One of the main problems of modern immunopathophysiology is to clarify the central mechanisms of neuro-immune interactions, which involve diverse neurotransmitter systems and are affected by different destabilizing factors. The present work concerns the effects of restraint stress on the lipopolysaccharide-induced reactions of orexinergic neurons. Morphological analysis of immunostained brain sections (25th-32th brain level according to Swanson's brain maps) revealed an increase of orexin-positive neurons on the 27th and 30th brain levels, 2/h after movement restriction. A single lipopolysaccharide (LPS) injection resulted in a decrease in the quantity of orexin-positive neurons at the 28th brain level. Pretreatment with movement restriction altered this reaction, causing an increase in orexin quantity at both the 28th and 29th brain levels. The intensity of prepro-orexin gene expression in hypothalamic cells were assessed by qPCR and a decrease was observed 2/h after restraint stress and increase was seen after the combination of movement restriction with LPS injection. The gene expression of both orexin receptors (OxR1 and OxR2) were decreased in adrenal cells, 2/h after restraint stress. Thus, restraint stress alters the pattern of the antigen-induced response of the orexinergic system, which involves OxR1 bearing neurons.