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“I would have everie man write what he knows and no more.”—MONTAIGNE BRITISH JOURNAL OF ANAESTHESIA VOLUME 81, NO. 6 DECEMBER 1998 EDITORIAL Opioids and the immune system There has been growing interest in the significance of neuropeptides in the immune system which has resulted in the recent publication of an editorial1 and review2 which are deserving of interest within the anaesthetic community. There is now a considerable body of literature which demonstrates a modulatory function of the immune system by opioids. This modulation takes the form of an alteration in the biochemical and proliferative properties of the various cellular components of the immune system. As many of the mechanisms and molecules are almost identical within vertebrates and invertebrates, it would seem that opioid peptide immunoregulatory mechanisms first evolved in primitive organisms. Because they have been conserved, it would suggest that this remains a highly significant mechanism in humans. Opioid precursors have been isolated and sequenced from a variety of invertebrate species (most work has been performed in the leech and marine mussel) and these have a very close sequence homology with the mammalian counterpart molecules. For instance, there is a 119 amino acid prodynorphin-like molecule which has an identical number of [Leu]enkephalin sequences to that of mammals. The leech has been shown to produce a mammalian-like pro-opiomelanocortin (POMC) molecule, and six of its peptides, including adrenocorticotropin (ACTH), a-melanocyte-stimulating hormone (a-MSH) and [Met]enkephalin. The proenkephalins from the leech and marine mussel possess [Met] and [Leu]enkephalins with relevant cleavage sites. In addition, opioid binding experiments have shown that delta 1 and delta 2 opioid receptor subtypes (in common with those in humans) are present in leech ganglia and immunocytes, and mussel immunocytes.3 Vertebrates and invertebrates have been shown to possess a peptide which is a proenkephalin and has a strong antibacterial action.4 This peptide is called enkelytin (proenkephalin-A) and there is a strong sequence homology between invertebrate and mammalian enkelytin.5 The presence of this strongly antibacterial enkelytin further strengthens the association between opioid peptides and the immune system. It has been suggested that immune or neural signalling leads to enhanced proenkephalin proteolytic cleaving thereby causing the release of both opioid peptides and enkelytin simultaneously. This scenario would allow a two-pronged attack. Opioid peptides would modulate neutrophil chemotaxis, phagocytic activity and the secretion of cytokines, while the simultaneously liberated enkelytin would exert an antibacterial action. Because of the involvement of the peripheral and central nervous systems with immune function it now becomes feasible to consider the link between pain and the immune system. A unified response to a painful stimulus which would include a sensing mechanism providing an initial avoidance response, together with a later local analgesic response in the tissues from endogenous opioids,6 and which is associated with the release of potent antibacterial peptides,5 is an ideal scenario. A similar pattern may exist in humans.7 Corticotropin releasing hormone (CRH) is an important hormone released under stress conditions from both the hypothalamus and cells of the immune system. Injection of CRH has been shown to produce analgesia when injected into sites of local inflammation, an effect which is blocked by co-injection of antiserum to -endorphin.8 This again suggests a possible mechanism whereby local activation of the endogenous opioid system from immunocompetent cells provides both an analgesic action and anti-inflammatory effect. Further evidence for the role of immune cells in pain control pathways comes from work in rats following injection of antigen to induce inflammation in a paw. Concentrations of -endorphin were found to increase in peripheral tissues while concentrations in the lymph nodes which were previously high, decreased.9 It is suggested that T lymphocytes may be acting as vectors for -endorphin to inflamed tissues. The significance of this hypothesis is that it would allow the potential for highly specific opioid control of peripheral analgesia by targeted delivery of -endorphin directly to sites of inflammation. This would maximize the potential analgesic and antiinflammatory effects of endogenous opioids acting at peripheral receptors and also by inhibiting the release of the inflammatory peptide substance P from primary afferent neurones.10 It is also possible that opioids released from cells of the immune system may modulate release of cytokines from the same and other cells of the immune system.11 Beta-endorphin, [Met]enkephalin and [Leu]enkephalin have been shown to inhibit the secretion of the pro-inflammatory cytokine interleukin-6 (IL-6) from mouse spleen.12 Also, IL-6 production from activated peripheral blood mononuclear cells is decreased by opioid peptides.13 On the other hand, cytokines have been shown to regulate opioid formation in neural tissue culture experiments. Interleukin-1 increases opioid receptor mRNA in cultured rat astrocytes and decreases proenkephalin mRNA in hippocampal cultures.14 15 Proenkephalin mRNA and proenkephalin derived peptides have been reported in human lymphocytes, monocytes and macrophages. [Met]enkephalin is released by human peripheral blood lymphocytes which have been activated by phytohaemagglutinin. Experiments using a blocking antibody to enkephalin 836 British Journal of Anaesthesia demonstrated decreased DNA synthesis in stimulated human lymphocytes.16 However, others have shown that delta opioid receptor agonists dose dependently inhibit the proliferation of cultured CD4+ and CD8+ T-cells from mice.18 A study using specific , ␦ and opioid receptor agonists have shown that they result in significantly decreased immunoglobulin production by activated human B lymphocytes.13 Perhaps these different results are caused by the effect of different cell types, different species studied or because of the differing effects of the various receptor subtypes. In addition, there is much interest in the ability of chronic opioid use to modify the immune system. Much of this work stems from the observation that parenteral drug abuse is a significant risk factor for contracting human immunodeficiency virus type I (HIV-1). Chronic morphine treatment is a mechanism used in laboratory experiments to render mice immunocompromised.18 Morphine significantly decreases in a dose dependent manner the proliferation of stimulated human lymphocytes in addition to reducing the production of IFN-␣ and IFN-, an effect reversed by naloxone.19 Gamma interferonstimulated natural killer cell cytotoxicity is significantly suppressed after short-term exposure to morphine in humans.20 There is now a substantial body of evidence which demonstrates that opioids and endogenous opioid peptides modulate immune function. Moreover, inflammatory mediators have been shown to modify the release of opioid peptides from immune system cells and also from cells of the peripheral and central nervous system. The potential effects of exogenously administered opioids on the immune system cannot be ignored. Variations in postoperative infection rate have not to date been attributed exclusively to the use of perioperative opioids as there are many other compounding factors. However, it would seem most likely that opioid use in both the surgical patient and the critically ill would have a profound immunomodulatory effect and we should be cognizant of this effect when we chose our anaesthetic, analgesic or sedative technique. N. R. WEBSTER Anaesthesia and Intensive Care Institute of Medical Sciences Foresterhill Aberdeen AB25 2ZD References 1. Jessop DS. -endorphin in the immune system—mediator of pain and stress? Lancet 1998; 351: 1828–1829. 2. Stefano GB, Salzet B, Fricchione GL. Enkelytin and opioid peptide association in invertebrates and vertebrates: immune activation and pain. Immunology Today 1998; 19: 265–268. 3. Salzet M, Stefano GB. Invertebrate proenkephalin: delta opioid 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. binding sites in leech ganglia and immunocytes. 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