Am J Physiol 1987 Oct;253(4 Pt 2):R646-54 Enhancement of quiet sleep in rabbit neonates by muramyl dipeptide. Davenne D, Krueger JM Department of Physiology and Biophysics, University of Tennessee, Memphis 38163. Muramyl peptides that induce excess slow-wave sleep have been isolated from urine and brain. A synthetic analogue to those substances, muramyl dipeptide (MDP, N-acetylmuramyl-L-alanyl-D-isoglutamine), was found to induce prolonged increases in slow-wave sleep and to increase electroencephalographic (EEG) delta-wave activity. MDP is also pyrogenic, although this activity can be separated from its somnogenic activity. To further investigate the somnogenic actions of MDP, neonatal rabbits were used in the present study. Intraperitoneal injection of 100 micrograms/kg MDP induced differential somnogenic and pyrogenic effects; from postnatal days 7-9, MDP increased duration of quiet sleep (QS, the precursor of adult slow-wave sleep) and decreased active sleep (AS) as judged by behavioral criteria. These animals were not febrile during the period of enhanced QS, nor did MDP alter EEG delta-wave activity at this age. From postnatal days 10-15, MDP induced prolonged (6 h) increases in duration of QS; both behavioral and EEG criteria were used at this age to determine duration of QS and AS. Maximum MDP-induced effects occurred during the 2nd h, with a parallel increase in amplitudes of EEG delta-wave activity. At this age, MDP also elicited monophasic fevers and inhibition of AS, with maximum effects observed during hours 3-4 postinjection. After postnatal day 16, MDP-induced somnogenic and febrile responses were similar to those observed in adult rabbits. We conclude that the mechanisms responsible for behavioral sleep states are responsive to a sleep-promoting substance early in ontogenesis. PMID: 3661760, UI: 88021395 ----------

Physiol Behav 1987;41(2):179-85 Muramyl dipeptide, amphetamine, and physostigmine: effects on sleep of rabbits. Shoham S, Davenne D, Krueger JM Department of Physiology and Biophysics, University of Tennessee, Memphis 38163. Muramyl peptides (MPs) are constituents of bacterial cell walls and mammalian tissue. Some MPs have the capacity to enhance slow-wave sleep (SWS). In rabbits, it was unknown whether MPs enhanced SWS by prolonging SWS episodes or by increasing the number of SWS episodes. In rabbits, there is a frequent alternation between sleep and waking; thus, demonstration of induction of new SWS episodes is difficult unless pharmacologic manipulations are used. We injected amphetamine subcutaneously to reduce duration of sleep (from about 45% to 20%) for a period of two hours; it reduced the number of SWS episodes. Muramyl dipeptide (MDP: NAM-L-ala-D-isogln) injected into a lateral ventricle one hour before amphetamine significantly increased the number of SWS episodes. Physostigmine, a cholinergic agonist, was also used. By itself, physostigmine greatly reduced SWS and rapid eye movement sleep. Pretreatment of animals with MDP two hours before physostigmine injection failed to reverse subsequent physostigmine-induced wakefulness. We conclude that MDP has the ability to induce SWS episodes but does not act directly on the thalamocortical cholinergic mechanisms of EEG phenomena. Our results, together with earlier evidence on anatomical levels of action of amphetamine and physostigmine, suggest that the somnogenic mechanisms of MPs likely involve the midbrain. PMID: 3685166, UI: 88068937 ----------

Fed Proc 1986 Oct;45(11):2552-5 Somnogenic muramyl peptides. Krueger JM, Karaszewski JW, Davenne D, Shoham S Sleep-promoting materials isolated from human urine and rabbit brain are muramyl peptides (MPs). The most active component of the urinary material is N-acetylglucosaminyl-1,6-anhydro-N-acetylmuramyl-Ala-Glu-diaminopimel yl-Ala; 1 pmol, infused into a lateral cerebral ventricle of rabbits, induced excess slow-wave sleep (SWS) for several hours. MP-induced sleep is normal in that it is similar to the deep sleep that follows sleep deprivation. Other biological actions of MPs (e.g., pyrogenicity and immunomodulatory activity) could be dissociated, but only in part, from somnogenic actions. Interleukin 1, a substance thought to mediate many MP activities, is somnogenic, and thus may be involved in MP-induced sleep. That MPs and other immunologically active substances can greatly enhance SWS suggests that some immunological mechanisms integrate sleep in their actions. PMID: 3758373, UI: 87005314

Methods Find Exp Clin Pharmacol 1986 Feb;8(2):105-10 Muramyl peptide enhancement of slow-wave sleep. Krueger JM Sleep-promoting Factor S, derived from brain or urine, has been characterized as a muramyl peptide. In rabbits, one pmol of Factor S induced excess slow-wave sleep (SWS) for several hours following cerebral intraventricular infusion. Factor S also induced increases in EEG slow-wave (1/2-4 Hz) amplitudes similar to those observed during the deep sleep that follows sleep deprivation. Sleep following Factor S treatment remained normal in that it was episodic and waking behaviours such as eating, drinking and grooming persisted. The structure of Factor S is similar to those of naturally occurring monomers of bacterial cell wall peptidoglycans. Other muramyl peptides such as muramyl dipeptide (MDP) were also found to be somnogenic. Structure-activity studies of various MDP derivatives indicated that somnogenic activity is dependent on precise structural requirements. Muramyl peptides also are immunomodulators and pyrogens. These activities could be separated from somnogenic activity by using various MDP derivatives or by pharmacologic intervention. Muramyl peptides may induce their somnogenic effects through the release of the cytokine interleukin-1; interleukin-1 also has the capacity to induce excess SWS. Although muramyl peptides have many biological activities in mammals, the role(s) they may play in mammalian physiology remains unknown. It is possible that mammalian tissue may store and/or modify muramyl peptides in conjunction with their use as modulators of sleep, temperature and immune responses. PMID: 3713370, UI: 86229465 ----------

J Exp Med 1984 Jan 1;159(1):68-76 Muramyl peptides. Variation of somnogenic activity with structure. Krueger JM, Walter J, Karnovsky ML, Chedid L, Choay JP, Lefrancier P, Lederer E Sleep-promoting activities of muramyl dipeptide (MDP) (NAc-Mur-L-ala-D-isogln) and the naturally occurring muramyl peptide(s), factor S, have recently been demonstrated. We now have amplified our understanding of structural requirements for somnogenic activity. The effects of several analogs of MDP on rabbit slow-wave sleep are presented and these results are compared to the dose-response relationship for MDP. Some tentative conclusions as to structural requirements for somnogenic activity are presented; most notably, amidation of the free gamma-carboxyl of MDP and several of its analogs resulted in the loss of somnogenic activity. MDP also can induce febrile and immunostimulatory responses. In the present paper, we show that some analogs possess immunostimulatory and pyrogenic activity but not somnogenic activity, thus suggesting that these biological activities of muramyl peptides may, in part, be mediated by separate mechanisms. PMID: 6693833, UI: 84113337 ----------