Role of PBN-CeA Circuit in Paclitaxel-Induced Neuropathic Pain and Negative Emotions.

Paclitaxel produces a chronic, glove-stocking neuropathy that is frequently accompanied by anxiety and depression. However, the neural circuits and molecular signals driving this pain-affect comorbidity remain unclear. Chemotherapy-induced neuropathic pain (CINP) was established by paclitaxel injections in male rats. Mechanical and thermal sensitivity and negative emotional behaviors were assessed using behavioral tests. Parabrachial nucleus (PBN)-central amygdala (CeA) projections were traced with viral vectors, and optogenetics was used to manipulate PBN terminals. Prodynorphin (PDYN) and κ-opioid receptor (KOR) mRNA levels were quantified by reverse transcription quantitative polymerase chain reaction (RT-qPCR). CINP rats developed persistent pain hypersensitivity and negative emotional behaviors, accompanied by increased CeA c-Fos and PDYN expression without changes in KOR mRNA. Intra-CeA administration of the KOR antagonist Navacaprant alleviated both pain and negative emotional behaviors. Optogenetic inhibition of the PBN-CeA pathway reduced CeA activation, attenuated pain hypersensitivity, and improved negative emotional behaviors, whereas pathway activation elicited both changes in naïve rats. Chronic inhibition of this pathway lowered CeA PDYN mRNA levels in CINP rats. The PBN-CeA pathway contributes to paclitaxel-induced neuropathic pain and anxiety-like behavior, and is associated with increased dynorphin expression in the CeA. Targeting this pathway or its downstream KOR may provide a therapeutic strategy for chemotherapy-related sensory and affective disturbances.