The Whitaker Foundation: 2002 Annual Report -- Khalsa: Perception of Pain

Perception of Pain

The French author and poet Victor Hugo once wrote, "Pain is as diverse as man." Few people know that as well as Partap Khalsa.

After studying the origins of pain for more than a decade, Khalsa knows that pain can be just as elusive as it is diverse.

“It’s pain that most often drives a patient to seek treatment,” says Khalsa, an assistant professor in the Biomedical Engineering Department at the State University of New York at Stony Brook.

“Sometimes the pain is the hardest thing to cure.” He hopes that what he learns in his search to understand the underlying mechanisms of how and why we feel pain can lead to safer, more effective treatments.

Interestingly, Khalsa’s hunt has led him not to the brain, the end point of all our perceptions, but to the peripheral nerves, specifically mechanoreceptors and mechano-nociceptors, two distinct types of neurons on the front lines of our sense of touch and pain.

Mechanoreceptors are most active during normal touching and feeling: shaking hands, dialing a phone or scratching an itch.

But when the level of physical distortion of our skin gets too high, like with a pinch or a slap to the face, the mechanical stimulus becomes too much for the mechanoreceptors to handle.

As they shut down, the “tougher” mechano-nociceptors kick in, telling us we are in pain. Other sensory pioneers before Khalsa determined that a single touch typically invokes in our skin hundreds of mechanoreceptors, or a “population” of neurons.

Each neuron in the population creates a unique and separate signal—some signals tell us what is touching us, some tell us how hard it’s touching us, etc.—and sends the signal on parallel pathways through the spinal cord to the brain.

The presumption has been that some part of our brain sorts out and computes all those different signals into a neural code, a complete picture of what’s happening at the place we are being touched.

This same process, it was also presumed, occurred when a touch becomes painful; each mechano-nociceptor creates a slightly different signal describing to our brain what the pain is, where it is, and how much it hurts.

In getting an accurate picture of the pain, our brain would act like a police sketch artist trying to form an accurate picture of someone he’s never seen using only descriptions from many different people.

Khalsa thought that a simpler and more efficient process might be at work. What if a more complete code was already embedded in the response of a population of mechano-nociceptors?

In other words, what if the population together supplied our sketch artist brain with a photo of the pain instead of merely a description from each neuron?

With support from the foundation, he recorded the neural signals from a population of mechano-nociceptors in patches of autopsied rat skin while deftly pinching them between small, flat cylinders.

He found that the signals from the neurons did, in fact, possess an identifiable code with information about the perpetrating pinch: the magnitude, the direction, the location, and even something about the shape of the object doing the pinching.

This meant that “the task of the brain is much simpler, which was unknown prior to this work,” he says. It enables your brain to know what’s happening at your hand without doing any complex computations on the pain signals themselves.

“All the central nervous system has to do is reliably transmit the code,” he says. “It greatly simplifies the whole process.”

This discovery spurred him on. He needed to uncover how the neurons encoded the mechanical stimulus. The foundation awarded him transitional research funding to find out.

Khalsa already knew that many types of cells use integrins, proteins that sit across a cell membrane, to help the cell connect and communicate with the extracellular matrix. In skin, this matrix is composed primarily of collagen, another type of protein that makes up most of the body’s connective tissue, such as tendons and cartilage.

He found that mechanoreceptors and mechano-nociceptors in skin express a specific type of integrin, called integrin a2b1, the primary receptor for the specific type of collagen found in skin.

In a study currently under review, Khalsa found that applying antibodies that block the integrin’s function or peptides that compete with the extracellular matrix to bind to the integrin virtually eliminated the neural responses of both the mechanoreceptors and the mechano-nociceptors. Their pain code disappeared.

Washing out the antibodies in many cases partially restored the neurons’ performance.

“That was strong evidence that this integrin functions as part of the signal transducing mechanism,” says Khalsa.

This new information could help develop topical drugs that would target the specific integrin receptor and turn the function of some of the neurons down or off. Instead of using powerful drugs that affect the whole body and may have side effects, “it becomes a way to treat pain directly at the receptor level,” says Khalsa.

“Anytime you can figure out the underlying mechanisms, you can better target drugs or other therapies.”