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Projects

Projects

It must be of the highest importance to perceive and react to painful stimuli instantly to avoid tissue damage. However, this is not what we teach our students. Every textbook in physiology and medicine states that the fastest conducting (Aβ) neurons in the skin exclusively signal touch, while pain is transmitted through a slower system of Aδ and C nociceptors. This raises a puzzling question: why shouldn’t reactions to painful stimuli be as rapid as possible?

Recently, we discovered a hitherto unknown class of neurons in human skin (Nagi*, Marshall*, et al. 2019, Science Adv). These high-threshold mechanoreceptors encode painful skin indentations and signal impulses as fast as touch neurons. The newly discovered class of neurons is henceforth referred to as ultrafast nociceptors (UFNs).

The newly discovered class of neurons is referred to as ultrafast nociceptors (UFNs).
The newly discovered class of neurons is referred to as ultrafast nociceptors (UFNs).

Projects

To better understand the UFN system, we are now pursuing the following aims:

1. Physiology and Molecular Makeup of UFNs

We are investigating how the nervous system creates and modulates mechanical sensations linked to the activation of UFNs. We are also examining their temperature-sensing properties by testing molecules that activate specific thermosensitive ion channels. To tease out their contribution to perception, we are utilizing rare patient groups with selective mutations that affect their ability to detect touch, temperature, or pain.

A direct comparison between UFNs and C nociceptors in responses to noxious skin indentations revealed that UFNs are much better suited to signal mechanical pain, with considerably higher discharge rates and less propensity for fatigue (Ng et al. 2024, eNeuro).

Recently, molecular profile-informed microneurography revealed two types of UFNs in humans: one uniquely expressing both the mechanotransduction channel PIEZO2 and cold-sensitive channel TRPM8 (Yu*, Nagi*, et al. 2024, Nature Neurosci, in press). Our ongoing work is focused on investigating their respective functions.

2. Role of UFNs in human nocifensive behaviors

We are investigating whether the spinally mediated withdrawal reflex to painful stimulation has an “ultrafast” component, its relationship to pain, and how the pain reflex is affected by reversible experimental block or deafferentation of thickly myelinated Aβ fibers. These questions are important for determining the role of UFNs in the protective pain reflex and for developing a modified reflex test to measure UFN function in clinical settings.

Initial observations suggest that UFNs play an important role in protective reflex responses to painful stimuli, where speed is critical (Thorell et al. 2023, Front Pain Res; Thorell et al. 2024, PLoS One). We are building on these observations by developing stimuli that preferentially target UFNs to elicit reflex responses.

3. Role of UFNs in pain hypersensitivity states

We are investigating whether UFNs develop spontaneous activity and/or “novel” responsiveness to nonpainful stimuli to which they normally do not respond using a controlled acute inflammatory model. We are also studying whether this switch is dependent on specific ion channels. These questions are important for understanding the role of UFNs in common symptoms of chronic pain, including spontaneous pain and hypersensitivity, and identifying the ion channels that UFNs rely on for these functions.

Potential for new therapeutic targets for chronic gains

These projects involve the powerful technique of microneurography combined with psychophysical measures to compare nerve function with behavioral changes. This combined strategy is implemented in both healthy individuals and rare patients with selective mutations. Further, we are developing a novel method to evoke an “ultrafast” withdrawal reflex in response to painful stimulation. These efforts aim to advance our understanding of the nociceptive/pain circuitry in humans, potentially leading to new therapeutic targets for chronic pain.