Study, in rodents, may lead to development of new medications for chronic pain that last longer and have fewer side effects.
A study led by Columbia University Medical Center (CUMC) shows 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 in the journal Science Translational Medicine.

“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 Columbia. “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 that can cross the cell membrane to compounds that block NK1R provided potent, durable pain relief in rodents.

“From these experiments, we have demonstrated that designing NK1R inhibitors that are capable of reaching the endosomal network within nerve cells may provide much longer–lasting pain relief than currently available analgesics,” said Dr. Bunnett. “More than a third of all currently available drugs act on GPCRs in some way. We think that modification of many existing compounds, as we did with NK1R inhibitors, may have the potential to enhance the effectiveness of many different classes of medications.”

The study is titled, “Neurokinin 1 Receptor Signaling in Endosomes Mediates Sustained Nociception and is a Viable Therapeutic Target for Prolonged Pain Relief.”