title: A role for protein kinase intracellular messengers in substance P- and nociceptor afferent-mediated excitation and expression of the transcription factor Fos in rat dorsal horn neurons in vitro.
abstract: Expression of the inducible transcription factor Fos in the spinal dorsal horn in vivo is associated with nociceptive afferent activation, but the underlying stimulation-transcription pathway is less clear. This in vitro spinal cord study concerns the role of protein kinase A and C second messengers in substance P receptor (NK1R)-mediated or nociceptive afferent-evoked neuronal excitation and Fos expression. Nociceptive afferent (dorsal root) stimulation of isolated spinal cords (10-14 day old rats) evoked a 'prolonged' excitatory polysynaptic potential (DR-EPSP) that was attenuated (P < 0.05) by: the protein kinase A inhibitor, Rp-cAMP; the protein kinase C inhibitor, bisindolymaleimide I; and the selective NK1R antagonist, GR82334. Neuronal excitations induced by the NK1R agonist [Sar9,Met(O2)11]-SP were attenuated by Rp-cAMP, bisindolymaleimide I and GR82334. Effects of the protein kinase A and C inhibitors on the DR-EPSP or the [Sar9,Met(O2)11]-SP-induced depolarization were nonadditive, suggesting convergence of these intracellular signalling pathways onto a common final target. Nociceptor afferent-induced Fos, detected by immunohistochemistry in superficial and deep dorsal horn laminae, was attenuated by Rp-cAMP, bisindolymaleimide I and GR82334. In spinal cords pretreated with TTX to eliminate indirect neuronal activation, [Sar9,Met(O2)11]-SP (1-20 microM) elicited a dose-related expression of Fos that was reduced by Rp-cAMP, bisindolymaleimide I and GR82334. The effects of these inhibitors were most pronounced in the deep laminae. These data support a causal relationship between protein kinase A- or C-dependent signal transduction, nociceptive afferent- or NK1R-induced neuronal excitation and Fos expression in dorsal horn. Implications for short- versus long-term modulation of nociceptive circuitry are discussed.
authors.affiliation: School of Biomedical Sciences, University of Leeds, Leeds, LS2 9NQ, UK.
authors.forename: H
authors.initials: H
authors.lastname: Badie-Mahdavi
authors.forename: M A
authors.initials: MA
authors.lastname: Worsley
authors.forename: M A
authors.initials: MA
authors.lastname: Ackley
authors.forename: A U
authors.initials: AU
authors.lastname: Asghar
authors.forename: J R
authors.initials: JR
authors.lastname: Slack
authors.forename: A E
authors.initials: AE
authors.lastname: King
mesh_terms: D000818:Animals; D004594:Electrophysiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D016762:Genes, fos; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology*; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D020671:Posterior Horn Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000502:physiology*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar; D018040:Receptors, Neurokinin-1 / Q000819:agonists; D015290:Second Messenger Systems / Q000502:physiology*; D013373:Substance P / Q000037:antagonists & inhibitors / Q000502:physiology*; D013569:Synapses / Q000378:metabolism
chemical_list: D064729:Neurokinin-1 Receptor Antagonists; D047428:Protein Kinase Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D018040:Receptors, Neurokinin-1; D013373:Substance P; D011494:Protein Kinases