Boosting the Body’s Natural Painkilling Power

Our nervous system’s pain receptors relay many messages from insults like wounds, heart attack, burns, and food poisoning. But some pain receptors actually help our bodies fend off pain. An HHMI early career scientist may have found a way to boost our innate painkilling power, which could help reduce the need for dangerous narcotic painkillers.

Xinzhong Dong has spent most of his career studying a family of 50 or so receptors called Mas-related gene, or Mrg, receptors, found exclusively in nerve cells involved in sensory perception. Over the last decade, the Johns Hopkins University School of Medicine neuroscientist has identified many of the genes responsible for the Mrg family and elucidated the functions of several of the receptors. In a paper published September 7, 2010, in the Proceedings of the National Academy of Sciences, he reported that a subgroup of those receptors may play a key role in reducing pain perception during times of acute pain. According to Dong, the receptor may act much like the body’s opioid receptors; his laboratory is now studying targeted Mrg therapies that could help relieve chronic pain.

Dong came upon the Mrg receptor family as a postdoctoral fellow in the California Institute of Technology lab of HHMI investigator David Anderson. He initially searched for the genes underlying receptors found only in sensory nerves, theorizing that identifying the genes would help explain the receptors’ functional roles. That led him to the poorly understood Mrg class of receptors. Eventually he identified the genes for the entire family. He and Anderson also showed that certain Mrg receptors provoke the itch sensation (see HHMI Bulletin, May 2010). Dong identified the mouse equivalent to the human gene for an Mrg receptor involved in pain sensation. He then engineered a mouse pain model to study how the Mrg receptor functions in humans.

First Dong’s group removed the human-equivalent Mrg in mice. Much to his surprise, the animals exhibited greatly heightened pain sensitivity. Then Dong’s team did the opposite experiment. Instead of deleting the Mrg gene, they added a small protein called BAM8-22, which stimulates Mrg activity. The treated mice appeared to sense no pain, even after exposure to high heat or traumatic injury. The study also showed that increasing the Mrg receptor’s action stopped hypersensitivity in mouse models for chronic pain disorders.

When Dong’s group removed the human-equivalent Mrg gene, BAM8-22 no longer worked to reduce pain. So the Mrg receptor was the key to the protein’s pain reduction ability. “Our findings make us think that Mrg and opioid receptors represent two parallel inhibitory pathways to block chronic pain,” Dong says. Unlike opioid receptors, though, the Mrg receptor is found only in sensory neurons. An analgesic agent developed to target only the specific pain-reducing Mrg receptors would, thus, be unlikely to cause problems in the central nervous system, such as those seen with opiates. “You could potentially reduce the use of morphine and solve many of the problems that [come with] it,” Dong says.

-- Marc Wortman

HHMI Bulletin, February 2012

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