Study identifies the spinoparabrachial pathway for mechanical itch

By Dr. Priyom Bose, Ph.D.Reviewed by Lily Ramsey, LLMApr 7 2023

Recently, in a study posted in the Neurons Journal,  scientists at the Salk Institute identified a brain pathway that is associated with the mechanical sensation of itching. It is distinctly different from neural pathways linked to chemical sensation.

Study: Identification of an essential spinoparabrachial pathway for mechanical itch. Image Credit: Photo-Vista.de/Shutterstock.com

Background

Itch is a protective function used by animals to defend themselves from parasitic attacks. For instance, when a mosquito lands on the arm, its presence is sensed on the skin, which is scratched immediately to remove it.

The itch can be mechanical (e.g., crawling of insects) or chemical (e.g., exposure to an irritant, such as mosquito saliva). Both forms of itch induce a similar response, i.e., scratching. However, the difference in the two cellular mechanisms that drive this response is unknown.

Introduction

As stated above, the itch is a protective function that manifests due to light, harsh or pruritogenic chemicals. Recent studies have shown that mechanical and chemical stimuli trigger molecular pathways in the periphery and spinal cord.

Mechanical itch is associated with spinal neurons and is characterized by the expression of neuropeptide Y (NPY) receptor Y1 and Ucn3::Cre. Further, the chemical itch is based on spinal neurons expressing the gastrin-releasing peptide receptor (Grpr). 

Scratching can be induced by a spinal reflex pathway, which is mediated by supraspinal pathways. Chemical itch stimuli activate brain regions connected with affective responses to aversive stimuli, threat evaluation, and induction of protective motor behaviors.

Pruritogens have been associated with the activation of anxiety-like behaviors in mice through the induction of itch-responsive neurons in the amygdala.

The ascending spinal pathways that transfer itch stimuli from the spinal cord to supraspinal centers remain unclear. Furthermore, no studies elucidate whether mechanical and chemical itch is transmitted through spinofugal neurons or a specific neuron population that shares the same cellular targets supraspinally.

It is also important to investigate whether parabrachial nucleus (PBN) and spinoparabrachial (SPB) pathways are associated with transmitting mechanical itch signals.

About the Study

The mechanical and chemical itch was found to be transmitted as distinct modalities along the neuraxis to the PBN, where unique subsets of FoxP2⁺ neurons employ a common motor program in response to the mechanical and chemical itch pathways. This results in chronic pathological itch.

The current study identified an important SPB neuron population for mechanical itch transmission from the spinal cord to the PBN in mice.

The mechanical itch-scratch motor program was found to be regulated at PBN levels, which implies that the mechanical itch SPB-PBN pathway delegates a noxious valence to an otherwise-innocuous tactile stimulus.

According to Martyn Goulding, professor and holder of the Frederick W. and Joanna J. Mitchell Chair at the Salk Institute…

…This study provides fundamental insights into how these two forms of itch are encoded by the brain and opens up new avenues for therapeutic interventions for patients that suffer from a range of chronic itch conditions, including ectopic dermatitis and psoriasis”.

This study builds on previous research conducted in Goulding’s lab, where neurons in the spinal cord, which regulate mechanical but not chemical itch, were identified.

Scientists from Goulding’s lab collaborated with Sung Hun, assistant professor, and holder of the Pioneer Fund Developmental Chair, for this study.

Dr. Hun has previously discovered a small region in the brain that acts as an alarm center, i.e., this region is associated with instant response to external and internal threat signals.

The researchers combined a genetic approach with wearable miniaturized microscopes to enable visualization of itch-induced activity in single neurons of mice.

It was observed that mechanical itch could be activated by removing an inhibitory pathway linked to itching.

All changes in the brainstem were studied, and how different cells responded to either mechanical or chemical itch was analyzed.

Consequently, a chemical itch pathway and a mechanical itch pathway were determined. In addition, molecules that play a crucial role in these pathways were identified.

Based on the experimental findings, it was inferred that the mechanical itch is transferred from the spinal cord to the PBN along a Calcrl⁺ /Lbx1⁺ SPB pathway.

The SPB pathway contains a subset of the Gpr83⁺ neurons, which do not express Tacr1. In contrast, the Tacr1+ SPB neurons are recruited during chemical itch stimuli, which are involved in the selective transmission of chemicals and chronic itch information.

The current discovery of the SPB neurons linked to the transmission of the chemical itch is Tacr1⁺ /Gpr83⁺, which does not imply that the Tacr1+ population does not play any role in particular chemical stimuli.

Also, the FoxP2^PBN neurons could connect the spinal reflex circuitry and the supraspinal circuitry for the itch. The transmission of external sensory information could be transformed internally and generate protective scratching behavior.

Conclusion

The current study identified that two pathways function together to drive chronic itch. Future research should investigate the region in the brain where the identified pathways converged and identify the region that receives signals and determines to scratch an itch.

Additionally, the underlying mechanism of the spinal cord and brainstem that differentiates between itch and pain must be elucidated.