Glycine inhibitory dysfunction turns touch into pain through astrocyte-derived D-serine

Area of Science:

• Neuroscience
• Pain Research
• Cellular Biology

Background:

• Dynamic mechanical allodynia is a neuropathic pain symptom.
• N-methyl-d-aspartate receptors (NMDARs) mediate allodynia.
• Astrocytes regulate NMDAR activation via d-serine.

Purpose of the Study:

• Investigate astrocyte involvement in dynamic mechanical allodynia.
• Determine if astrocytes contribute to neuropathic pain mechanisms.

Main Methods:

• Used a glycine inhibitory dysfunction model.
• Administered glia inhibitors (fluorocitrate) and microglia inhibitors (minocycline).
• Assessed Fos expression to reveal neural circuit activation.
• Used d-amino acid oxidase to degrade d-serine.
• Administered exogenous d-serine to reverse effects.

Main Results:

• Orofacial tactile stimuli activated medullary dorsal horn (MDH) astrocytes after glycine inhibition.
• Fluorocitrate prevented allodynia and astrocyte activation.
• Astrocytes were immunolabeled for serine racemase, the d-serine synthesizing enzyme.
• d-serine degradation prevented allodynia and neural circuit activation.
• Exogenous d-serine reversed fluorocitrate-induced allodynia blockade.

Conclusions:

• MDH astrocytes are required for dynamic mechanical allodynia.
• Activated astrocytes may provide d-serine to enable NMDAR activation and allodynia.
• Astrocytes play a critical role in neuropathic pain signaling.