A dual role for peripheral GDNF signaling in nociception and cardiovascular reflexes in the mouse

Area of Science:

• Neuroscience
• Physiology
• Molecular Biology

Background:

• Group III/IV muscle afferents transmit pain signals and influence exercise pressor reflexes (EPRs).
• Mechanisms controlling afferent sensitivity for dual modulation of nociception and EPRs are unclear.
• Ischemic injury in mice causes pain behaviors and heightened EPRs, linked to afferent sensitization and altered GDNF/GFRα1 expression.

Purpose of the Study:

• To investigate the role of glial cell line-derived neurotrophic factor (GDNF)/GDNF family receptor α1 (GFRα1) signaling in sensory neurons following ischemia/reperfusion.
• To determine how this signaling pathway modulates nociceptive behaviors, exercise reflexes, and muscle afferent sensitization.

Main Methods:

• Utilized mouse models of ischemia/reperfusion injury.
• Measured nociceptive-like behaviors and exercise-mediated reflexes.
• Assessed muscle afferent sensitization and expression of GDNF, GFRα1, cyclic adenosine monophosphate (cAMP) response element binding (CREB), and P2X5 in dorsal root ganglia (DRGs).

Main Results:

• Increased GDNF/GFRα1 signaling in sensory neurons from affected muscle directly influenced nociceptive behaviors and amplified exercise reflexes.
• Muscle GDNF signaling led to sensitization of group III/IV muscle afferents.
• This modulation involved increased CREB/CREB binding protein-mediated expression of the purinergic receptor P2X5 in DRGs.

Conclusions:

• Muscle GDNF signaling to sensory neurons plays a dual role in pain perception and sympathetic nervous system responses during exercise.
• The GDNF/GFRα1-CREB-P2X5 pathway is crucial for mediating these effects post-ischemia.
• This pathway represents a potential therapeutic target for managing pain and reflex abnormalities associated with ischemic injuries.