A study led by Columbia University Medical Center (CUMC) has shown that chronic pain may occur when pain receptors migrate from the nerve cell’s surface to the cell’s inner chambers, out of the reach of current pain medications. The discovery, in rodents, may lead to the development of a new class of medications for chronic pain that is more potent and less prone to side effects than currently available pain treatments.
The study was published online today in the journal Science Translational Medicine.
An estimated 20 percent of people have chronic pain at some point. Currently available therapies for chronic pain include opioids and nonsteroidal anti-inflammatory drugs (NSAIDs). Both have drawbacks: opioids are addictive and can cause constipation and respiratory distress, while frequent use of NSAIDs can cause stomach ulcers and kidney damage.
“Opioids and NSAIDs do not work for everyone and have unacceptable side effects, particularly when used over a long period of time,” said Nigel Bunnett, PhD, professor of surgery and pharmacology at CUMC. “However, previous efforts to develop more effective analgesics have been stalled by our limited understanding of the mechanisms that allow nerves to sense and transmit pain signals.”
Some pain medications work by targeting G protein-coupled receptors (GPCRs) on the cell surface. GPCRs are implicated in nearly all biological processes, including our brain’s ability to sense and transmit pain signals. Activation of opioid receptors-;one type of GPCR-;blocks pain.
Another type, the neurokinin 1 receptor (NK1R), causes pain and inflammation when activated. However, most clinical trials of compounds targeting NK1R have been unsuccessful.
In the current series of experiments, Dr. Bunnett and colleagues discovered that NK1R, when stimulated by pain, quickly moves from the cell surface to endosomes-;intracellular compartments-;within nerve cells. Once inside the endosomal network, NK1R continues to function for a prolonged period, causing pain and inflammation.
Additional experiments revealed that attaching a lipid (fat molecule) that can cross the cell membrane to compounds that block NK1R provided potent, durable pain relief in rodents.