Abstract

Pain of unknown etiology is frequent in individuals with the tumor predisposition syndrome Neurofibromatosis 1 (NF1), even when tumors are absent. Schwann cells (SC) were recently shown to play roles in nociceptive processing, and we find that chemogenetic activation of SCs is sufficient to induce afferent and behavioral mechanical hypersensitivity in mice. In mouse models, animals show afferent and behavioral hypersensitivity when SC, but not neurons, lack Nf1. Importantly, hypersensitivity corresponds with SC-specific upregulation of mRNA encoding glial cell line derived neurotrophic factor (GDNF), independent of the presence of tumors. Neuropathic pain-like behaviors in the NF1 mice were inhibited by either chemogenetic silencing of SC calcium or by systemic delivery of GDNF targeting antibodies. Together, these findings suggest that Nf1 loss in SCs causes mechanical pain by influencing adjacent neurons and, data may identify cell-specific treatment strategies to ameliorate pain in individuals with NF1. Graphical AbstractGDNF released from Schwann cells acts on sensory neurons leading to mechanical hypersensitivity and pain-like behaviors in preclinical models of NF1. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=181 SRC="FIGDIR/small/533004v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@d17177org.highwire.dtl.DTLVardef@706f56org.highwire.dtl.DTLVardef@19db1ccorg.highwire.dtl.DTLVardef@3e28d_HPS_FORMAT_FIGEXP M_FIG C_FIG