An international team of researchers have used nanoparticles to deliver a drug into a specific compartment of nerve cells, resulting in significantly greater pain relief in animal models, compared with conventional therapies.
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The drug had previously failed to be effective in clinical trials aiming to treat pain with non-opioid therapies.
"We have taken a drug--an FDA-approved anti-vomiting medication--and using a novel delivery method, improved its efficacy and duration of action in animal models of inflammatory pain and neuropathic pain," says senior author Nigel Bunnett, chair of the Department of Basic Science and Craniofacial Biology at New York University (NYU) College of Dentistry.
"The discovery that nanoparticle encapsulation enhances and prolongs pain relief in laboratory animals provides opportunities for developing much-needed non-opioid therapies for pain."
The opioid crisis
The use of opioids for pain relief is associated with devastating consequences including misuse, addiction, and overdose. The number of newborns experiencing withdrawal syndrome due to maternal use and misuse of opioids during pregnancy is also on the increase.
Furthermore, the effectiveness of opioids decreases over time meaning that higher doses are needed to relieve pain, and side effects such as suppressed breathing and constipation only worsen the more the dose is increased.
In the United States, more than 130 people overdose as a result of opioid misuse every day. Misuse and addiction represent a serious national health crisis that affects the public and the economy. Estimates from the Centers for Disease Control and Prevention indicate that prescription opioid misuse costs a total of $78.5 billion a year, including the cost of healthcare, treating addiction, loss of productivity and the involvement of criminal justice.
"There are many reasons that opioids are not ideal for treating pain. Given the ongoing opioid crisis, which has taken hundreds of thousands of lives, we need safer, more effective alternatives," says Bunnett.
Research into G protein-coupled receptors
Bunnett and colleagues are involved in researching a family of proteins called G protein-coupled receptors, a common target of clinically used drugs.
They had thought that these receptors perform their function at the surface of neurons, but they have now discovered that once activated, the receptors migrate to a specific compartment of the nerve cell called the endosome.
"The sustained activity of receptors in endosomes drives pain," explains Bunnett.
For the current study, Bunnett and colleagues from Columbia University, Monash University and the University of Santiago in Chile examined a G protein-coupled receptor called the neurokinin 1 receptor. Major pharmaceutical companies had planned to develop inhibitors of neurokinin receptors for the treatment of chronic pain, but Bunnett says “things fell apart” during clinical trials.
The neurokinin receptor is the poster child for failures in drug discovery to treat pain,"
Senior author Nigel Bunnett, Chair of the Department of Basic Science and Craniofacial Biology at New York University (NYU) College of Dentistry
Bunnett and colleagues suspected that the reason the drugs failed is that they were designed to block receptors at the surface of nerve cells rather than within the endosome.
Using nanoparticles to target the endosome for drug delivery
As reported in the journal Nature Nanotechnology, the researchers have now used nanoparticles as vesicles to deliver a neurokinin receptor blocker into the endosome of nerve cells. The drug is FDA-approved for the treatment of nausea and vomiting but previously failed when tested as a pain relief agent in clinical trials.
Nanoparticles containing the inhibitor were designed to enter neurons involved in the transmission of pain signals and release it into endosomes containing the neurokinin receptor.
“It became highly effective as a pain treatment”
By delivering the receptor blocker in this way, the researchers found they could treat pain more successfully in mice and rats, compared with conventional therapies. Pain relief was greater and lasted for longer than when standard therapies, including opioids, were used.
In addition, nanoparticle delivery reduced the dose of medication required, which could be an advantage in terms of avoiding adverse side effects.
"The process we've developed is essentially like giving a drug infusion into the endosome of the cell," says Bunnett. "By delivering a previously ineffective pain drug to the right compartment within the cell, it became highly effective as a pain treatment."
The researchers are now trying to use the nanoparticles to deliver non-opioid pain medication exclusively to nerve cells that sense pain, which would lower the dosage of drug needed.
They are also looking at encapsulating multiple pain receptor blockers into the nanoparticles, which could result in even better efficacy. Bunnett and team acknowledge that further studies are needed before this drug-delivery method can be tested in humans.
Nanoparticle drug delivery provides pain relief and more effective opioid alternative in animal study. Eurekalert. Available at: https://www.eurekalert.org/pub_releases/2019-11/nyu-ndd103119.php