Brain-Derived Neurotrophic Factor in the Mesolimbic Reward Circuitry Mediates Nociception in Chronic Neuropathic Pain

Abstract

BACKGROUND The mesolimbic reward system plays a critical role in modulating nociception; however, its underlying molecular, cellular, and neural circuitry mechanisms remain unknown. METHODS Chronic constrictive injury (CCI) of the sciatic nerve was used to model neuropathic pain. Projection-specific in vitro recordings in mouse brain slices and in vivo recordings from anesthetized animals were used to measure firing of dopaminergic (DA) neurons in the ventral tegmental area (VTA). The role of VTA–nucleus accumbens (NAc) circuitry in nociceptive regulation was assessed using optogenetic and pharmacological manipulations, and the underlying molecular mechanisms were investigated by Western blotting, enzyme-linked immunosorbent assays, and conditional knockdown techniques. RESULTS c-Fos expression in and firing of contralateral VTA–NAc DA neurons were elevated in CCI mice, and optogenetic inhibition of these neurons reversed CCI-induced thermal hyperalgesia. CCI increased the expression of brain-derived neurotrophic factor (BDNF) protein but not mRNA in the contralateral NAc. This increase was reversed by pharmacological inhibition of VTA DA neuron activity, which induced an antinociceptive effect that was neutralized by injecting exogenous BDNF into the NAc. Moreover, inhibition of BDNF synthesis in the VTA with anisomycin or selective knockdown of BDNF in the VTA–NAc pathway were antinociceptive in CCI mice. CONCLUSIONS These results reveal a novel mechanism of nociceptive modulation in the mesolimbic reward circuitry and provide new insight into the neural circuits involved in the processing of nociceptive information.

The Mesolimbic Dopamine System in Chronic Pain and Associated Affective Comorbidities

“…Several of the identified genes and pathways have documented roles in neuropsychiatric disorders. For example, recent studies pointed to the role of brainderived neurotrophic factor and tumor necrosis factor-alpha (TNF-a) in regulating symptoms of chronic pain, depression, and addiction (127)(128)(129)(130). RNA sequencing studies by Mitsi et al, which used the SNI model to monitor gene expression adaptations in response to desipramine treatment, showed that recovery from chronic pain states coincides with an upregulation of genes and intracellular cascades in neurons of the indirect pathway.…”

Physical Activity Induces Nucleus Accumbens Genes Expression Changes Preventing Chronic Pain Susceptibility Promoted by High-Fat Diet and Sedentary Behavior in Mice

“…However, it is important to emphasize that studies with humans from functional magnetic resonance imaging showed evidence that chronic pain and neuroplasticity are a cognitive maladaptive learning process (Apkarian et al, 2011;Mansour et al, 2014;DosSantos et al, 2017). Whereas studies with animal models investigated the role of one single molecular signaling related to neuroplasticity, such as BDNF/TrkB pathway, for instance (Zhang et al, 2014(Zhang et al, , 2017Wang et al, 2017). This controversy associating neuroplasticity to chronic pain facilitation or chronic pain susceptibility prevention, may be explained, in our study, by the early gene expression changes in the NAc caused by HFD employed 6 weeks before the voluntary physical activity period.…”

Ginsenoside Rf relieves mechanical hypersensitivity, depression‐like behavior, and inflammatory reactions in chronic constriction injury rats

“…Both clinical observations and animal studies demonstrate the comorbidity of neuropathic pain and depression (Li, ; Zhang et al, ). The treatment of these subjects usually requires the combinatorial medications to respectively relieve pain symptoms and depression.…”