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

      Journal of Pain Research

      Dove Medical Press

      chronic pain, adult neurogenesis, depression, cognition, opiates, tapentadol, pregabalin

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          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.

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          Most cited references 60

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          Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression.

          Understanding the physiopathology of affective disorders and their treatment relies on the availability of experimental models that accurately mimic aspects of the disease. Here we describe a mouse model of an anxiety/depressive-like state induced by chronic corticosterone treatment. Furthermore, chronic antidepressant treatment reversed the behavioral dysfunctions and the inhibition of hippocampal neurogenesis induced by corticosterone treatment. In corticosterone-treated mice where hippocampal neurogenesis is abolished by X-irradiation, the efficacy of fluoxetine is blocked in some, but not all, behavioral paradigms, suggesting both neurogenesis-dependent and -independent mechanisms of antidepressant action. Finally, we identified a number of candidate genes, the expression of which is decreased by chronic corticosterone and normalized by chronic fluoxetine treatment selectively in the hypothalamus. Importantly, mice deficient in one of these genes, beta-arrestin 2, displayed a reduced response to fluoxetine in multiple tasks, suggesting that beta-arrestin signaling is necessary for the antidepressant effects of fluoxetine.
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            Early determination and long-term persistence of adult-generated new neurons in the hippocampus of mice.

            New neurons are continually generated in the adult hippocampus, but the important question, whether adult neurogenesis is transient or leads to the lasting presence of new neurons, has not yet been answered. Dividing cells were labeled with bromodeoxyuridine (BrdU) and were investigated by means of immunofluorescence and confocal microscopy at several time-points 1 day to 11 months thereafter. BrdU-labeled neurons remained stable in number and in their relative position in the granule cell layer over at least 11 months. This finding implies that the addition of new neurons is not transient and that their final number and localization are determined early. By contrast, expression of immature markers beta-III-tubulin and doublecortin in BrdU-labeled cells, peaked early after division and was not detectable after 4 weeks. In transgenic mice expressing enhanced green fluorescent protein under the nestin promoter none of the BrdU/nestin-positive cells early after division expressed the mature marker NeuN, confirming that no dividing neurons were detected. These new data suggest that new neurons are recruited early from the pool of proliferating progenitor cells and lead to a lasting effect of adult neurogenesis.
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              Mood and anxiety disorders associated with chronic pain: an examination in a nationally representative sample.

              Chronic pain and psychiatric disorders frequently co-occur. However, estimates of the magnitude of these associations have been biased by the use of select clinical samples. The present study utilized the National Comorbidity Survey [Arch. Gen. Psychiatry 51 (1994) 8-19] Part II data set to investigate the associations between a chronic pain condition (i.e. arthritis) and common mood and anxiety disorders in a sample representative of the general US civilian population. Participants (N=5877) completed the Composite International Diagnostic Interview [World Health Organization (1990)], a structured interview for trained non-clinician interviewers based on the revised third edition of the Diagnostic and Statistical Manual of Mental Disorders [American Psychiatric Association (1987)], and provided self-reports of pain and disability associated with a variety of medical conditions. Significant positive associations were found between chronic pain and individual 12-month mood and anxiety disorders [odds ratios (OR) ranged from 1.92 to 4.27]. The strongest associations were observed with panic disorder (OR=4.27) and post-traumatic stress disorder (OR=3.69). The presence of one psychiatric disorder was not significantly associated with pain-related disability, but the presence of multiple psychiatric disorders was significantly associated with increased disability. The findings of the present study raise the possibility that improved efforts regarding the detection and treatment of anxiety disorders may be required in pain treatment settings.
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                Author and article information

                Journal
                J Pain Res
                J Pain Res
                Journal of Pain Research
                Journal of Pain Research
                Dove Medical Press
                1178-7090
                2017
                21 September 2017
                : 10
                : 2281-2286
                Affiliations
                Laboratory of Neuroplasticity, Department of Pharmaceutical Sciences, University of Piemonte Orientale, Novara, Italy
                Author notes
                Correspondence: Mariagrazia Grilli, Department of Pharmaceutical Sciences, University of Piemonte Orientale, Via Bovio 6, 28100 Novara, Italy, Tel +39 03 2137 5828, Fax +39 03 2137 5821, Email mariagrazia.grilli@ 123456uniupo.it
                Article
                jpr-10-2281
                10.2147/JPR.S146399
                5614764
                © 2017 Grilli. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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