Extracellular Signal-Regulated Kinase-Regulated Microglia–Neuron Signaling by Prostaglandin E2 Contributes to Pain after Spinal Cord Injury

The Journal of Neuroscience, 2007 · DOI: 10.1523/JNEUROSCI.0138-07.2007 · Published: February 28, 2007

Spinal Cord Injury Neurology Pain Management

Simple Explanation

This study investigates the mechanisms behind chronic pain that persists after spinal cord injury (SCI). It focuses on how microglia, a type of immune cell in the spinal cord, communicate with neurons to maintain this pain. The researchers found that after SCI, microglia release a substance called prostaglandin E2 (PGE2). This release is regulated by an enzyme called extracellular signal-regulated kinase 1/2 (ERK1/2). PGE2 then binds to receptors on neurons, making them more sensitive and contributing to the experience of chronic pain. Blocking either the release of PGE2 or its binding to neurons can reduce this pain.

Study Duration

4 Weeks

Participants

Adult male Sprague Dawley rats (200–225 g)

Evidence Level

Not specified

Key Findings

1
Phosphorylated ERK1/2 (pERK1/2), an upstream regulator of PGE2 release, is specifically localized to microglial cells in the lumbar dorsal horn after SCI.
2
The PGE2 receptor E-prostanoid 2 (EP2) is localized to neurons in the lumbar dorsal horn after SCI, indicating that PGE2 acts on these neurons.
3
Pharmacological antagonism of PGE2 release or blockade of the EP2 receptor resulted in decreased hyperresponsiveness of dorsal horn neurons and partial restoration of behavioral nociceptive thresholds.

Research Summary

This study demonstrates a PGE2-dependent, ERK1/2-regulated microglia–neuron signaling pathway that mediates the microglial component of pain maintenance after injury to the spinal cord. The researchers showed that after SCI, microglia become activated and release PGE2, which is regulated by ERK1/2. This PGE2 then acts on EP2 receptors on dorsal horn neurons, leading to neuronal hyperresponsiveness and pain. Blocking PGE2 release or its binding to EP2 receptors can reduce neuronal hyperresponsiveness and pain-related behaviors, suggesting a potential therapeutic target for chronic pain after SCI.

Practical Implications

Therapeutic Target

Targeting the PGE2-dependent, ERK1/2-regulated microglia-neuron signaling pathway may offer a novel approach for managing chronic pain after SCI.

Microglial Inhibition

Inhibiting microglial activation or downstream ERK1/2 activation could reduce PGE2 release and alleviate pain.

EP2 Receptor Antagonism

Blocking the EP2 receptor on dorsal horn neurons could prevent PGE2 from inducing neuronal hyperresponsiveness and pain.

Study Limitations

1
The study focuses on male rats, and the results may not be generalizable to females.
2
The incomplete reduction in PGE2 release after microglial or ERK1/2 inhibition could indicate additional sources of PGE2.
3
The study does not completely eliminate PGE2 in the dorsal horn, PGE2 release by primary afferent remains a possibility.

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