Metabotropic Glutamate Receptor 5 in the Medial Prefrontal Cortex as a Molecular Determinant of Pain and Ensuing Depression

Abstract

Pain and depression affect one another, and this bidirectional interaction implies the existence of common or interacting neural pathways. Among the neural circuits relevant to negative affection, the medial prefrontal cortex (mPFC) is known to be involved in both pain and depression. Persistent stress from physical pain and mental distress can evoke maladaptive changes in mPFC circuits to induce depression. Conversely, the unpleasant mood condition alters mPFC circuits to distort the appraisal of aversion and make individuals vulnerable to pain. In this article, recent findings regarding mPFC in chronic pain and/or depression are reviewed, with particular focus on the metabotropic glutamate receptor 5 (mGluR5). Although the involvement of mGluR5 within the mPFC in both pain and depressive disorders has been extensively studied, there are controversies regarding changes in the activity of the mPFC during chronic pain and depression, and the functional roles of mGluR5 on altered mPFC activity. We discuss alterations in the availability of mGluR5 in the mPFC in these disorders, its role in behavioral manifestations, and its possible influence on cellular subpopulations that mediate dysfunction in the mPFC. We also propose molecular mechanisms that may cause expressional changes in mGluR5 within the mPFC circuitry.

Multiregional profiling of the brain transmembrane proteome uncovers novel regulators of depression

“…5F and table S7). In accordance with the PCA plot, the largest number of DE transmembrane proteins were found in PFC and HY, two brain regions critical for mood regulation and stress response ( 31 – 34 ). A total of 91 up-regulated and 142 down-regulated unique proteins from the three families were identified from our brain proteome profiling of the CUMS model, which uncovered the most comprehensive landscape of transmembrane proteome remodeling associated with depression pathogenesis.…”

“…After an extensive literature search, we were excited to find 19 DE GPCRs identified from the three regions turned out to be disclosed regulators of depressive-like behaviors and serve as potential antidepression targets, all uncovered by pharmacological intervention and/or genetic manipulation in vivo ( Fig. 6 ; individual target references in table S8) ( 34 , 36 – 57 ). Adenosine receptor A1 (A 1 R) was significantly down-regulated in the PFC and HIP of CUMS mice ( Fig.…”

“…Given our particular interest in mining the GPCR family in search of the molecular regulators, we examined 35 GPCRs showing significant differential expression in PFC, HIP, or HY, three regions engaged in mood disorder and development of depression (31)(32)(33)(34). After an extensive literature search, we were excited to find 19 DE GPCRs identified from the three regions turned out to be disclosed regulators of depressive-like behaviors and serve as potential antidepression targets, all uncovered by pharmacological intervention and/or genetic manipulation in vivo (Fig.…”

Light-Induced Activation of a Specific Type-5 Metabotropic Glutamate Receptor Antagonist in the Ventrobasal Thalamus Causes Analgesia in a Mouse Model of Breakthrough Cancer Pain

“…To examine the efficacy of light-induced activation of JF-NP-26 in the ET-1 BTcP model, different groups of mice were bilaterally implanted with optic fibers in the ventral basal thalamus or in the prelimbic cortex, two brain regions in which mGlu5 receptors are involved in pain transmission and nociceptive sensibilization [ 17 , 18 ]. Light was delivered at a wavelength of 405 nm, which has been identified as the optimal VS wavelength causing photolysis of JF-NP-26, into the active mGlu5 receptor NAM, raseglurant [ 6 ].…”

Neuroimmune Interactions in Pain and Stress: An Interdisciplinary Approach

“…Chronic back pain was also found to be associated with reduced gray matter density in the dorsolateral prefrontal cortex and anterior thalamus (Apkarian and others 2004). Notably, increased activity of the medial prefrontal cortex has been demonstrated in patients with high levels of back pain (Baliki and others 2006) and depressive disorders (Chung and others 2018). Functional imaging studies in patients with complex regional pain syndrome, which is manifested by sensory, motor, and autonomic symptoms, revealed functional cortical changes that reversed with resolution of symptoms (Henry and others 2011).…”