Presynaptically Localized Cyclic GMP-Dependent Protein Kinase 1 Is a Key Determinant of Spinal Synaptic Potentiation and Pain Hypersensitivity

• DOI: 10.1371/journal.pbio.1001283
• Publication Date: 2012-03-13T21:01:11Z
• Authors: Ceng Luo; Vijayan Gangadharan; Kiran Kumar Bali; Rou-Gang Xie; Nitin Agarwal; Martina Kurejova; Anke Tappe-Theodor; Irmgard Tegeder; Susanne Feil; Gary Lewin; Erika Polgar; Andrew J. Todd; Jens Schlossmann; Franz Hofmann; Da-Lu Liu; San-Jue Hu; Robert Feil; Thomas Kuner; Rohini Kuner
• Keywords: Nociceptor

Synaptic long-term potentiation (LTP) at spinal neurons directly communicating pain-specific inputs from the periphery to brain has been proposed serve as a trigger for pain hypersensitivity in pathological states. Previous studies have functionally implicated NMDA receptor-NO pathway and downstream second messenger, cGMP, these processes. Because cGMP can broadly influence diverse ion-channels, kinases, phosphodiesterases, pre- well post-synaptically, precise identity of targets mediating LTP, their mechanisms action, locus circuitry are still unclear. Here, we found that Protein Kinase G1 (PKG-I) localized presynaptically nociceptor terminals plays an essential role expression LTP. Using Cre-lox P system, generated nociceptor-specific knockout mice lacking PKG-I specifically presynaptic nociceptors cord, but not post-synaptic or elsewhere (SNS-PKG-I(-/-) mice). Patch clamp recordings showed activity-induced LTP identified synapses between projecting periaqueductal grey (PAG) was completely abolished SNS-PKG-I(-/-) mice, although basal synaptic transmission affected. Analyses failure rates paired-pulse ratios indicated regulating probability neurotransmitter release. Inositol 1,4,5-triphosphate receptor 1 myosin light chain kinase were recruited key phosphorylation nociceptive neurons. Finally, behavioural analyses vivo marked defects several models hypersensitivity, pharmacological clear contribution expressed nociceptors. Our results thus indicate involving increase release operational on spinal-PAG projection this process regulate sensitivity.