The emerging role of the BDNF-TrkB signaling pathway in the modulation of pain perception

Cappoli, Natalia; Tabolacci, Elisabetta; Aceto, Paola; Russo, Cinzia Dello

doi:10.1016/j.jneuroim.2020.577406

Cited by 81 publications

(79 citation statements)

References 137 publications

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“…Evidence suggests that early-stage neuroinflammation, potentially caused by acute injury, inhibits GABAAα1 expression through astrocyte activation, which subsequently downregulates the BDNF-TrkB signal pathway and results in an impairment of neurogenesis, thus affecting depression-like symptoms concurrently associated with chronic pain comorbidities [ 50 ]. Accordingly, TrkB receptor modulation has been identified for its apparent role in nociceptive signaling [ 51 ], with further anti-depressive effects being linked to BDNF-TrkB-ERK/Akt signaling activation and upregulation [ 52 ]. Additionally, the phosphorylation of certain TrkB residues is largely responsible for inducing intracellular Ca 2+ release and activation of calcium-dependent signaling, which represents the primary regulator of synaptic plasticity [ 53 ], and accordingly can be linked to TRPV1 functioning as a Ca 2+ channel respondent.…”

Section: Discussionmentioning

confidence: 99%

TRPV1 Responses in the Cerebellum Lobules VI, VII, VIII Using Electroacupuncture Treatment for Chronic Pain and Depression Comorbidity in a Murine Model

Lottering

Lin

2021

IJMS

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Depression is a prominent complex psychiatric disorder, usually complicated through expression of comorbid conditions, with chronic pain being among the most prevalent. This comorbidity is consistently associated with a poor prognosis and has been shown to negatively impact patient outcomes. With a global rise in this condition presenting itself, the importance of discovering long-term, effective, and affordable treatments is crucial. Electroacupuncture has demonstrated renowned success in its use for the treatment of pain and is a widely recognized therapy in clinical practice for the treatment of various psychosomatic disorders, most notably depression. Our study aimed to investigate the effects and mechanisms of Acid-Saline (AS) inducing states of chronic pain and depression comorbidity in the cerebellum, using the ST36 acupoint as the therapeutic intervention. Furthermore, the role of TRPV1 was relatedly explored through the use of TRPV1−/− mice (KO). The results indicated significant differences in the four behavioral tests used to characterize pain and depression states in mice. The AS and AS + SHAM group showed significant differences when compared to the Control and AS + EA groups in the von Frey and Hargreaves’s tests, as well as the Open-Field and Forced Swimming tests. This evidence was further substantiated in the protein levels observed in immunoblotting, with significant differences between the AS and AS + SHAM groups when compared to the AS + EA and AS + KO groups being identified. In addition, immunofluorescence visibly served to corroborate the quantitative outcomes. Conclusively these findings suggest that AS-induced chronic pain and depression comorbidity elicits changes in the cerebellum lobules VI, VII, VIII, which are ameliorated through the use of EA at ST36 via its action on TRPV1 and related molecular pathways. The action of TRPV1 is not singular in CPDC, which would suggest other potential targets such as acid-sensing ion channel subtype 3 (ASIC3) or voltage-gated sodium channels (Navs) that could be explored in future studies.

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Section: Discussionmentioning

confidence: 99%

TRPV1 Responses in the Cerebellum Lobules VI, VII, VIII Using Electroacupuncture Treatment for Chronic Pain and Depression Comorbidity in a Murine Model

Lottering

Lin

2021

IJMS

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“…For instance, the PI3K/AKT pathway promotes anti-apoptotic signaling and pro-survival activity and regulates N-methyl-D-aspartic acid (NMDA) receptor-dependent synaptic plasticity [ 30 , 31 , 32 ]. MAPK/ERK pathways activated by BDNF seem to be relevant for local protein synthesis involved in prolonged increase in synaptic transmission, essential in neuronal plasticity and long-term potentiation [ 33 ], and they have an important role in neuronal growth and differentiation [ 34 ].…”

Section: Introductionmentioning

confidence: 99%

7,8-Dihydroxiflavone Protects Adult Rat Axotomized Retinal Ganglion Cells through MAPK/ERK and PI3K/AKT Activation

