Dysfunction of cortical dendritic integration in neuropathic pain reversed by serotoninergic neuromodulation

Neuron. 2015 Apr 8;86(1):233-46. doi: 10.1016/j.neuron.2015.03.003. Epub 2015 Mar 26.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiovascular Agents / pharmacology
  • Cerebral Cortex / pathology*
  • Dendrites / metabolism
  • Dendrites / pathology*
  • Disease Models, Animal
  • Excitatory Postsynaptic Potentials / physiology
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / metabolism
  • Lysine / analogs & derivatives
  • Male
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Mice
  • Mice, Inbred C57BL
  • Neuralgia / pathology*
  • Neuralgia / therapy*
  • Neurons / pathology*
  • Neurons / physiology
  • Neurons / ultrastructure
  • Pain Measurement
  • Potassium Channels / metabolism
  • Pyrimidines / pharmacology
  • Receptors, Serotonin / metabolism
  • Serotonin / metabolism*
  • Serotonin Agents / pharmacology
  • Time Factors


  • Cardiovascular Agents
  • Hcn1 protein, mouse
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Potassium Channels
  • Pyrimidines
  • Receptors, Serotonin
  • Serotonin Agents
  • serotonin 7 receptor
  • ICI D2788
  • Serotonin
  • biocytin
  • Lysine