Chronic pain and adult hippocampal neurogenesis: translational implications from preclinical studies

Abstract

Adult hippocampal neurogenesis (ahNG) occurs in the human brain. Adult generated neurons have been proposed to functionally contribute to relevant hippocampal functions such as learning and memory, mood regulation, and stress response. Learning, environmental enrichment, and physical exercise exert positive effects on ahNG. In parallel, these proneurogenic stimuli have been shown to ameliorate cognitive performance and/or depressive-like behavior in animal models. Conversely, aging, social isolation, and chronic stress exert negative effects on ahNG. Interestingly, reduction of hippocampal neurogenesis is suggested to potentially contribute to cognitive decline and mood alterations associated with aging and several neuropsychiatric disorders. Clinical observation demonstrates that patients affected by chronic pain often exhibit increased anxiety and depression, impaired cognitive flexibility, and memory capacities. As of today, our understanding of the molecular and cellular events that may underlie the comorbidity of chronic pain, depression, and cognitive impairment is limited. Herein we review recent preclinical data suggesting that chronic pain may induce profound changes in hippocampal plasticity, including reduced ahNG. We discuss the possibility that deregulated hippocampal neurogenesis in chronic pain may, at least in part, contribute to cognitive and mood alterations. Based on this hypothesis, the mechanisms underlying chronic pain-associated changes in hippocampal neurogenesis and related functions need to be addressed experimentally. One interesting feature of ahNG is its susceptibility to pharmacological modulation. Again, based on preclinical data we discuss the possibility that, at least in principle, distinct analgesic drugs commonly used in chronic pain states (typical and atypical opiates, α2δ ligands, and acetyl-l-carnitine) may differentially impact ahNG and that this aspect could be taken into account to reduce and/or prevent the potential risk of cognitive and emotional side effects in the clinical setting.

Mast Cells in Stress, Pain, Blood-Brain Barrier, Neuroinflammation and Alzheimer’s Disease

“…Immobilization stress increases the number of open junctions and damaged tight junctions, increases the thickness of the basal membrane, and edema of astrocytes in the hippocampus (Santha et al, 2015). Stress and aging contribute to the cognitive decline and hippocampal neurogenesis (Grilli, 2017).…”

l-Acetylcarnitine: A Mechanistically Distinctive and Potentially Rapid-Acting Antidepressant Drug

“…The fact that both induction and prevention of depressive-like behavior and ahNG may rely on activation of NF-κB signaling pathway is likely to reflect the complexity within that regulatory system. The NF-κB protein family is composed of several members, in addition to p65, which can combine to form dimers with different subunit composition which can be differentially activated and exert distinct, even opposite, functions through activation of specific sets of gene targets [ 87 , 88 , 89 , 90 , 91 ]. The p65 as well as other NF-κB subunits can undergo different posttranslational modifications in addition to acetylation, including ubiquitination, phosphorylation, sumoylation, nitrosylation, and methylation [ 92 ].…”

Circular RNA expression profiling in dorsal root ganglion of rats with peripheral nerve injury-induced neuropathic pain

“…Increased phosphorylation of MAPK in DRG has also been shown to be an early event in neuropathic pain following peripheral nerve injury and the ERK/MAPK pathway has been considered as a novel therapeutic target for neuropathic pain [37]. Dysregulation of neuro-genes in the hippocampus has also been suggested to be involved in neuropathic pain [38]. Therefore, we hypothesized that the biological functions of DRG are widely modulated in neuropathic pain.…”