Waist pain: identification of a protein associated with pain sensitivity

Summary: The Kif2a protein acts as a “gardener” for sensory neurons, regulating the growth of their axons. This pruning process is crucial for managing pain sensitivity. The absence of Kif2a in genetically modified mice led to increased axon density and increased sensitivity to pain over time. However, a compensatory mechanism reduces long-term pain sensitivity, providing potential insights for chronic pain management.

Highlights:

1. The Kif2a protein regulates axon growth in sensory neurons, thereby affecting pain sensitivity.
2. Lack of Kif2a results in increased axonal density and increased sensitivity to pain.
3. A compensatory mechanism eventually reduces pain sensitivity over time.

Source: Weizmann Institute of Science

Like the tops of trees reaching high into the sky to detect sunlight, our sensory neurons, whose role is to collect information about what is happening in and around the body, develop long, complex extensions called axons. .

These extensions extend throughout the body, transmitting various sensations in response to different stimuli. But who is the constant gardener who ensures that these extensions do not become wild over time?

In research published in Cell ReportsProfessor Avraham Yaron and his team from the Departments of Biomolecular Sciences and Molecular Neuroscience at the Weizmann Institute of Science have discovered a regulatory protein responsible for grooming nerve endings.

The study results, which shed light on the mechanisms that regulate our sensitivity to pain, could pave the way for the development of new methods for managing chronic pain.

The cell bodies of sensory neurons are implanted along the spine and, to do their job well, each of them develops an axon which divides in two during its creation: one branch grows towards the central nervous system, while others extend to various parts of the body.

These axons can be incredibly long; the longest of these extends from the base of the spine to the toes. When they reach the outer layers of the skin, they further divide into complex “treetops” that monitor heat, pain, touch and other stimuli.

In a 2013 study, Yaron's research group discovered that one of the cellular skeleton regulatory proteins, known as Kif2a, is necessary for pruning axons during nervous system development in mouse embryos, and that the absence of this protein creates an excess of axons in embryonic skin tissue.

In the new study, a team led by student Swagata Dey looked at what happens in adult mice. The researchers first faced a major challenge: mice cannot survive without the gene that codes for this regulatory protein. The scientists therefore had to genetically engineer a mouse in which the Kif2a gene is inhibited only in sensory neurons.

Using these genetically modified mice, the researchers discovered that the Kif2a protein continues to act like a gardener even after birth, and they showed that its absence causes the growth of “weeds”: each parent axon divides into several branches girls.

Researchers identified a slight increase in axon density in the skin of one-month-old mice lacking the gene encoding Kif2a; after three months the situation deteriorated.

The scientists concluded that the protein's activity plays an important role in sensory neurons throughout life and that the consequences of its absence become increasingly evident with age.

But does the absence of protein affect sensitivity to stimuli and pain? “During the first month after birth, the mice did not reveal any hypersensitivity to stimuli in the different experiments we conducted, despite the minor increase in the density of sensory axons in their skin,” explains Yaron.

“However, after three months, they showed hypersensitivity to pain and heat, and the intensity of their response to these stimuli increased, as did the duration of this response, while sensitivity to touch remained unchanged .”

To examine whether this hypersensitivity to pain was linked to structural change in axon terminals, Dey and his colleagues joined forces with researchers at the Hebrew University of Jerusalem, Prof. Alexander Binshtok and Dr. Omer Barkai, a student researcher in his lab, who developed a computer model mimicking the relationships between structural changes and nerve activity.

The model suggests that changes in the structure of axon terminals in mutant mice could explain both the more intense response to stimuli and the longer duration of this response.

Pain now, relief later

To validate their findings, the researchers genetically modified mice in which the regulatory protein was absent only in sensory neurons that express a receptor known to be involved in pain detection: the capsaicin receptor, the same compound that gives its chili heat.

When these neurons were activated, the mice exhibited hypersensitivity and behaved in a manner indicating an increased level of pain.

But the most surprising discovery took place six months after birth: although the density of axonal terminals remained high, the hypersensitivity to pain disappeared. “Most of the researchers we consulted didn't understand why we were looking at the mice again after six months,” says Yaron.

“Ultimately, however, this repeated examination revealed that over time, the body activates a clever compensatory mechanism, designed to curb overly exuberant axon terminals in the skin by reducing their sensitivity.”

To understand how this compensatory mechanism works, researchers sequenced messenger RNA molecules from the sensory neurons of mice at different ages and mapped changes in the expression levels of various genes. They found that when the mice reached six months of age, there was a decline in the expression of several proteins that play a key role in transmitting the sensation of pain.

Using the computer model, they showed that these changes in expression levels are enough to compensate for the hypersensitivity caused by excess axon terminals.

“Even if silencing the regulatory protein results in an increase in pain sensitivity in the short term, it may well be that, through the compensatory mechanism, we can achieve a decrease in this sensitivity in the long term,” says Yaron.

“What we discovered is a type of 'exposure therapy,' in which prolonged exposure to pain leads to desensitization to the pain-causing stimulus. A better understanding of this compensatory mechanism could facilitate future studies aimed at providing relief to people suffering from chronic pain.

Dr. Irena Gokhman, Sapir Suissa and Dr. Andrew Kovalenko from Weizmann's Departments of Biomolecular Sciences and Molecular Neuroscience also participated in the study; Dr. Rebecca Haffner-Krausz of the Weizmann Veterinary Resources Department; and Dr. Noa Wigoda, Dr. Ester Feldmesser and Dr. Shifra Ben-Dor of Weizmann's Life Sciences Core Facilities Department.

About this news from research on pain, genetics and neuroscience

Author: Abraham Yaron
Source: Weizmann Institute of Science
Contact: Avraham Yaron – Weizmann Institute of Science
Picture: Image is credited to Neuroscience News

Original research: Free access.
“Kinesin family member 2A triggers nociception” by Avraham Yaron et al. Cell Reports

Abstract

A member of the Kinesin 2A family triggers nociception

Strong points

• Loss of Kif2a in sensory neurons causes hyperinnervation and hypernociception
• Modeling predicts that aberrant innervation is sufficient to increase sensitivity
• Kif2a deficiency triggers a late homeostatic transcriptional response
• This response correlates with resolution of pain hypersensitivity

Summary

Nociceptive axons undergo remodeling as they innervate their targets during development and in response to environmental insults and pathological conditions. How is nociceptive morphogenesis regulated?

Here we show that the microtubule destabilizer kinesin family member 2A (Kif2a) is a key regulator of nociceptive terminal structures and pain sensitivity.

Ablation of Kif2a in sensory neurons causes hyperinnervation and hypersensitivity to noxious stimuli in young adult mice, whereas touch sensitivity and proprioception remain unchanged. Computer modeling predicts that structural remodeling is sufficient to explain the phenotypes.

Furthermore, Kif2a deficiency triggers a transcriptional response including sustained upregulation of injury-related genes and homeostatic downregulation of highly specific channels and receptors in late stages.

The latter effect can be predicted to relieve hyperexcitability of nociceptive neurons, despite persistent morphological aberrations, and is indeed correlated with resolution of pain hypersensitivity.

Overall, we reveal a critical control node defining the nociceptive terminal structure, which regulates nociception.