Scientists from Columbia University Medical Center may have discovered a new way of treating chronic pain – a powerful analgesic dubbed N60 that leads to neither tolerance nor dependence. 

We've long known that pain is a perception in the brain triggered by signals sent along nerves in the peripheral nervous system.  But exactly how that process works has been difficult to unravel. 

Chronic Pain's On/Off Switch Discovered

Then four years ago, Dr. Ying-Ju Sung, Assistant Professor of Clinical Pathology at Columbia, led a research team that discovered the pathway that neurons use to inform the brain of an injury.  Left uncontrolled, this pathway persistently alters the electrical properties of the neuron, ultimately causing chronic pain.

The Columbia team found that a specific protein in the pathway, called PKG, acts like an on/off switch. As long as the switch is on, the pathway is activated and the brain continues to receive signals that are perceived as pain, even after an injury has healed.

Developing N60

Following up on Dr. Sung's discovery and realizing that PKG would be an excellent target for drug development, a research team, led by Dr. Richard Ambron, Professor of Pathology & Cell Biology at Columbia, began working to develop what would become N60.

Turning off all pain signals would be extremely dangerous since pain is designed to warn us when something is causing us injury.  But since PKG is specific for biochemical signaling involved with chronic pain, shutting off PKG will not prevent a patient from feeling fresh injuries. It also operates in the peripheral nervous system, rather than the central nervous system. This means that a drug that blocks PKG does not have to cross the blood-brain barrier, a formidable challenge in drug development.

Once they understood the function of PKG, the team began to work with medicinal chemists in Dr. Donald Landry’s group, also at Columbia, to design a compound that would block PKG from sending signals to the brain. After considerable effort, they discovered N60, which laboratory tests have shown to be a powerful and very selective PKG blocker.

“We found in PKG a well-defined target that has been implicated in several types of pain that are particularly refractory to treatment,” Ambron said. “Now, we have an excellent inhibitor of the target which imparts no evident toxic or behavioral side effects and which also alleviates chronic pain in animal models of nerve injury and inflammation. N60 is non-addictive and non-sedative, and a single dose attenuates pain for at least 24 hours.”

“We believe a compound like N60 has significant potential to transform the way chronic pain is treated,” Ambron said. “If it works the way we think it can, we may be able to alleviate chronic pain in some of its most intractable forms without the risk of addiction, a problem that conveys a whole set of economic and social issues for our country and society at-large.”