title: Hyperpolarization-activated and cyclic nucleotide-gated cation channel subunit 2 ion channels modulate synaptic transmission from nociceptive primary afferents containing substance P to secondary sensory neurons in laminae I-IIo of the rodent spinal dorsal horn.
abstract: We have previously demonstrated that hyperpolarization-activated and cyclic nucleotide-gated cation channel subunit 2 (HCN2) is expressed by terminals of peptidergic nociceptive primary afferents in laminae I-IIo of the rat spinal dorsal horn. In this study, we investigated the possible neurotransmitters and postsynaptic targets of these HCN2-expressing primary afferent terminals in the superficial spinal dorsal horn by using immunocytochemical methods. We demonstrated that HCN2 widely colocalizes with substance P (SP), and that HCN2-positive terminals that are also immunoreactive for SP form serial close appositions with dendrites and perikarya of neurokinin 1 receptor-immunoreactive neurons. It was also found that HCN2-immunoreactive terminals are frequently apposed to neurons that are immunoreactive for calbindin, micro-opioid receptor and the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor subunit GluR2, markers for excitatory interneurons. Investigating HCN2 immunoreactivity in glutamic acid decarboxylase 65-green fluorescent protein transgenic mice, we found that HCN2-positive terminals occasionally also contact cells that contain an isoform of glutamic acid decarboxylase (glutamic acid decarboxylase 65), a marker for GABAergic inhibitory neurons. Application of ZD7288, an antagonist of HCN channels, onto neurons that were recorded in spinal cord slices with whole-cell patch-clamp electrodes reduced the number of monosynaptic excitatory postsynaptic potentials evoked by electrical stimulation of primary afferents at nociceptive intensities. The results suggest that HCN2 may contribute to the modulation of membrane excitability of SP-containing nociceptive primary afferent terminals, may increase the reliability of synaptic transmission from primary afferents to secondary sensory neurons and thus may play a role in the fine-tuning of pain transmission from nociceptive primary afferents to neurons in the spinal dorsal horn.
authors.affiliation: Department of Anatomy, Histology and Embryology, Faculty of Medicine, Medical and Health Science Center, University of Debrecen, H-4012 Debrecen, Hungary.
authors.forename: Ildikó
authors.initials: I
authors.lastname: Papp
authors.forename: Péter
authors.initials: P
authors.lastname: Szucs
authors.forename: Krisztina
authors.initials: K
authors.lastname: Holló
authors.forename: Ferenc
authors.initials: F
authors.lastname: Erdélyi
authors.forename: Gábor
authors.initials: G
authors.lastname: Szabó
authors.forename: Miklós
authors.initials: M
authors.lastname: Antal
mesh_terms: D000344:Afferent Pathways / Q000502:physiology*; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D005968:Glutamate Decarboxylase / Q000096:biosynthesis; D049452:Green Fluorescent Proteins / Q000096:biosynthesis; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D066298:In Vitro Techniques; D007473:Ion Channels / Q000502:physiology*; D007527:Isoenzymes / Q000096:biosynthesis; D051379:Mice; D008822:Mice, Transgenic; D009431:Neural Conduction / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D018408:Patch-Clamp Techniques / Q000379:methods; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D015221:Potassium Channels; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology*; D013373:Substance P / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D050496:Vesicular Glutamate Transport Proteins / Q000378:metabolism
chemical_list: D002316:Cardiotonic Agents; C578711:Hcn2 protein, mouse; C578712:Hcn2 protein, rat; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels; D007527:Isoenzymes; D015221:Potassium Channels; D011743:Pyrimidines; D018091:Receptors, AMPA; D018040:Receptors, Neurokinin-1; D017450:Receptors, Opioid, mu; D050496:Vesicular Glutamate Transport Proteins; C082246:ICI D2788; D049452:Green Fluorescent Proteins; D013373:Substance P; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2; C104722:glutamate receptor ionotropic, AMPA 2