Fig. (2).

Cytokines such as IL1, TNF, nerve growth factor (NGF), EGF, interleukin 4 (IL4), interleukin 10 (IL10), and associated soluble and membrane-bound receptors all form part of the sleep biochemical regulatory network. Cell activity affects levels of these substances. Within brain for example, ATP, co-released during neurotransmission, induces the release of the gliotransmitters IL1 and TNF from glia. These substances induce their own production and interact with multiple other substances via NFkB activation. These effects are associated with gene transcription and translation and take several hours. Downstream events include well-known metabolic substances and regulators of the microcirculation such as NO, adenosine and prostaglandins. Neurotransmission, acting on an even faster time scale, is altered by substances such as IL1 via actions on the production of receptors that alter postsynaptic neuron sensitivity such as AMPA and adenosine A1 receptors (A1AR). State oscillations within local networks occur as a result of this ultra-complex biochemical regulatory scheme [2,3,56]. Abbreviations:P2, purine type 2 receptors; NFkB, nuclear factor kappa B; NOS, nitric oxide synthase; NGF, nerve growth factor; EGF, epidermal growth factor; GHRH, growth hormone releasing hormone; CRH, corticotrophin releasing hormone; IL1RA, IL1 receptor antagonist; sIL1R, soluble IL1 receptor; sTNFR, soluble TNF receptor; PGs, prostaglandins; COX, cyclooxygenase; glu, glutamic acid; GABA, gamma amino butyric acid; CRH, corticotrophin releasing hormone; sTNFR, soluble TNF receptor;, sIL1R, soluble IL1 receptor; TGF, transforming growth factor beta; cry, cryptochrome; per, period.