Sprouting sympathetic fibres release CXCL16 and norepinephrine to synergistically mediate sensory neuronal hyperexcitability in a rodent model of neuropathic pain.
Summary
In rodent spared nerve injury models, sprouting sympathetic fibers in the dorsal root ganglia maintained mechanical allodynia. These fibers co-released norepinephrine and the chemokine CXCL16, which synergistically increased sensory neuronal excitability, revealing a neuroimmune mechanism for neuropathic pain maintenance.
Key Findings
- Sprouting tyrosine hydroxylase-positive sympathetic fibers in DRG maintained mechanical allodynia after SNI.
- Sympathetic terminals co-released norepinephrine and CXCL16, synergistically increasing sensory neuron excitability.
- Lumbar sympathectomy and targeted DRG manipulations modulated pain behaviors, supporting a causal role of sympathetic-sensory interactions.
Clinical Implications
Targeting CXCL16 signaling and/or sympathetic activity (e.g., chemokine blockade, adrenergic modulation, sympathectomy) may provide new strategies for refractory neuropathic pain, with implications for perioperative and chronic pain management.
Why It Matters
This is among the first demonstrations that sympathetic sprouting drives neuropathic pain via co-release of a chemokine (CXCL16) and norepinephrine, opening therapeutic avenues beyond conventional analgesics.
Limitations
- Rodent models may not fully recapitulate human neuropathic pain complexity.
- Dose-response and temporal dynamics of CXCL16/norepinephrine co-release in vivo require further quantification.
Future Directions
Validate CXCL16-adrenergic co-signaling in human tissues; test CXCL16 blockade or combined adrenergic modulation in translational models; and explore biomarkers for patient stratification.
Study Information
- Study Type
- Basic/Mechanistic research (rodent models)
- Research Domain
- Pathophysiology/Treatment
- Evidence Level
- V - Preclinical mechanistic experiments in animal models without human clinical outcomes.
- Study Design
- OTHER