Dynamic change of endocannabinoid signaling in the medial prefrontal cortex controls the development of depression after neuropathic pain

Christina M. Mecca, Dongman Chao, Guoliang Yu, Yin Feng, Ian Segel, Zhiyong Zhang, Dianise M. Rodriguez-Garcia, Christopher Pawela, Cecilia J. Hillard, Quinn H. Hogan, Bin Pan

Research output: Contribution to journalArticlepeer-review

Abstract

Many patients with chronic pain conditions suffer from depression. The mechanisms underlying pain-induced depression are still unclear. There are critical links of medial prefrontal cortex (mPFC) synaptic function to depression, with signaling through the endocannabinoid (eCB) system as an important contributor. We hypothesized that afferent noxious inputs after injury compromise activity-dependent eCB signaling in the mPFC, resulting in depression. Depression-like behaviors were tested in male and female rats with traumatic neuropathy (spared nerve injury, SNI) and neuronal activity in the mPFC was monitored using the immediate early gene, c-Fos, and in vivo electrophysiological recordings. mPFC eCB concentrations were determined using mass spectrometry while behavioral and electrophysiological experiments were employed to evaluate role of alterations in eCB signaling in depression after pain. SNI-induced pain induced the development of depression phenotypes in both male and female rats. Pyramidal neurons in mPFC showed increased excitability followed by reduced excitability in the onset and prolonged phases of pain, respectively. Concentrations of the eCBs, 2-arachidonoylglycerol (2-AG) in the mPFC, were elevated initially after SNI and our results indicate that this resulted in loss of CB1R function on GABAergic interneurons in the mPFC. These data suggest that excessive release of 2-AG as a result of noxious stimuli triggers use-dependent loss of function of eCB signaling leading to excessive GABA release in the mPFC, with the final result being behavioral depression.

Original languageEnglish (US)
JournalJournal of Neuroscience
Volume41
Issue number35
DOIs
StatePublished - Sep 1 2021
Externally publishedYes

ASJC Scopus subject areas

  • General Neuroscience

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