Brain site-specific regulation of hedonic intake by orexin and DYN peptides: role of the PVN and obesity

Nutr Neurosci. 2022 May;25(5):1105-1114. doi: 10.1080/1028415X.2020.1840049. Epub 2020 Nov 5.


The orexin peptides promote hedonic intake and other reward behaviors through different brain sites. The opioid dynorphin peptides are co-released with orexin peptides but block their effects on reward in the ventral tegmental area (VTA). We previously showed that in the paraventricular hypothalamic nucleus (PVN), dynorphin and not orexin peptides enhance hedonic intake, suggesting they have brain-site-specific effects. Obesity alters the expression of orexin and dynorphin receptors, but whether their expression across different brain sites is important to hedonic intake is unclear. We hypothesized that hedonic intake is regulated by orexin and dynorphin peptides in PVN and that hedonic intake in obesity correlates with expression of their receptors. Here we show that in mice, injection of DYN-A1-13 (an opioid dynorphin peptide) in the PVN enhanced hedonic intake, whereas in the VTA, injection of OXA (orexin-A, an orexin peptide) enhanced hedonic intake. In PVN, OXA blunted the increase in hedonic intake caused by DYN-A1-13. In PVN, injection of norBNI (opioid receptor antagonist) reduced hedonic intake but a subsequent OXA injection failed to increase hedonic intake, suggesting that OXA activity in PVN is not influenced by endogenous opioid activity. In the PVN, DYN-A1-13 increased the intake of the less-preferred food in a two-food choice task. In obese mice fed a cafeteria diet, orexin 1 receptor mRNA across brain sites involved in hedonic intake correlated with fat preference but not caloric intake. Together, these data support that orexin and dynorphin peptides regulate hedonic intake in an opposing manner with brain-site-specific effects.

Keywords: CeA, central amygdala; DH, dorsal hypothalamus; DYN, dynorphin; KOR, kappa opioid receptor; LH, lateral hypothalamus; NAc, nucleus accumbens; OFC, orbitofrontal cortex; OR, opioid receptor; OX1R, orexin 1 receptor; OX2R, orexin 2 receptor; OXA, 1orexin-A; Orexin; PVN, paraventricular hypothalamic nucleus; PVT, paraventricular thalamic nucleus; VH, ventral hypothalamus; VTA, ventral tegmental area; cafeteria diet; dynorphin; fat; feeding behavior; food choice; hedonic intake; hypocretin; hypothalamus; norBNI, nor-binaltorphimine; obesity; opioid receptors; orexin 1 receptor.

MeSH terms

  • Analgesics, Opioid / metabolism
  • Analgesics, Opioid / pharmacology
  • Animals
  • Brain / metabolism
  • Dynorphins* / metabolism
  • Dynorphins* / pharmacology
  • Mice
  • Obesity / metabolism
  • Orexins / metabolism
  • Paraventricular Hypothalamic Nucleus*


  • Analgesics, Opioid
  • Orexins
  • Dynorphins