A recent breakthrough in pain signaling could lead to improved treatments for chronic pain.

Researchers at Linköping University, Sweden, have made a groundbreaking discovery in understanding how pain signals are transmitted in the nervous system. Their work focuses on calcium channels, proteins crucial for processing pain signals, and identifies a specific mechanism that could lead to the development of more effective and safer chronic pain medications.

Pain signals travel through the nervous system primarily as electrical impulses, which are converted into biochemical signals at key points. These signals are mediated by calcium ions, released when voltage-sensitive calcium channels open in response to electrical stimuli. These channels play a pivotal role in transmitting pain signals between nerve cells.

The study centers on a particular calcium channel subtype, CaV2.2, located at the ends of sensory nerve cells. CaV2.2 channels are hyperactive during chronic pain, and drugs that inhibit their activity can reduce pain signal transmission to the brain. However, existing treatments face significant limitations:

• Complete blockers of CaV2.2 have severe side effects, requiring delivery directly into the spinal fluid.

• Gabapentin, which reduces the number of CaV2.2 channels, is not highly effective for chronic pain.

• Opioids, such as morphine, inhibit CaV2.2 effectively but carry risks of addiction and dependency.

The researchers explored how opioids suppress CaV2.2 activity. Opioids release G proteins, which bind to calcium channels, making them less responsive to electrical signals. Using light-emitting molecules, the team tracked the movement of voltage sensors in the CaV2.2 channel and discovered that G proteins specifically affect certain voltage sensors, making the channel less likely to open in response to nerve impulses.

This precise understanding of how G proteins interact with calcium channels opens the door to designing next-generation pain medications. Instead of completely blocking the channel, future drugs could fine-tune its activity, mimicking the pain-relief effects of opioids without their addictive properties or severe side effects.

“Our findings highlight a specific target within the calcium channel that could revolutionize pain management,” says Antonios Pantazis, associate professor at Linköping University and lead author of the study published in Science Advances.

This research, supported by the Knut and Alice Wallenberg Foundation, the Swedish Brain Foundation, the Swedish Research Council, and others, paves the way for developing advanced therapies to relieve chronic pain more effectively and safely.

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