title: Phospholipase C-related but catalytically inactive protein modulates pain behavior in a neuropathic pain model in mice.
abstract: BACKGROUND
  An inositol 1,4,5-trisphosphate binding protein, comprising 2 isoforms termed PRIP-1 and PRIP-2, was identified as a novel modulator for GABAA receptor trafficking. It has been reported that naive PRIP-1 knockout mice have hyperalgesic responses.
  
  
  RESULTS
  To determine the involvement of PRIP in pain sensation, a hind paw withdrawal test was performed before and after partial sciatic nerve ligation (PSNL) in PRIP-1 and PRIP-2 double knockout (DKO) mice. We found that naive DKO mice exhibited normal pain sensitivity. However, DKO mice that underwent PSNL surgery showed increased ipsilateral paw withdrawal threshold. To further investigate the inverse phenotype in PRIP-1 KO and DKO mice, we produced mice with specific siRNA-mediated knockdown of PRIPs in the spinal cord. Consistent with the phenotypes of KO mice, PRIP-1 knockdown mice showed allodynia, while PRIP double knockdown (DKD) mice with PSNL showed decreased pain-related behavior. This indicates that reduced expression of both PRIPs in the spinal cord induces resistance towards a painful sensation. GABAA receptor subunit expression pattern was similar between PRIP-1 KO and DKO spinal cord, while expression of K(+)-Cl(-)-cotransporter-2 (KCC2), which controls the balance of neuronal excitation and inhibition, was significantly upregulated in DKO mice. Furthermore, in the DKD PSNL model, an inhibitor-induced KCC2 inhibition exhibited an altered phenotype from painless to painful sensations.
  
  
  CONCLUSIONS
  Suppressed expression of PRIPs induces an elevated expression of KCC2 in the spinal cord, resulting in inhibition of nociception and amelioration of neuropathic pain in DKO mice.
authors: Department of Cellular and Molecular Pharmacology, Division of Basic Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
authors: Tomoya
authors: T
authors: Kitayama
authors: Katsuya
authors: K
authors: Morita
authors: Rizia
authors: R
authors: Sultana
authors: Nami
authors: N
authors: Kikushige
authors: Keisuke
authors: K
authors: Mgita
authors: Shinya
authors: S
authors: Ueno
authors: Masato
authors: M
authors: Hirata
authors: Takashi
authors: T
authors: Kanematsu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009437:Neuralgia / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000378:metabolism; D012584:Sciatic Nerve / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism; D027981:Symporters / Q000378:metabolism; D000096922:K Cl- Cotransporters
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D011963:Receptors, GABA-A; D027981:Symporters; D000096922:K Cl- Cotransporters; C496391:Plcl1 protein, mouse; C530633:Plcl2 protein, mouse
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