include cellular adherence, locomotory activity and conformational changes of immunocompetent cells (see Scharrer and Stefano, 1994). Adherence of mammalian neutrophils and invertebrate immunocytes is enhanced by opioid neuropeptides (see [10, 11]). In human neutrophils substance P (10- 11 M) modulates the expression of two cell-surface adhesion molecules, Mo 1 and LAM-1 [12]. Polymorphonuclear leukocytes (PMN), lymphocytes, and monocytes as well as invertebrate immunocytes in addition to random movements (chemokinesis), show migratory behavior directed toward sites of inflammation or antigenic challenge (chemotaxis). In an vitro study by Heagy [13-18] and colleagues, T-lymphocytes exhibited chemotaxis in the presence of a concentration gradient of Met- enkephalin or b-endorphin. Synthetic enkephalin analogs, including DADLE (D-Ala2-D-Leu5- enkephalin), DPDPE (D-Pen2-D-Pen5-enkephalin), and DAG0 (D-Ala2-MePhe4Gly5-enkephalin) stimulated the T-cells to a lesser extent, a finding that will be discussed below. In vitro tests with immunocytes of Mytilus and Leucophaea showed chemotactic movements and the formation of large cellular clumps after opioid peptide exposure along with the same poor reaction to DADLE (see [19-21]). Furthermore, changes in the activity of human and invertebrate immunocytes are preceded by characteristic conformational alterations. Prior to the onset of locomotory behavior, stimulated by opioid peptides, the following signs indicative of cellular activation are observed. Mammalian and invertebrate cells in the inactive condition are more or less rounded, upon activation show an increase in cellular size and surface area and/or the formation of pseudopodia. D’Ala2-Met5-enkephalinamide (DAMA) is most effective in inducing these changes. DADLE, the compound most closely related to DAMA, is not as potent in mammalian and invertebrate immunocytes (see [19-25]). The distinctly lower effectiveness of DADLE in both human and invertebrate immune reactions is in contrast to the situation in the mammalian nervous system where no discrepancy in the binding potency of Met- enkephalin and Leu-enkephalin has been observed (see [10]). Taken together, these studies demonstrate that opioid peptides exhibit, in general, immuno- stimulatory actions. Immunocyte opioid receptors Deltorphin I, a naturally occurring opioid peptide isolated from amphibian skin, has the ability to modulate both human and invertebrate immuno- regulatory activities in a manner quite similar to Met-enkephalin [26]. Its binding and pharma- cological studies also have provided evidence for a special subtype of δ opioid receptor δ , 2 sensitive to naltrindole antagonism [3, 4, 10, 27], on Opioid peptides and opiate alkaloids in immunoregulatory processes human and invertebrate immune cells [26]. The results obtained with deltorphin I support the view that the special role played by endogenous Met- enkephalin in immunobiological activities of vertebrates and invertebrates is mediated by a special subtype of delta opioid receptor, δ2. It is also of interest to note that both the invertebrate immunocytes and human granulocytes thus have a δ1 and δ2 receptor. Opiate alkaloids While opiate alkaloids, e.g., morphine, are not opioid peptides they do deserve special attention within the context of this review for several reasons. First, unlike antinociceptive mechanisms, opiate alkaloids and opioid peptides initiate different immunocyte behaviors [10]. As noted above, opioid peptides may be generally regarded as immunocyte stimulatory and/or activating ligands whereas morphine, noted first by Wybran et al. [28], is inhibi- tory. Secondly, confusion exists in the scientific literature as to the proper terminology for these ligands, e.g., opioid alkaloid and opiate peptide. Thirdly a novel opiate alkaloid and opioid peptide insensitive receptor, namely µ 3, has been demon- strated which does not recognize µ-opioid ligands [6, 29-37]. Lastly, opiate alkaloids appear to be naturally occurring substances found both in mammals and invertebrates (see [6-10, 29, 32, 33, 35-42]). The above reports demonstrate that morphine and codeine substances were found in the pedal ganglia, hemolymph and mantle tissues of the mollusc Mytilus edulis [38, 39]. The pharmacological activities of the endogenous morphine material resemble those of authentic morphine. Both substances were found to counteract, in a dose dependent manner, the stimulatory effect of tumor necrosis factor (TNF)-α or interleukin (IL)-1α on human monocytes and Mytilus immunocytes. The immunosuppressive effect of this opiate material expresses itself in a lowering of chemotactic activity, cellular velocity and adherence as well as making active immunocytes inactive (rounded). These pharmacological effects of morphine on immunocytes are consistent with those actions attributed to opiates reported in the literature (see [10]). Indeed, it has been surmised that mor- phinergic transmission may regulate the down regulation of immune activation (see [6-8, 31, 32, 35-37, 40, 41, 43-49]). Along with the opiate substances found in animal tissues came the recent discovery of a specific high-affinity and novel receptor site (µ 3) for opiate alkaloids on human monocytes as well as Mytilus immunocytes [29, 30, 50]. A variety of opioid peptides, tested by two methods, were found to be ineffective in displacing specifically bound Arch Med Sci 3, June / 2010 457