Human Mas-related G protein-coupled receptors-X1 induce chemokine receptor 2 expression in rat dorsal root ganglia neurons and release of chemokine ligand 2 from the human LAD-2 mast cell line

Primate-specific Mas-related G protein-coupled receptors-X1 (MRGPR-X1) are highly enriched in dorsal root ganglia (DRG) neurons and induce acute pain. Herein, we analyzed effects of MRGPR-X1 on serum response factors (SRF) or nuclear factors of activated T cells (NFAT), which control expression of various markers of chronic pain. Using HEK293, DRG neuron-derived F11 cells and cultured rat DRG neurons recombinantly expressing human MRGPR-X1, we found activation of a SRF reporter gene construct and induction of the early growth response protein-1 via extracellular signal-regulated kinases-1/2 known to play a significant role in the development of inflammatory pain. Furthermore, we observed MRGPR-X1-induced up-regulation of the chemokine receptor 2 (CCR2) via NFAT, which is considered as a key event in the onset of neuropathic pain and, so far, has not yet been described for any endogenous neuropeptide. Up-regulation of CCR2 is often associated with increased release of its endogenous agonist chemokine ligand 2 (CCL2). We also found MRGPR-X1-promoted release of CCL2 in a human connective tissue mast cell line endogenously expressing MRGPR-X1. Thus, we provide first evidence to suggest that MRGPR-X1 induce expression of chronic pain markers in DRG neurons and propose a so far unidentified signaling circuit that enhances chemokine signaling by acting on two distinct yet functionally co-operating cell types. Given the important role of chemokine signaling in pain chronification, we propose that interruption of this signaling circuit might be a promising new strategy to alleviate chemokine-promoted pain

Adaptive tuning functions arise from visual observation of past movement

Visual observation of movement plays a key role in action. For example, tennis players have little time to react to the ball, but still need to prepare the appropriate stroke. Therefore, it might be useful to use visual information about the ball trajectory to recall a specific motor memory. Past visual observation of movement (as well as passive and active arm movement) affects the learning and recall of motor memories. Moreover, when passive or active, these past contextual movements exhibit generalization (or tuning) across movement directions. Here we extend this work, examining whether visual motion also exhibits similar generalization across movement directions and whether such generalization functions can explain patterns of interference. Both the adaptation movement and contextual movement exhibited generalization beyond the training direction, with the visual contextual motion exhibiting much broader tuning. A second experiment demonstrated that this pattern was consistent with the results of an interference experiment where opposing force fields were associated with two separate visual movements. Overall, our study shows that visual contextual motion exhibits much broader (and shallower) tuning functions than previously seen for either passive or active movements, demonstrating that the tuning characteristics of past motion are highly dependent on their sensory modality