Sciatic nerve injury induces functional pro-nociceptive chemokine receptors in bladder-associated primary afferent neurons in the rat

Abstract

Visceral sensory afferents during disease or following injury often produce vague, diffuse body sensations and pain referred to somatic targets. Alternatively, injury due to trauma or disease of somatic nerve targets can also lead to referred pain in visceral targets via a somatovisceral reflex. Both phenomenons are thought to be due to convergence of visceral and somatic afferents within the spinal cord. To investigate a potential peripheral influence for referred pain in visceral targets following somatic nerve injury, we examined whether a sciatic nerve injury known to produce known to produce hindpaw tactile hyperalgesia alters the frequency of micturition and the sensitivity of bladder-associated sensory neurons to pro-nociceptive chemokines. Adult female Sprague-Dawley rats received injections of cholera toxin b subunit conjugated to 555 into urinary bladder wall to retrogradely label visceral primary afferent neurons. Seven days later, the right sciatic nerve of these animals was subjected to a lysophosphatidylcholine (LPC)-induced focal demyelination injury. Pre- and post-injury tactile sensitivity in the hind paw and micturition frequency were assayed. Animals were allowed to survive for 14–28 days. Lumbosacral and lumbar dorsal root ganglia (DRG) ipsilateral to the nerve injury were acutely dissociated from sham and nerve injured animals. Bladder wall-associated sensory neurons identified via the retrograde marker were assayed for fluxes in intracellular calcium following administration of pro-nociceptive chemokines. The assayed chemokines included monocyte chemoattractant protein-1 (MCP1/CCL2) and stromal cell derived factor-1 alpha (SDF1/CXCL12). LPC nerve injured animals exhibited tactile hyperalgesia and increased micturition frequency for at least 28 days. Focal demyelination of the sciatic nerve also increased the number of injured L4L5 and non-injured L6-S2 bladder-associated sensory neurons that responded to MCP1 and SDF1 when compared with sensory neurons derived from uninjured naïve and sham-injured control animals. Taken together, this data suggests that some visceral hypersensitivity states may have a somatic origin. More importantly, nociceptive somatovisceral sensation may be mediated by upregulation of chemokine signaling in visceral sensory neurons.

Toll-like Receptor 4 and comorbid pain in Interstitial Cystitis/Bladder Pain Syndrome: A Multidisciplinary Approach to the Study of Chronic Pelvic Pain research network study

“…laparotomy) can prime spinal microglia activation and subsequent LPS induced allodynia for as long as two weeks (Hains et al, 2010). More direct implications for IC/BPS symptoms have been demonstrated in an animal study that found a demyelination injury to the sciatic nerve increased the sensitivity of bladder-associated sensory neurons to chemokines and increased the frequency of micturition (Foster et al, 2011). …”

CXCL12/CXCR4 axis: an emerging neuromodulator in pathological pain

“…By assessing [Ca 2+ ] i in DRG cells acutely isolated from LPC-treated rats in vitro, the number of DRG cells responding to CXCL12 increased following PLC administration. In another study, sciatic nerve injury induced by LPC increased the frequency of micturition and caused visceral pain hypersensitivity (Foster et al, 2011). It was found that CXCL12 increased [Ca 2+ ] i in somatic-and bladder-associated DRG neurons that were isolated from these PLC-treated animals.…”

The development of myelin repair agents for treatment of multiple sclerosis

“…55 Since then LPC has been shown to cause demyelination in other central nervous system regions 56 as well as exhibiting demyelinating properties when applied to the peripheral nervous system. 57,58 In the context of CNS remyelination, LPC-induced spinal cord lesions still appear be the model of choice as the unidirectional path of axons in the spinal cord makes it easy to assess myelination and axon numbers by microscopy. Upon LPC injection, measurable demyelination can be seen within hours.…”