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

Abstract

BackgroundThe mesolimbic reward system plays a critical role in modulating nociception; however, its underlying molecular, cellular, and neural circuitry mechanisms remain unknown. MethodsChronic 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 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. Resultsc-Fos expression in and firing of contralateral VTA−NAc dopaminergic 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 messenger RNA in the contralateral NAc. This increase was reversed by pharmacological inhibition of VTA dopaminergic 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 was antinociceptive in CCI mice. ConclusionsThese 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.