Orexin (hypocretin) neurons contain dynorphin

Orexins (also called hypocretins) are peptide neurotransmitters expressed i n neurons of the lateral hypothalamic area (LHA). Mice lacking the orexin p eptides develop narcolepsy-like symptoms, whereas mice with a selective los s of the orexin neurons develop hypophagia and severe obesity in addition t o the narcolepsy phenotype. These different phenotypes suggest that orexin neurons may contain neurotransmitters besides orexin that regulate feeding and energy balance. Dynorphin neurons are common in the LHA, and dynorphin has been shown to influence feeding; hence, we studied whether dynorphin an d orexin are colocalized. In rats, double-label in situ hybridization revea led that nearly all (94%) neurons expressing prepro-orexin mRNA also expres sed prodynorphin mRNA. The converse was also true: 96% of neurons in the LH A containing prodynorphin mRNA also expressed prepro-orexin mRNA. Double-la bel immunohistochemistry confirmed that orexin-A and dynorphin-A peptides w ere highly colocalized in the LHA. Wild-type mice and orexin knock-out mice showed abundant prodynorphin mRNA-expressing neurons in the LHA, but orexi n/ataxin-3 mice with a selective loss of the orexin neurons completely lack ed prodynorphin mRNA in this area, further confirming that within the LHA, dynorphin expression is restricted to the orexin neurons. These findings su ggest that dynorphin-A may play an important role in the function of the or exin neurons.