Galindo‐Romero

Vidal‐Villegas

Asís‐Martínez

et al. 2021

IJMS

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We analyze the 7,8-dihydroxyflavone (DHF)/TrkB signaling activation of two main intracellular pathways, mitogen-activated protein kinase (MAPK)/ERK and phosphatidylinositol 3 kinase (PI3K)/AKT, in the neuroprotection of axotomized retinal ganglion cells (RGCs). Methods: Adult albino Sprague-Dawley rats received left intraorbital optic nerve transection (IONT) and were divided in two groups. One group received daily intraperitoneal DHF (5 mg/kg) and another vehicle (1%DMSO in 0.9%NaCl) from one day before IONT until processing. Additional intact rats were employed as control (n = 4). At 1, 3 or 7 days (d) after IONT, phosphorylated (p)AKT, p-MAPK, and non-phosphorylated AKT and MAPK expression levels were analyzed in the retina by Western blotting (n = 4/group). Radial sections were also immunodetected for the above-mentioned proteins, and for Brn3a and vimentin to identify RGCs and Müller cells (MCs), respectively (n = 3/group). Results: IONT induced increased levels of p-MAPK and MAPK at 3d in DHF- or vehicle-treated retinas and at 7d in DHF-treated retinas. IONT induced a fast decrease in AKT in retinas treated with DHF or vehicle, with higher levels of phosphorylation in DHF-treated retinas at 7d. In intact retinas and vehicle-treated groups, no p-MAPK or MAPK expression in RGCs was observed. In DHF- treated retinas p-MAPK and MAPK were expressed in the ganglion cell layer and in the RGC nuclei 3 and 7d after IONT. AKT was observed in intact and axotomized RGCs, but the signal intensity of p-AKT was stronger in DHF-treated retinas. Finally, MCs expressed higher quantities of both MAPK and AKT at 3d in both DHF- and vehicle-treated retinas, and at 7d the phosphorylation of p-MAPK was higher in DHF-treated groups. Conclusions: Phosphorylation and increased levels of AKT and MAPK through MCs and RGCs in retinas after DHF-treatment may be responsible for the increased and long-lasting RGC protection afforded by DHF after IONT.

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“…The emerging field of epigenetics may partially explain our findings, suggesting that early‐life adversity, or even pre‐natal maternal trauma, may increase vulnerabilities to future pain and trauma through DNA methylation (Jiang et al., 2019; Maddox et al., 2013). A review by Jiang and colleagues (Jiang et al., 2019) described several gene targets with evidence of methylation following childhood adversity, among those are genes that have also been associated with post‐trauma distress, pain severity and pain persistence including genes for FK‐Binding Protein‐5 (Ulirsch et al., 2014), Brain‐Derived Neurotrophic Factor (Cappoli et al.,) and the serotonin transporter gene SLC6A4 (Farmer et al., 2013). While these may indicate a shared aetiology between childhood adversity, traumatic distress and physical pain, long‐term prospective studies starting from childhood will be needed to more fully explore these hypotheses.…”

Section: Discussionmentioning

confidence: 99%

Effects of childhood trauma on pain‐related distress in adults

Walton

Tremblay

Seo

et al. 2021

European Journal of Pain

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Background Much of the work in post‐musculoskeletal (MSK) trauma and distress has been conducted through frameworks that start from the injury and go forward to better understand the trajectories and predictors of recovery. However, stress–diatheses models suggest that reactions to trauma are shaped by pre‐existing experiences of the person more than the parameters of the event itself. In this study, we explore the effects of adverse childhood experiences (ACEs) on traumatic threat appraisal, distress and pain‐related functional interference in adulthood. Methods Adult participants with acute, non‐catastrophic musculoskeletal trauma completed a battery of questionnaires that included the Adverse Childhood Experiences Questionnaire (ACEQ), the Brief Illness Perceptions Questionnaire (BIPQ), the Traumatic Injuries Distress Scale (TIDS) and the Brief Pain Inventory (BPI). An a priori model was evaluated through path analysis to determine the variance in BPI Interference scores explained through direct or indirect pathways between these variables (ACEQ‐>BIPQ, BIPQ‐>TIDS, TIDS‐>BPI). The analysis was repeated for the sample when disaggregated by sex. Results In n = 114, the base model was saturated. After removing non‐significant pathways, the ACEQ‐>BIPQ‐>TIDS‐>BPI paths were significant and in the expected direction, explaining 57.1% of variance in acute BPI Interference score. When disaggregated by sex, the effect of ACEs on threat appraisal was only significant in men and not women, although this analysis was exploratory. Conclusions Acute pain‐related interference could be predicted by post‐traumatic distress and threat appraisal. Threat appraisal could be further predicted through ACEs, more childhood adversities were associated with more threatening appraisal of trauma in adulthood. The disaggregated finding that the effects of childhood adversities were only significant in males requires further exploration. Significance This study explores the potential pathways of the stress–diathesis model while focusing on adverse childhood experiences as a novel contribution to the field of acute post‐trauma pain. The findings may inform future research design and interpretation of acute‐to‐chronic pain risk stratification tools.

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The emerging role of the BDNF-TrkB signaling pathway in the modulation of pain perception

Cited by 81 publications

References 137 publications

TRPV1 Responses in the Cerebellum Lobules VI, VII, VIII Using Electroacupuncture Treatment for Chronic Pain and Depression Comorbidity in a Murine Model

TRPV1 Responses in the Cerebellum Lobules VI, VII, VIII Using Electroacupuncture Treatment for Chronic Pain and Depression Comorbidity in a Murine Model

7,8-Dihydroxiflavone Protects Adult Rat Axotomized Retinal Ganglion Cells through MAPK/ERK and PI3K/AKT Activation

Effects of childhood trauma on pain‐related distress in adults

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