Dynamic Change of Endocannabinoid Signaling in the Medial Prefrontal Cortex Controls the Development of Depression After Neuropathic Pain.

Autor:	Mecca CM; Departments of Anesthesiology.; Cell Biology, Neurobiology, and Anatomy., Chao D; Departments of Anesthesiology., Yu G; Departments of Anesthesiology., Feng Y; Departments of Anesthesiology., Segel I; Departments of Anesthesiology., Zhang Z; Departments of Anesthesiology., Rodriguez-Garcia DM; Cell Biology, Neurobiology, and Anatomy., Pawela CP; Departments of Anesthesiology.; Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226., Hillard CJ; Pharmacology and Toxicology.; Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226., Hogan QH; Departments of Anesthesiology.; Cell Biology, Neurobiology, and Anatomy.; Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226., Pan B; Departments of Anesthesiology bpan@mcw.edu.; Cell Biology, Neurobiology, and Anatomy.; Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226.
Jazyk:	angličtina
Zdroj:	The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2021 Sep 01; Vol. 41 (35), pp. 7492-7508. Date of Electronic Publication: 2021 Jul 09.
DOI:	10.1523/JNEUROSCI.3135-20.2021
Abstrakt:	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, and behavioral and electrophysiological experiments were used to evaluate the 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 a 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. SIGNIFICANCE STATEMENT Pain has both somatosensory and affective components, so the complexity of mechanisms underlying chronic pain is best represented by a biopsychosocial model that includes widespread CNS dysfunction. Many patients with chronic pain conditions develop depression. The mechanism by which pain causes depression is unclear. Although manipulation of the eCB signaling system as an avenue for providing analgesia per se has not shown much promise in previous studies. An important limitation of past research has been inadequate consideration of the dynamic nature of the connection between pain and depression as they develop. Here, we show that activity-dependent synthesis of eCBs during the initial onset of persistent pain is the critical link leading to depression when pain is persistent. (Copyright © 2021 the authors.)
Databáze:	MEDLINE
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