A critical role of spinal Shank2 proteins in NMDA-induced pain hypersensitivity

Molecular Pain, 2017 · DOI: 10.1177/1744806916688902 · Published: January 1, 2017

Simple Explanation

This research explores the connection between Shank2 protein, NMDA receptors, and pain sensitivity, particularly in the context of Autism Spectrum Disorder (ASD). The study investigates how mutations in the Shank2 gene affect pain responses induced by NMDA receptors in mice. The researchers found that mice with a Shank2 knockout (KO) exhibited reduced pain responses to NMDA injections compared to wild-type mice. This suggests that Shank2 plays a significant role in NMDA receptor-mediated pain transmission in the spinal cord. Further investigation revealed that the reduced pain behavior in Shank2 KO mice is associated with a decrease in the activation of ERK signaling, a key pathway involved in pain transmission. This finding provides new insights into the mechanisms underlying pain deficits associated with self-injurious behaviors in ASD.

Study Duration

Not specified

Participants

Shank2 KO and wild-type mice

Evidence Level

Not specified

Key Findings

1
Intrathecal NMDA injection evoked spontaneous nociceptive behaviors, which were significantly reduced in Shank2 KO mice, suggesting that the spinal Shank2 protein is involved in NMDA-induced pain transmission.
2
NMDA-induced currents were significantly decreased in spinal cord lamina II neurons from Shank2 KO mice compared to wild-type mice, indicating that Shank2 regulates NMDA receptor function in spinal cord interneurons.
3
The NMDA-induced increase in spinal p-ERK expression was significantly reduced in Shank2 KO mice, and the ERK inhibitor, PD98059, decreased NMDA-induced spontaneous pain behaviors in wild-type mice, suggesting that Shank2 mutation-induced dysfunction of NMDA receptors suppresses the normal NMDA-ERK pathway.

Research Summary

The study investigates the role of Shank2 protein in NMDA-induced pain hypersensitivity in mice, focusing on the spinal cord mechanisms involved. It demonstrates that Shank2 knockout mice exhibit reduced pain responses to NMDA injection. The research identifies that the reduced pain sensitivity in Shank2 KO mice is linked to decreased NMDA-induced currents and reduced ERK signaling in the spinal cord dorsal horn. This suggests that Shank2 is crucial for NMDA receptor function and downstream ERK activation in pain transmission. The findings imply that Shank2 mutations can lead to dysfunction of the NMDA receptor and suppression of the NMDA-ERK pathway, potentially contributing to pain deficits associated with self-injurious behaviors in autism spectrum disorder.

Practical Implications

Understanding Pain Deficits in ASD

This study provides insights into the mechanisms underlying pain deficits in individuals with Autism Spectrum Disorder (ASD), which may contribute to self-injurious behaviors.

Therapeutic Targets for ASD

The findings suggest that targeting NMDA receptor function or ERK signaling could be potential therapeutic strategies for managing pain deficits and self-injurious behaviors in ASD patients.

Further Research on Shank2 Mutations

The research highlights the need for further investigation into the detailed mechanisms associated with Shank2 mutation-NMDA-ERK signaling in the context of ASD and pain perception.

Study Limitations

1
The study is conducted on mice, and the results may not directly translate to humans.
2
The study focuses on NMDA-induced pain and may not fully represent other types of pain.
3
The study does not fully elucidate the synaptic function and plasticity at glutamatergic synapses in higher brain areas including the anterior cingulate cortex that is involved in pain perception.

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