George B. Stefano, Richard M. Kream 3-dihydromorphine. By contrast, the opiate alkaloid m ligands were potent and κ ligands dynorphin 1-17 and ethyl-keto-cyclazocine (EKC) were weak. Based on this novel displacement information we assigned this opioid peptide insensitive and opiate alkaloid sensitive site the name µ 3 [29]. Studies demonstrate that human granulocytes also contain the µ 3 subtype opiate receptor mediating inhibition by morphine and other opiates of cytokine-induced activation and chemotaxis [51-53]. Furthermore, in the presence of NaCl (50 mM) plus the GTP analog GppNHp (100 µM), there was a significant decrease in specific high-affinity binding of the agonist ligand 3H-morphine. The influence of the GTP analog GppNHp on binding indicated that the granulocyte receptor was linked to a G protein [52]. The discovery of this receptor site mediating opiate effects was first found in an invertebrate and then in man, again demonstrating the value of the comparative approach [54]. It is important to note that the cloning of delta, mu and κ receptors has now been accomplished [55-58]. As a result of these and other studies now published it will be possible to study individual receptors regarding their effector coupling, pharmacological characteristics, regulation of expression as well as their regional distributions. Important information will also become available regarding their evolvement. Biomedical significance The biomedical importance of a well balanced immunoregulatory system is illustrated by the consequence of interference with its normal operation (see [27, 59]). Recent studies have shown that immunosuppression effected by neuropeptides may determine the course of certain diseases caused by parasites or viral infection [60-66]. There is experimental evidence supporting the concept that in schistosomiasis the parasite escapes detection and an effective immune reaction in the host by using the same signal molecules operating in the human immune and autoimmunoregulatory system. The release of ACTH by the adult parasite, and its conversion to a-MSH by NEP on human PMNs, inactivates specific defense cells and thus interferes with proper surveillance. Furthermore, the human immunodeficiency virus appears to have the ability to stimulate the production of ACTH by human immune cells [65] thus creating a scenario similar to that described for the parasitic worm. It is becoming quite clear that these peptides play important immunoregulatory roles, actions that include neuroimmune as well as autoimmuno- regulatory mechanisms. Furthermore, recent work has elucidated the enzymes and other regulatory phenomena involved with morphine biosynthesis and their regulation [31, 34-40, 44, 45, 67-73]. It is important to note that substances of abuse impact this system and appear to work, in part, by releasing morphine from cells that make it [7, 31, 34-36, 74-76]. Conclusions I surmise that we are just scratching the surface of the involvement of neuropeptides and opiate alkaloids in immune and vascular regulation. This review has mainly emphasized the roles of opioid and related peptides, clearly leaving out many other types of peptidergic signaling compounds. For the most part, it is the opioid/opiate “story” that has emerged in recent years. Thus, we will undoubtedly look forward to the activities and presence of other peptidergic signaling molecules being used both in autoimmunoregulation and neuroimmunoregu- lation. Given the presence of many of these signaling molecules in neuroendocrine structures the field of neurosecretion will grow to include, if it hasn’t already done so, neuroimmunology. R e f e r e n c e s 1. Hughes TK, Chin R. Interactions of neuropeptides and cytokines. In: Scharrer B, Smith EM, Stefano GB (eds). Neuropeptides and Immunoregulation. Berlin: Springer- Verlag 1994; 101-19. 2. Scharrer B, Smith EM, Stefano GB. Neuropeptides in neuroimmunology. Heidelberg, Springer 1994. 3. Stefano GB. Pharmacological and binding evidence for opioid receptors on vertebrate and invertebrate blood cells. In: Scharrer B, Smith EM, Stefano GB (eds). Neuropeptides and Immunoregulation. Springer-Verlag; 1994; 139-51. 4. Weigent DA, Blalock JE. Neuropeptides in bidirectional communication between the immune and neuro- endocrine systems. In: Scharrer B, Smith EM, Stefano GB (eds). Neuropeptides and immunoregulation. Heidelberg: Springer-Verlag 1994; 14-27. 5. Stefano GB, Salzet M. Invertebrate opioid precursors: evolutionary conservation and the significance of enzymatic processing. Int Rev Cytol 1999; 187: 261-86. 6. Fricchione G, Zhu W, Cadet P, et al. Identification of endogenous morphine and a mu3-like opiate alkaloid receptor in human brain tissue taken from a patient with intractable complex partial epilepsy. Med Sci Monit 2008; 14: CS45-9. 7. Kream RM, Stefano GB. Homeopathic ethanol. Med Sci Monit 2008; 14: SC11-3. 8. Stefano GB, Kream RM, Mantione KJ, et al. Endogenous morphine/nitric oxide-coupled regulation of cellular physiology and gene expression: implications for cancer biology. Semin Cancer Biol 2008; 18: 199-210. 9. Stefano GB, Kream R. Endogenous opiates, opioids, and immune function: evolutionary brokerage of defensive behaviors. Semin Cancer Biol 2008; 18: 190-8. 10. Stefano GB, Scharrer B. Endogenous morphine and related opiates, a new class of chemical messengers. Adv Neuroimmunol 1994; 4: 57-68. 11. Stefano GB, Bilfinger TV, Fricchione GL. The immune neuro- link and the macrophage: postcardiotomy delirium, HIV- 458 Arch Med Sci 3, June / 2010