Mary P. FitzGerald, Kara Brogan, Matthew Ripsch, Fletcher A. White.
Loyola University Medical Center, Maywood, IL.

Objectives: Many patients with painful bladder syndrome can recall a somatic injury that predated the onset of their symptoms, suggesting that relevant somatic injury might alter visceral sensation and/or function. A prime candidate for this type of neuronal plasticity following peripheral injury is the chronic upregulation of the chemokine, monocyte chemoattractant protein-1 (MCP-1/CCL2). Prior animal studies from our center have demonstrated upregulation of MCP-1 and its cognate receptor, CCR2, in neurons directly impacted by a sciatic nerve injury (L4-L6 dorsal root ganglion (DRG)) as well as adjacent, uninjured neurons (L3 DRG). Our objective was to determine whether visceral sensory neurons present in the thoracic, lumbar and sacral DRGs might also exhibit upregulation of chemokines/receptors and hyperexcitability following somatic injury.

Methods: We used an established model of neuropathic pain (transient focal demyelination of the sciatic nerve) as a model of somatic injury. We utilized a combination of retrograde axon tracing techniques to label primary afferent neurons after bilateral injections into the rat bladder wall (cholera toxin β subunit conjugated to a fluorescent marker; CTB-555) to identify bladder afferent neurons, and used immunocytochemistry to identify chemokine/receptor-positive neurons in thoracolumbar and sacral DRGs. Control rats underwent retrograde labeling of bladder afferents but did not undergo sciatic nerve injury.

Figure: Bladder afferent neurons in L6 DRG exhibiting de novo expression of MCP-1/CCL2 (left panel) and CCR-2(right panel) in rats that underwent sciatic nerve injury, but not in sham-treated control rats (insets).

Result: CTB-555 positive bladder afferents were present in T13-L2 and L6-S2 DRGs. Many CTB-555-positive neurons in those ganglia also exhibited de novo expression of MCP-1/CCL2 and to a lesser degree, the chemokine receptor CCR2, following sciatic nerve injury (Figure). No such expression of chemokines was seen in control rats that underwent retrograde labeling of bladder afferents but did not undergo sciatic nerve injury.

Conclusions: In an animal model, sciatic nerve injury has been shown to produce neuronal phenotype changes in both the somatic primary afferent neurons in the DRGs directly impacted by the somatic injury and also in adjacent, uninjured visceral primary afferent neurons affiliated with the bladder. As MCP-1/CCR2 signaling is known to influence excitability of sensory neurons and neuropathic pain behavior; upregulation of this ligand/receptor pairing may impact visceral sensory neurons in a similar fashion and contribute to the symptomatology of PBS/IC.

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