Differential Rearrangement of Excitatory Inputs to the Medial Prefrontal Cortex in Chronic Pain Models

Abstract

Chronic pain patients suffer a disrupted quality of life not only from the experience of pain itself, but also from comorbid symptoms such as depression, anxiety, cognitive impairment, and sleep disturbances. The heterogeneity of these symptoms support the idea of a major involvement of the cerebral cortex in the chronic pain condition. Accordingly, abundant evidence shows that in chronic pain the activity of the medial prefrontal cortex (mPFC), a brain region that is critical for executive function and working memory, is severely impaired. Excitability of the mPFC depends on the integrated effects of intrinsic excitability and excitatory and inhibitory inputs. The main extracortical sources of excitatory input to the mPFC originate in the thalamus, hippocampus, and amygdala, which allow the mPFC to integrate multiple information streams necessary for cognitive control of pain including sensory information, context, and emotional salience. Recent techniques, such as optogenetic methods of circuit dissection, have made it possible to tease apart the contributions of individual circuit components. Here we review the synaptic properties of these main glutamatergic inputs to the rodent mPFC, how each is altered in animal models of chronic pain, and how these alterations contribute to pain-associated mPFC deactivation. By understanding the contributions of these individual circuit components, we strive to understand the broad spectrum of chronic pain and comorbid pathologies, how they are generated, and how they might be alleviated.

Identification and characterization of genetic risk shared across 24 chronic pain conditions in the UK Biobank

“…These findings are consistent with emerging views that chronic pain is a disease in its own right [116, 92, 124], meaning that one systemic pathology underlies disparate types of pain. Our results help identify and characterize the genetic components of this pathology and suggest that brain prefrontal and affective/motivational circuits may play a key role, supporting converging evidence from animal [117, 54, 141, 41, 52] and human [8, 91, 62, 70] studies. Together, this evidence underscores the importance of new ways to diagnose and treat chronic pain, whereby a given chronic pain condition is not considered as only a symptom of a localized somatic disease but is seen as a manifestation of an underlying shared pathology with concurrent risk for other pain conditions and previously unexplored centralized treatment targets.…”

“…There is converging evidence for the involvement of the nervous system: gene expression data shows an enrichment exclusively for brain tissues, and FUMA gene set analysis implicates biological processes specific to the nervous system. Echoing a recent report of heritability enrichment for chronic overlapping pain conditions exclusive to the CNS [59], these findings provide a genetic line of evidence for the reported alterations in brain circuitry shared by chronic pain conditions [116, 5, 62, 52]. In addition to CNS activity, however, the pathways mapped in FUMA implicate a broad range of other functions, such as gut development, locomotion, and protein secretion, suggesting that susceptibility to chronic pain may involve other systemic biological changes.…”

“…Evidence for central processes beyond local pathophysiology has been accumulating, including recent studies demonstrating that chronic pain is best conceptualized as a combination of biopsychosocial factors that may lead to a variety of pain conditions [21, 125, 75, 20, 124, 16]. Studies in rodents have identified neuroinflammation- and neuroplasticity-related changes in brain pathways that mediate persistent pain behavior in animal models of different pain modalities [143, 96, 91, 27, 6, 122, 52, 5, 37, 87]. Neuroimaging studies have identified common brain systems involved in musculoskeletal pain [79, 68, 17, 44, 67, 61, 90], IBS [106, 4], orofacial pain [2], neuropathic pain [95, 100, 139], and postsurgical pain [47].…”

Cholinergic basal forebrain nucleus of Meynert regulates chronic pain-like behavior via modulation of the prelimbic cortex

“…Latency (s) then sought to dissect the significance of NBM neuronal projections to the medial prefrontal cortex (mPFC), which represents a key hub in brain circuits underlying pain. The mPFC undergoes marked plasticity in several human clinical chronic pain conditions and particularly, a major focus has emerged on its deactivation observed in some chronic pain patients 15 , a finding that is also reported in animal models of neuropathic pain [16][17][18][19] . We therefore expressed ChR2-YFP in ChAT neurons of the NBM and placed the optic fiber for blue light illumination in the prelimbic cortex (PL), the mouse counterpart of the human mPFC (Fig.…”

Sleep deprivation and recovery sleep affect healthy male resident’s pain sensitivity and oxidative stress markers: The medial prefrontal cortex may play a role in sleep deprivation model

“…In chronic pain, the activity of the medial prefrontal cortex (mPFC), a brain region critical for executive function and working memory, is severely impaired. The major extracortical sources of excitatory input to the mPFC come from the thalamus, the hippocampus, and the amygdala, which enables the mPFC to integrate multiple streams of information required for the cognitive control of pain, namely, sensory information, context, and emotional salience ( Jefferson et al, 2021 ). One study found that one night of total SD impaired descending pain pathways and sensitized peripheral pathways to cold and pressure pain ( Staffe et al, 2019 ).…”