Touch and Pain Are More Entangled Than We Thought

A new survey of the skin’s primary sensory neurons has upended previous assumptions, finding that many neurons—including those that sense pain—can detect a wider range of stimuli than previously thought.  

The new reference of sensory neurons, created by Nikhil Sharma, analyzed different types of sensory neurons—including some never described before—and their functions. 

“What this study describes is a new way to think about the neurons that are going into the skin,” Sharma says. 

Nikhil Sharma standing in his lab

Nikhil Sharma

From a light brush of the skin to a sharp jab or searing hot temperature—if you can feel it, there’s a sensory neuron in your skin that relays the information to the spinal cord and then to the brain for further processing. Neuroscientists had believed that each feeling was relayed by neurons specialized to do the job: light touch conveyed by one set of neurons, pain by another set.  

The new research shows that multiple subtypes of sensory neurons can transmit information about different degrees of touch or temperature. 

“We now have to think of pain-sensing neurons as having day jobs. They're not just sitting around waiting for you to fall and cut yourself or touch a burning stove; they're responsible for detecting stimuli that happen all the time,” he says. 

We talked to Sharma about why he undertook the work, how the findings might impact pain research, and how further research may reveal hidden connections between the nervous and immune systems. 

Why is it a surprise that sensory neurons detect more sensations than we thought? 

The reason it's a surprise is that you either feel pain or you don't; pain is very binary. And because the perception is so distinct, you might think that's how every step of the process has to work. So that's the surprise: Even though the perception is so binary, the initial detection of force at the skin is not.” 

Finding these neurons took years and an examination of more than 40,000 different neurons: What’s your overall goal? 

You can think of the primary sensory neuron as the truest reporter of facts: It’s telling you what's happening at the skin. 

And the primary sensory neuron is the first domino in the whole pathway—from skin to spinal cord to brain—that lets us perceive the world.  

Ultimately, we want to understand what does it mean to feel something. How does that happen? I think it will be hard to do that unless we know what the first domino looks like and that's why we went after this with the level of intensity we did. 

Do your findings have any implications for treating pain? 

Since it’s almost certainly the case that pain-sensing neurons have other functions, or day jobs, if you just block the pain-sensing neuron from signaling, people will lose the pain response but they’ll very likely lose responses related to normal day-to-day function. 

What did it take to identify and characterize the neurons? 

A lot of sensory neurons have been defined already. We’ve been able to label and record from them, but many others have defied classic techniques. 

We took advantage of progress in mouse genetics that allowed us to be unbiased and identify multiple distinct sensory cell types that go to the skin, as best as we can approximate. We then made dozens of different mouse lines, each labeling a different type of sensory neuron, and recorded activity in these neurons while we applied different types of touch or temperature to the skin. That allowed us to determine, in a quantitative fashion, what each type of neuron responds to.

New optical tools, variants of GFP, also allowed us to do this work. Over the past maybe five years, there have been big advances in optical reporters that let us visualize neural activity by light. So, if you just look down at the neuron, when it's more active, it's got a higher degree of fluorescence; if it's less active, it's dark. So, it was a confluence of things that made this work possible. 

Where do you go from here? 

One question is what happens at the other end of the sensory neuron. You have a neuron that goes to the skin, that's half of the neuron, the other half goes to the spinal cord. The sensory neuron is just a relay in a lot of ways; it records what's happening in the skin and then dumps it off into the spinal cord.  

Once you get to the spinal cord, all hell breaks loose. No one knows what's going on there. It's a zoo because you have all these streams of information coming in. And somehow it's got to get organized; that's where the first step of processing happens. How is the spinal cord turning these streams into something that’s meaningful? 

And I would say, there are more sensory neurons in the skin to discover. Before our study, maybe about half had been identified; now, we probably have 75% or 80%. Right now, we don't have clear cut access to the remaining 20%. Some of those missing neurons we know are tuned to vibration. We didn't find them, but we know they're there. So there are examples of neurons that exist that we haven't necessarily touched, if you will. 

Another interesting feature of sensory neurons that’s just emerging is their close connection to the immune system. There was an interesting case in a patient who developed rheumatoid arthritis, inflammation in their hands and ankles. Earlier in life, an accident had severed the sensory nerve to one of their fingers, so they couldn't feel anything in that one finger. When they developed rheumatoid arthritis later in life, every knuckle got inflamed, except the one in the damaged finger. There’s an idea that the sensory nerves cause the inflammation, or at least direct the immune system where to go. We didn’t have a way to rigorously study these neural-immune connections before, but we think we can start looking with our new mouse models and find unique relationships that we never expected to see before. That’s a new branch of investigation for us that I’m pretty excited about.