Loss of M1 receptor dependent cholinergic excitation contributes to mPFC deactivation in neuropathic pain

Daniel Radzicki, Sarah L. Pollema-Mays, Antonio Sanz-Clemente, Marco Martina*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

38 Scopus citations


In chronic pain, the medial prefrontal cortex (mPFC) is deactivated and mPFC-dependent tasks such as attention and working memory are impaired. We investigated the mechanisms of mPFC deactivation in the rat spared nerve injury (SNI) model of neuropathic pain. Patch-clamp recordings in acute slices showed that, 1 week after the nerve injury, cholinergic modulation of layer 5 (L5) pyramidal neurons was severely impaired. In cells from sham-operated animals, focal application of acetylcholine induced a left shift of the input/output curve and persistent firing. Both of these effects were almost completely abolished in cells from SNI-operated rats. The cause of this impairment was an ~ 60% reduction of an M1-coupled, pirenzepine-sensitive depolarizing current, which appeared to be, at least in part, the consequence of M1 receptor internalization. Although no changes were detected in total M1 protein or transcript, both the fraction of theM1receptor in the synaptic plasma membrane and the biotinylatedM1protein associated with the total plasma membrane were decreased in L5 mPFC of SNI rats. The loss of excitatory cholinergic modulation may play a critical role in mPFC deactivation in neuropathic pain and underlie the mPFC-specific cognitive deficits that are comorbid with neuropathic pain.

Original languageEnglish (US)
Pages (from-to)2292-2304
Number of pages13
JournalJournal of Neuroscience
Issue number9
StatePublished - Mar 1 2017


  • Internalization
  • Muscarinic
  • Pyramidal cell
  • SNI
  • Working memory

ASJC Scopus subject areas

  • Neuroscience(all)


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