Our data show OSM induced thermal hypersensitivity via direct regulation of nociceptor sensitivity to heat stimuli. Furthermore, the gp130 signal tranducer, which heteromerizes with the OSMR to form a functional receptor complex, is of critical importance in mediating the OSM-induced heat hypersensitivity in mice. This is justified by the observation that nociceptors from SNS-gp130
mice are largely protected from OSM-induced heat sensitization and by the absence of OSM induced potentiation of Icaps in gp130-deficient sensory neurons. Furthermore, we show that the TRPV1 ion channel is the convergence point for thermal hypersensitivity mediated by Oncostatin M.
Proinflammatory cytokines including OSM that depend on gp130 for signal transduction require the presence of specific ligand binding, soluble or membrane bound, receptor subunits as well as the presence of gp130 signal transducer to transduce the signal into the cytosol [23, 24]. The majority of nociceptive neurons in mice express gp130 and can be activated by classical transsignaling routes via soluble receptors, e g. for IL-6 . Therefore, activation of specific DRG neuron subpopulations can only be discriminated by different expression patterns for specific membrane bound receptors. Approximately 13% of the DRG neurons of C57BL6 wild type mice express the OSMR and it is most prevalent in small-sized neurons . Furthermore, all OSMR-positive neurons express the signal transducer gp130 and classical nociceptive markers TRPV1 and P2X3 receptors. Typically, the OSMR expressing neurons are non-peptidergic, but are rather characterized by expression of TrkA (63%), Ret (28%) and/or IB4 (58%). Our observation that all OSMR positive cells derived from C57BL6J or gp130
DRG neurons are co-expressing gp130 is in agreement with these previous findings . As expected, all OSMR-positive neurons were responsive to capsaicin in our electrophysiogical recordings and responded to OSM with a potentiation of Icaps.
Oncostatin M has an important role in the development of nociceptive neurons. The OSMR expression is induced after p0 in the DRGs and reaches maximal expression after p14. The kinetics of OSMR expression is not altered in OSM
mice, however the total number of OSMR-positive cells is dramatically reduced. Moreover, the number of TRPV1 and/or P2X3 positive neurons is even further decreased, resulting in decreased nociceptive behavior upon various nociceptive models . Our data obtained from SNS-gp130
mice in behavioral studies and skin-nerve preparations similarly show decreased OSM-induced nociceptive behavior to heat. The PWL in Hargreaves tests are not reduced after OSM injection neither is the discharge rate in skin-nerve preparations after OSM-perfusion. Undoubtedly, according to our results, OSM and the OSM receptor are important mediators of thermal hypersensitivity of preexisting polymodal nociceptors in adult mice.
Furthermore, our behavioral studies show that both gp130 and TRPV1 are required for developing OSM-induced heat hypersensitivity. Previously, our lab presented data that IL-6 increases heat sensitivity of nociceptors through modulation of TRPV1 and is completely dependent on gp130. Both OSM and IL-6 require gp130 for signal transduction, OSMR dimerizes with a single gp130 molecule whereas the IL-6R associates with two gp130 molecules [27, 28]. Although, the intracellular signal transduction pathways are quite similar, both will activate Shp2-Gab1 and the JAK/STAT signaling pathway, with the only difference that OSMR can activate STAT1, -3, and -5, whereas IL-6 only activates STAT1 and -3 [29, 30]. However, the heat hypersensitivity induced by IL-6 relies on TRPV1 modulation via Gab1, PI3K and PKCδ . Since, the time course of OSM-induced potentiation of capsaicin currents is very similar to the IL-6 mediated potentiation of TRPV1 currents in gp130
and wildtype DRGs we therefore assume that OSMR/gp130 uses the same pathway for heat sensitization as we have previously published for IL-6/gp130.
OSM and the OSMR are well-known players during various inflammatory conditions. For example, OSM is a potent cytokine that induces cutaneous inflammation after intradermal injection in mice, and results in neutrophil infiltration . Besides, skin and breast tissue inflammation is associated with psoriasin (S100A7) expression, which is potently increased by OSM in human breast cancer cells in vitro
. Moreover, many (auto-) inflammatory diseases are related to OSM, like rheumatoid arthritis , atherosclerosis , psoriasis and atopic dermatitis . Oncostatin M has a pivotal role in rheumatoid arthritis (RA), where increased levels of OSM are found in the synovial fluid of RA patients. Synovial fibroblasts are stimulated to proliferate and to produce IL-6 by OSM . These findings combined with the fact that RA coincides with increased mechanical and thermal sensitivity [35, 36], we assume that inhibiting OSM signaling by a novel strategy with soluble gp130 [6, 37] or by a soluble OSMR-gp130 fusion protein  would effectively reduce OSM-induced hypersensitivity in RA.
Although expression of OSM and OSMR has been reported previously and a role for OSM has been shown for nociceptor development, our data for the first time demonstrate the function of OSM in inducing thermal hypersensitivity in mice. Our data show that OSM potentiates Icaps and sensitizes nociceptors via regulation of TRPV1. Although we cannot rule out the OSM mediated indirect influence of immune cells, like neutrophils and macrophages, or keratinocytes in in vivo experiments, we have provided genetic evidence that OSM acts directly on capsaicin-responsive nociceptive neurons via the common gp130 signal transducer expressed in sensory neurons.