title: Ht31 peptide inhibited inflammatory pain by blocking NMDA receptor-mediated nociceptive transmission in spinal dorsal horn of mice.
abstract: A kinase anchoring proteins (AKAPs) assemble cAMP-dependent protein kinase (PKA) into signaling complexes with a wide range of ion channels, including N-methyl-d-aspartate (NMDA)-subtype glutamate receptor (NMDAR) that is critical for the central sensitization of nociceptive behaviors. Although PKA has been widely described in the regulation of NMDAR-dependent nociceptive transmission and plasticity, the roles of AKAPs in these processes are largely unknown as yet. The present study interfered with AKAPs/PKA interaction by introducing stearated Ht31 peptide (St-Ht31) into spinal dorsal horn neurons, and investigated the possible changes of primary afferent-evoked, NMDAR-mediated excitatory postsynaptic currents (NMDAR-EPSCs). Whole-cell patch clamp recordings demonstrated that intracellular loading of St-Ht31 through the glass pipettes didn't affect NMDAR-mediated synaptic responses in the spinal cord slices from intact mice. When inflammatory pain was established by intraplantar injection of Complete Freund's Adjuvant (CFA), however, St-Ht31 significantly repressed the amplitudes of NMDAR-EPSCs by selectively removing GluN2B subunit-containing NMDAR out of synapses. With the inhibition of NMDAR-mediated nociceptive transmission, St-Ht31 effectively ameliorated CFA-induced inflammatory pain. Pharmacological manipulation of microtubule-based NMDAR transport, dynamin-dependent NMDAR endocytosis or actin depolymerization abolished the inhibitory effects of St-Ht31 peptide on NMDAR-EPSCs, suggesting that disruption of AKAPs/PKA interaction by St-Ht31 might disturb multiple NMDAR trafficking steps to reduce the receptor synaptic expression and spinal sensitization.
authors.affiliation: Department of Molecular Pharmacology, School of Pharmacy, Lanzhou University, Lanzhou, Gansu, 730000, PR China.
authors.forename: Wen-Tao
authors.initials: WT
authors.lastname: Wang
authors.affiliation: Department of Molecular Pharmacology, School of Pharmacy, Lanzhou University, Lanzhou, Gansu, 730000, PR China.
authors.forename: Guo-Qiang
authors.initials: GQ
authors.lastname: Pan
authors.affiliation: Department of Molecular Pharmacology, School of Pharmacy, Lanzhou University, Lanzhou, Gansu, 730000, PR China.
authors.forename: Zi-Yang
authors.initials: ZY
authors.lastname: Zhang
authors.affiliation: Department of Molecular Pharmacology, School of Pharmacy, Lanzhou University, Lanzhou, Gansu, 730000, PR China.
authors.forename: Zhan-Wei
authors.initials: ZW
authors.lastname: Suo
authors.affiliation: Department of Molecular Pharmacology, School of Pharmacy, Lanzhou University, Lanzhou, Gansu, 730000, PR China.
authors.forename: Xian
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Molecular Pharmacology, School of Pharmacy, Lanzhou University, Lanzhou, Gansu, 730000, PR China. Electronic address: huxxiaodong@lzu.edu.cn.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Hu
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000777:Anesthetics / Q000627:therapeutic use*; D000818:Animals; D004195:Disease Models, Animal; D005620:Freund's Adjuvant / Q000633:toxicity; D005727:Ganglia, Spinal / Q000166:cytology*; D066298:In Vitro Techniques; D007249:Inflammation / Q000139:chemically induced / Q000150:complications; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000648:ultrastructure; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D011506:Proteins / Q000627:therapeutic use*; D011984:Sensory Receptor Cells / Q000187:drug effects*; D013116:Spinal Cord / Q000473:pathology; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism
chemical_list: D000777:Anesthetics; C400224:Ht 31 protein, synthetic; D011506:Proteins; D005620:Freund's Adjuvant
keywords: A kinase anchoring proteins; Inflammatory pain; NMDA receptor; Spinal cord; cAMP–dependent protein kinase