay the foundation for the development of new types of medication beyond opioids that alleviate chronic pain including inflammatory, neuropathic, and cancer pain,” said Schmidt.
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