Oncostatin M induces hyperalgesic priming and amplifies signaling of cAMP to ERK by RapGEF2 and PKA

Abstract

Hyperalgesic priming is characterized by enhanced nociceptor sensitization by pronociceptive mediators, prototypically PGE2. Priming has gained interest as a mechanism underlying the transition to chronic pain. Which stimuli induce priming and what cellular mechanisms are employed remains incompletely understood. In adult male rats, we present the cytokine Oncostatin M (OSM), a member of the IL‐6 family, as an inducer of priming by a novel mechanism. We used a high content microscopy based approach to quantify the activation of endogenous PKA‐II and ERK of thousands sensory neurons in culture. Incubation with OSM increased and prolonged ERK activation by agents that increase cAMP production such as PGE2, forskolin, and cAMP analogs. These changes were specific to IB4/CaMKIIα positive neurons, required protein translation, and increased cAMP‐to‐ERK signaling. In both, control and OSM‐treated neurons, cAMP/ERK signaling involved RapGEF2 and PKA but not Epac. Similar enhancement of cAMP‐to‐ERK signaling could be induced by GDNF, which acts mostly on IB4/CaMKIIα‐positive neurons, but not by NGF, which acts mostly on IB4/CaMKIIα‐negative neurons. In vitro, OSM pretreatment rendered baseline TTX‐R currents ERK‐dependent and switched forskolin‐increased currents from partial to full ERK‐dependence in small/medium sized neurons. In summary, priming induced by OSM uses a novel mechanism to enhance and prolong coupling of cAMP/PKA to ERK1/2 signaling without changing the overall pathway structure.

RNA Profiling of Neuropathic Pain-Associated Human DRGs Reveal Sex-differences in Neuro-immune Interactions Promoting Pain

“…OSM signals through the GP-130 complex, using OSMR as a co-receptor (Taga, 1996). OSM is known to promote nociceptor sensitization in rodents (Langeslag et al, 2011; Garza Carbajal et al, 2021) suggesting that it may be a key signaling molecule for neuropathic pain in humans, in particular males. Our RNAscope imaging showed TNF expression in both nociceptors (TRPV1+ cells) and some TRPV1 -sensory neurons, AIF + immune cells and some AIF - non-neuronal cells, suggesting that immune cell driven TNF signaling could promote TNF expression in nociceptors, or vice versa, in a feedback loop (Figure 6A and B).…”

Neurobiology of SARS-CoV-2 interactions with the peripheral nervous system: implications for COVID-19 and pain

“… 46 , 92 , 104 In addition to the aforementioned role of EREG in pain processing, oncostatin-M (OSM) has previously been demonstrated to have a role in nociceptor sensitization. 22 , 43 β2 Microglobulin (B2M) is associated with the heavy chain of major histocompatibility complex, class I (MHC-I). In TRPV1-expressing mouse DRG neurons, B2M was found to increase Erk phosphorylation, indicative of neuronal activation.…”

“… 59 These mediators all have at least one known hDRG receptor, with some having previously been documented to sensitize rodent or human nociceptors. 22 , 43 , 54 …”

“…59 These mediators all have at least one known hDRG receptor, with some having previously been documented to sensitize rodent or human nociceptors. 22,43,54 The validation of transcriptional changes at the protein level is an essential component of understanding the true mechanism(s) driving nociceptive plasticity in COVID-19. As might be expected, the plasma concentrations of prototypical inflammatory mediators TNFa, IL-1b, and IL-6 have been frequently reported in COVID-19 studies and seem to increase relative to infection severity in most patients.…”

Druggable Targets and Compounds with Both Antinociceptive and Antipruritic Effects

“…OSMR-knockout mice displayed attenuated pain behaviors [ 165 ]. In the murine model, the administration of OSM enhanced hyperalgesia via prolonged ERK signaling and, eventually, led to the priming of chronic pain [ 166 ]. Recent investigations on OSMR reveal that it plays more important roles in itch sensitization.…”