title: Potentiation of glutamatergic synaptic transmission by protein kinase C-mediated sensitization of TRPV1 at the first sensory synapse.
abstract: Sensory input from the periphery to the CNS is critically dependent on the strength of synaptic transmission at the first sensory synapse formed between primary afferent dorsal root ganglion (DRG) and superficial dorsal horn (DH) neurons of the spinal cord. Transient receptor potential vanilloid 1 (TRPV1) expressed on a subset of sensory neurons plays an important role in chronic inflammatory thermal nociception. Activation of protein kinase C (PKC) sensitizes TRPV1, which may contribute to the pathophysiology of chronic pain conditions. In this study, we have examined the modulation of TRPV1-mediated enhancement of excitatory synaptic transmission in response to PKC activation. Miniature excitatory postsynaptic currents (mEPSCs) from embryonic rat DRG-DH neuronal cocultures were recorded by patch clamping DH neurons. Capsaicin potently increased the frequency but not the amplitude of mEPSCs in a calcium-dependent manner, suggesting TRPV1-mediated glutamate release from presynaptic terminals of sensory neurons. Continued or repeated applications of capsaicin reduced the frequency of mEPSCs over time. The PKC activator phorbol 12,13-dibutyrate (PDBu) alone increased mEPSC events to a certain extent in a reversible manner but capsaicin further synergistically enhanced the frequency of mEPSCs. The PKC inhibitor bisindolylmaleimide (BIM) abolished PDBu-mediated potentiation of TRPV1-dependent increases in mEPSC frequency, suggesting modulation of TRPV1 by PKC-induced phosphorylation. In addition, at normal body temperatures ( approximately 37 degrees C) PKC-mediated enhancement of mEPSC frequency is significantly decreased by a specific TRPV1 antagonist, suggesting a physiological role of TRPV1 at the central terminals. Furthermore, bradykinin (BK) significantly potentiated TRPV1-modulated synaptic responses by activating the PLC-PKC pathway. Our results indicate that TRPV1 activation can modulate excitatory synaptic transmission at the first sensory synapse and its effects can further be augmented by activation of PKC. Increased gain of sensory input by TRPV1-induced enhancement of glutamate release and its potentiation by various inflammatory mediators may contribute to persistent pain conditions. Selective targeting of TRPV1 expressed on the central terminals of sensory neurons may serve as a strategy to alleviate chronic intractable pain conditions.
authors.affiliation: Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, IL 62702, USA.
authors.forename: Parul
authors.initials: P
authors.lastname: Sikand
authors.forename: Louis S
authors.initials: LS
authors.lastname: Premkumar
mesh_terms: D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D002478:Cells, Cultured; D018920:Coculture Techniques; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials; D005727:Ganglia, Spinal / Q000187:drug effects / Q000196:embryology / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D009473:Neuronal Plasticity / Q000187:drug effects; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism*; D010146:Pain / Q000378:metabolism / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D010766:Phosphorylation; D020671:Posterior Horn Cells / Q000187:drug effects / Q000196:embryology / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission / Q000187:drug effects; D050916:TRPV Cation Channels / Q000378:metabolism*; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D005973:Glutamine; D015240:Phorbol 12,13-Dibutyrate; D011493:Protein Kinase C; D010738:Type C Phospholipases; C088060:bisindolylmaleimide; D002211:Capsaicin; D001920:Bradykinin; D002118:Calcium