Neuroinflammation, Pain and Depression: An Overview of the Main Findings

Abstract

Chronic pain is a serious public health problem with a strong affective-motivational component that makes it difficult to treat. Most patients with chronic pain suffer from severe depression; hence, both conditions coexist and exacerbate one another. Brain inflammatory mediators are critical for maintaining depression-pain syndrome and could be substrates for it. The goal of our paper was to review clinical and preclinical findings to identify the neuroinflammatory profile associated with the cooccurrence of pain and depression. In addition, we aimed to explore the regulatory effect of neuronal reorganization on the inflammatory response in pain and depression. We conducted a quantitative review supplemented by manual screening. Our results revealed inflammatory signatures in different preclinical models and clinical articles regarding depression-pain syndrome. We also identified that improvements in depressive symptoms and amelioration of pain can be modulated through direct targeting of inflammatory mediators, such as cytokines and molecular inhibitors of the inflammatory cascade. Additionally, therapeutic targets that improve and regulate the synaptic environment and its neurotransmitters may act as anti-inflammatory compounds, reducing local damage-associated molecular patterns and inhibiting the activation of immune and glial cells. Taken together, our data will help to better elucidate the neuroinflammatory profile in pain and depression and may help to identify pharmacological targets for effective management of depression-pain syndrome.

Keywords: depression; depression-pain syndrome; glial cells; neuroinflammation; pain.

FIGURE 1

Flowchart of the study.

FIGURE 2

Schematic representation of depressive-pain syndrome and the relationship between target structures and mediators. Target structures with inflammatory signatures in the identified articles. AMY, amygdala; DHSC, dorsal horn of the spinal cord; HC, hippocampus; HPT, hypothalamus; LC, locus coeruleus; PAG, periaqueductal gray matter; PFC, prefrontal cortex; PIT, pituitary; RN, raphe nuclei.

FIGURE 3

Schematic representation of the classic mechanisms of the different classes of medications investigated in this review. CCK2, cholecystokinin 2; CCK-R, cholecystokinin receptors; GZA, glycyrrhizic acid; HMGB-1, high mobility group box-1; IDO1, indolamine 1,3 deoxygenase; KMO, kynurenine 3-monooxygenase; NMDA, N-methyl-D-aspartate; NSAIDs, non-steroidal anti-inflammatory drugs; PKR, prokineticin family; PPARy, peroxisome proliferator-activated receptor gamma; PRF, pulsed radiofrequency; TLRs, toll-like receptors; TSPO, translocator protein; ZBD, N-benzyl-Nethyl-2-(7,8-dihydro-7-benzyl-8-oxo-2-phenyl-9H-purin-9-yl) acetamide.

FIGURE 4

Review of inflammatory signature and neural network modulation. Depressive pain syndrome is related to activation of glial cells, such as microglia and astrocytes. Once classically activated (M1/A1), these cells release proinflammatory cytokines, especially TNF-α and IL-1β, and upon specific receptor activation, increase glutamate release in the synaptic cleft. Classically activated astrocytes induce a decrease in GLT-1, which enables the reuptake of glutamate and decreases glutamate-induced cytotoxicity. Hence, both AMPA and NMDA postsynaptic receptors are strongly activated, decreasing the frequency amplitude and contributing to neural network imbalance. On the other hand, anti-inflammatory treatments inhibit the classic activation of glial cells and the exacerbated release of proinflammatory mediators, decreasing neural network imbalance. In addition, the success of pharmacological treatments that act through mechanisms related to neuronal dysfunction, such as ketamine and fluoxetine, which improve neuronal network dysfunction and attenuating depressive pain syndrome, also corroborate the negative feedback of inflammation. GLT, glutamate transporter; PGE, prostaglandin.