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Click the blue word to follow us Tickling is a somatic sensation that causes unpleasantness in the body
.
Acute itch acts as a defense mechanism that alerts the organism to harmful external threats, while chronic itch can cause great discomfort, ranging from skin sloughing to sleep deprivation, anxiety, and depression
.
Anatomically, the neural pathways of itch and pain are almost shared, but can cause different sensory outputs
.
One of the theories is that itch input can specifically use neurotransmitters to "talk" to downstream dorsal horn (DH) interneurons, and then travel up the spinothalamic tract to the sensory cortex of the brain, ultimately forming itch
.
MrgprA3 (Mas-related G protein-coupled receptor A3)-positive neurons are a class of itch-specific neurons in the peripheral nervous system of mice
.
MrgprA3 is specifically expressed in the dorsal root ganglia (DRG) and trigeminal ganglia (TG) of the peripheral nervous system, and is a specific receptor for the antimalarial drug chloroquine.
The side effects of chloroquine that cause itching are mainly achieved through MrgprA3
.
On January 3, 2022, Wenqin Luo of the University of Pennsylvania School of Medicine discovered that neurotransmitters derived from MrgprA3-positive sensory neurons can transmit itch information
.
Figure 1: Neurotransmitter expressed by MrgprA3-positive neurons.
The researchers were able to induce scratching in mice by light-activating MrgprA3-positive neurons in the DRG region
.
In situ hybridization experiments found that MrgprA3-positive neurons in the DRG region were enriched to express type 2 vesicular glutamate transporter (Vglut2) and neuromedin B (NMB, Figure 1).
.
Electrophysiological experiments further found that light-activated MrgprA3-positive neurons in the DRG region projecting to fibers in the DH region induced excitatory synaptic currents, which could be blocked by glutamate receptor antagonists
.
This suggests that MrgprA3-positive neurons communicate with DH neurons by releasing glutamate
.
Through genetic tool mouse-specific knockout of Vglut2 in MrgprA3-positive neurons (Vglut2-CKO mice), it was found that this knockout mouse caused an age-related glutamate release disorder: Vglut2-CKO was small before 4 months of age.
Glutamate release in mice was normal, and glutamate release decreased after 6 months of age
.
Injection of pruritogens such as histamine and chloroquine induced hypoitch in 6-month-old Vglut2-CKO mice, but did not affect mechanical pain sensitivity
.
This suggests that glutamate plays an important role in the synaptic transmission of primary itch afferents and itch behavior
.
Figure 2: Nmb receptors are mainly expressed in the DH region.
NMB is a neuropeptide with 10 amino acids, belonging to the bombesin family, and is a bombesin-related peptide
.
By constructing the NMBR-cre (Nmb receptor) tool mouse, it was found that the Nmb receptor is mainly expressed in the DH region, but not in the DRG region (Figure 2)
.
In vitro electrophysiological experiments found that Nmb-expressing neurons in the DH region could be induced to release action potentials after incubating with Nmb
.
In addition, MrgprA3-positive neurons also formed direct synaptic connections with neurons expressing Nmb receptors in the DH region
.
Specific knockout of NMB in MrgprA3-positive neurons can only reduce the itching behavior induced by chloroquine, while pharmacological knockout of NMB receptors on neurons in the DH region can reduce the itching behavior induced by chloroquine and histamine
.
This suggests that NMB/NMB receptor signaling is involved in the regulation of itching behavior
.
Overall, this paper reveals that MrgprA3-positive neurons in the dorsal root ganglia transmit itch information to medulla dorsal horn interneurons through glutamate receptors to regulate itch behavior, and NMB/NMB receptor signaling further enhances the above process
.
[References] 1.
https://doi.
org/10.
1016/j.
neuron.
2021.
12.
007 The pictures in the text are from the references
.
Acute itch acts as a defense mechanism that alerts the organism to harmful external threats, while chronic itch can cause great discomfort, ranging from skin sloughing to sleep deprivation, anxiety, and depression
.
Anatomically, the neural pathways of itch and pain are almost shared, but can cause different sensory outputs
.
One of the theories is that itch input can specifically use neurotransmitters to "talk" to downstream dorsal horn (DH) interneurons, and then travel up the spinothalamic tract to the sensory cortex of the brain, ultimately forming itch
.
MrgprA3 (Mas-related G protein-coupled receptor A3)-positive neurons are a class of itch-specific neurons in the peripheral nervous system of mice
.
MrgprA3 is specifically expressed in the dorsal root ganglia (DRG) and trigeminal ganglia (TG) of the peripheral nervous system, and is a specific receptor for the antimalarial drug chloroquine.
The side effects of chloroquine that cause itching are mainly achieved through MrgprA3
.
On January 3, 2022, Wenqin Luo of the University of Pennsylvania School of Medicine discovered that neurotransmitters derived from MrgprA3-positive sensory neurons can transmit itch information
.
Figure 1: Neurotransmitter expressed by MrgprA3-positive neurons.
The researchers were able to induce scratching in mice by light-activating MrgprA3-positive neurons in the DRG region
.
In situ hybridization experiments found that MrgprA3-positive neurons in the DRG region were enriched to express type 2 vesicular glutamate transporter (Vglut2) and neuromedin B (NMB, Figure 1).
.
Electrophysiological experiments further found that light-activated MrgprA3-positive neurons in the DRG region projecting to fibers in the DH region induced excitatory synaptic currents, which could be blocked by glutamate receptor antagonists
.
This suggests that MrgprA3-positive neurons communicate with DH neurons by releasing glutamate
.
Through genetic tool mouse-specific knockout of Vglut2 in MrgprA3-positive neurons (Vglut2-CKO mice), it was found that this knockout mouse caused an age-related glutamate release disorder: Vglut2-CKO was small before 4 months of age.
Glutamate release in mice was normal, and glutamate release decreased after 6 months of age
.
Injection of pruritogens such as histamine and chloroquine induced hypoitch in 6-month-old Vglut2-CKO mice, but did not affect mechanical pain sensitivity
.
This suggests that glutamate plays an important role in the synaptic transmission of primary itch afferents and itch behavior
.
Figure 2: Nmb receptors are mainly expressed in the DH region.
NMB is a neuropeptide with 10 amino acids, belonging to the bombesin family, and is a bombesin-related peptide
.
By constructing the NMBR-cre (Nmb receptor) tool mouse, it was found that the Nmb receptor is mainly expressed in the DH region, but not in the DRG region (Figure 2)
.
In vitro electrophysiological experiments found that Nmb-expressing neurons in the DH region could be induced to release action potentials after incubating with Nmb
.
In addition, MrgprA3-positive neurons also formed direct synaptic connections with neurons expressing Nmb receptors in the DH region
.
Specific knockout of NMB in MrgprA3-positive neurons can only reduce the itching behavior induced by chloroquine, while pharmacological knockout of NMB receptors on neurons in the DH region can reduce the itching behavior induced by chloroquine and histamine
.
This suggests that NMB/NMB receptor signaling is involved in the regulation of itching behavior
.
Overall, this paper reveals that MrgprA3-positive neurons in the dorsal root ganglia transmit itch information to medulla dorsal horn interneurons through glutamate receptors to regulate itch behavior, and NMB/NMB receptor signaling further enhances the above process
.
[References] 1.
https://doi.
org/10.
1016/j.
neuron.
2021.
12.
007 The pictures in the text are from the references
