Glycoprotein 130 (gp130) is part of the signalling complex for Interleukin 6 (Il-6) and Il-6 related cytokines. We have generated a conditional knock-out mouse for gp130 (SNS-gp130-/-) in which the protein is depleted specifically in nociceptive neurons. Inflammation of the hind paw and spared nerve injury lesions of the sciatic nerve lead to mechanical hypersensitivity. In contrast to control mice, SNS-gp130-/- mice recover from mechanical hypersensitivity in three different models of chronic pain. Transient Receptor Potential Ankyrin 1 (TRPA1) channel has emerged as a potential candidate for mechanotransduction in sensory neurons as it can be activated by mechanical stimulation in cultured neurons obtained from dorsal root ganglia and plays a significant role in nociception. We addressed a putative role of TRPA1 as a molecular entity for neuropathic mechanical hypersensitivity in an interdisciplinary approach.

Differential expression of TRPA1 mRNA with quantitative Taqman®-PCR revealed upregulation in gp130fl/fl but not SNS-gp130-/- mice following spared nerve injury. Furthermore we tested functional expression of TRPA1 with microfluorimetric calcium measurements. In line with the downregulation of TRPA1 mRNA, a significantly smaller proportion of cultured SNS-gp130-/- DRG neurons responded to the selective TRPA1 agonist NPPB with calcium transients. In behavioural experiments SNS-gp130-/- mice also showed a reduced nocifensive response to the injection of TRPA1 agonist cinnamaldehyde into the hind paw of the mice.

We conclude that depletion of gp130 leads to downregulation of TRPA1 in nociceptive neurons which supports the possibility that TRPA1 may contribute to the increased mechanical hypersensitivity of mice in pathological inflammatory and neuropathic conditions.

This work was supported by the Austrian FWF (DK-SPIN)