Orexin-A signaling modulates dopamine neurons and palatable food seeking: potential involvement of μ-opioid receptor signaling pathway.

Obesity is associated with binge eating and abnormal activation of the reward pathway. Hypothalamic neuropeptides such as orexin-A and μ-opioid receptor signaling are closely involved in feeding behavior and reward processing; however, the interaction between orexin-A and μ-opioid receptor signaling in palatable food seeking remains unclear. We used fluorogold retrograde tracing to examine neural projection between the perifornical region (PeF) and the ventral tegmental area (VTA). Immunohistochemical staining was performed to assess the distribution of orexin-A receptor 1 (OX1-R) and tyrosine hydroxylase (TH) neurons in the VTA. Subsequently, drugs were administered into the VTA to investigate the interactions between orexin-A and μ-opioid receptor antagonist naltrexone (NTX) in regulating palatable food seeking and the firing frequency of VTA dopamine (DA) neurons. Fluorogold-labeled orexin-A neurons were observed in the PeF, and co-localization of OX1R and TH neurons was detected in the VTA. Furthermore, electrical stimulation (ES) of the PeF or administration of orexin-A into the VTA increased the expression of c-Fos in TH-positive neurons, providing an anatomical basis for this study. Microinjection of orexin-A into the VTA promoted palatable food seeking in rats, an effect that was completely blocked by pre-administration of the OX1R antagonist SB-334867. In addition, orexin-A and NTX were found to modulate the firing frequency of VTA DA neurons, suggesting that orexin-A and μ-opioid receptor signaling may regulate palatable food seeking through their actions on VTA DA neurons. This study sheds light on the interaction between orexin-A and the μ-opioid system in regulating palatable food seeking and the firing frequency of VTA DA neurons.