cardiovascular-agents and biocytin

Neuropathic pain is caused by long-term modifications of neuronal function in the peripheral nervous system, the spinal cord, and supraspinal areas. Although functional changes in the forebrain are thought to contribute to the development of persistent pain, their significance and precise subcellular nature remain unexplored. Using somatic and dendritic whole-cell patch-clamp recordings from neurons in the anterior cingulate cortex, we discovered that sciatic nerve injury caused an activity-dependent dysfunction of hyperpolarization-activated cyclic nucleotide-regulated (HCN) channels in the dendrites of layer 5 pyramidal neurons resulting in enhanced integration of excitatory postsynaptic inputs and increased neuronal firing. Specific activation of the serotonin receptor type 7 (5-HT7R) alleviated the lesion-induced pathology by increasing HCN channel function, restoring normal dendritic integration, and reducing mechanical pain hypersensitivity in nerve-injured animals in vivo. Thus, serotoninergic neuromodulation at the forebrain level can reverse the dendritic dysfunction induced by neuropathic pain and may represent a potential therapeutical target.

Topics: Animals; Cardiovascular Agents; Cerebral Cortex; Dendrites; Disease Models, Animal; Excitatory Postsynaptic Potentials; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Lysine; Male; Membrane Potentials; Mice; Mice, Inbred C57BL; Neuralgia; Neurons; Pain Measurement; Potassium Channels; Pyrimidines; Receptors, Serotonin; Serotonin; Serotonin Agents; Time Factors

Whole-cell recordings were obtained from tyrosine hydroxylase-expressing (TH(+)) neurons in striatal slices from bacterial artificial chromosome transgenic mice that synthesize enhanced green fluorescent protein (EGFP) selectively in neurons expressing TH transcriptional regulatory sequences. Stereological cell counting indicated that there were approximately 2700 EGFP-TH(+) neurons/striatum. Whole-cell recordings in striatal slices demonstrated that EGFP-TH(+) neurons comprise four electrophysiologically distinct neuron types whose electrophysiological properties have not been reported previously in striatum. EGFP-TH(+) neurons were identified in retrograde tracing studies as interneurons. Recordings from synaptically connected pairs of EGFP-TH(+) interneurons and spiny neurons showed that the interneurons elicited GABAergic IPSPs/IPSCs in spiny neurons powerful enough to significantly delay evoked spiking. EGFP-TH(+) interneurons responded to local or cortical stimulation with glutamatergic EPSPs. Local stimulation also elicited GABA(A) IPSPs, at least some of which arose from identified spiny neurons. Single-cell reverse transcription-PCR showed expression of VMAT1 in EGFP-TH(+) interneurons, consistent with previous suggestions that these interneurons may be dopaminergic as well as GABAergic. All four classes of interneurons were medium sized with modestly branching, varicose dendrites, and dense, highly varicose axon collateral fields. These data show for the first time that there exists in the normal rodent striatum a substantial population of TH(+)/GABAergic interneurons comprising four electrophysiologically distinct subtypes whose electrophysiological properties differ significantly from those of previously described striatal GABAergic interneurons. These interneurons are likely to play an important role in striatal function through fast GABAergic synaptic transmission in addition to, and independent of, their potential role in compensation for dopamine loss in experimental or idiopathic Parkinson's disease.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Action Potentials; Analysis of Variance; Animals; Anti-Inflammatory Agents; Bicuculline; Calcium Channel Blockers; Cardiovascular Agents; Cell Count; Colchicine; Corpus Striatum; Electric Stimulation; Excitatory Amino Acid Antagonists; Flufenamic Acid; GABA Antagonists; Green Fluorescent Proteins; In Vitro Techniques; Lysine; Mice; Mice, Transgenic; Neural Pathways; Neurons; Nimodipine; Patch-Clamp Techniques; Pyrimidines; Synapses; Synaptic Transmission; Time Factors; Tubulin Modulators; Tyrosine 3-Monooxygenase; Vesicular Monoamine Transport Proteins