title: Nuclear calcium signaling in spinal neurons drives a genomic program required for persistent inflammatory pain.
abstract: Persistent pain induced by noxious stimuli is characterized by the transition from normosensitivity to hypersensitivity. Underlying mechanisms are not well understood, although gene expression is considered important. Here, we show that persistent nociceptive-like activity triggers calcium transients in neuronal nuclei within the superficial spinal dorsal horn, and that nuclear calcium is necessary for the development of long-term inflammatory hypersensitivity. Using a nucleus-specific calcium signal perturbation strategy in vivo complemented by gene profiling, bioinformatics, and functional analyses, we discovered a pain-associated, nuclear calcium-regulated gene program in spinal excitatory neurons. This includes C1q, a modulator of synaptic spine morphogenesis, which we found to contribute to activity-dependent spine remodelling on spinal neurons in a manner functionally associated with inflammatory hypersensitivity. Thus, nuclear calcium integrates synapse-to-nucleus communication following noxious stimulation and controls a spinal genomic response that mediates the transition between acute and long-term nociceptive sensitization by modulating functional and structural plasticity.
authors: Institute for Pharmacology, University of Heidelberg, Im Neuenheimer Feld, Heidelberg 69120, Germany.
authors: Manuela
authors: M
authors: Simonetti
authors: Anna M
authors: AM
authors: Hagenston
authors: Daniel
authors: D
authors: Vardeh
authors: H Eckehard
authors: HE
authors: Freitag
authors: Daniela
authors: D
authors: Mauceri
authors: Jianning
authors: J
authors: Lu
authors: Venkata P
authors: VP
authors: Satagopam
authors: Reinhard
authors: R
authors: Schneider
authors: Michael
authors: M
authors: Costigan
authors: Hilmar
authors: H
authors: Bading
authors: Rohini
authors: R
authors: Kuner
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D020013:Calcium Signaling / Q000502:physiology*; D002467:Cell Nucleus / Q000502:physiology*; D002478:Cells, Cultured; D059350:Chronic Pain / Q000235:genetics* / Q000473:pathology; D023281:Genomics / Q000379:methods; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000473:pathology / Q000502:physiology; D010147:Pain Measurement / Q000379:methods; D020671:Posterior Horn Cells / Q000473:pathology / Q000502:physiology*; D013116:Spinal Cord / Q000166:cytology / Q000473:pathology / Q000502:physiology