Mechanisms associated with Low Dose Naltrexone Therapy in

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Mechanisms associated with Low Dose Naltrexone Therapy in Autism and HIV Aristo Vojdani, Ph.

Mechanisms associated with Low Dose Naltrexone Therapy in Autism and HIV Aristo Vojdani, Ph. D. , M. T. Immunosciences Lab. , Inc. drari@msn. com LDN Conference, USC October 11, 2008

Raynor K. , et al. 45(2): 330 -334, 1994 Pharmacological characterization of the cloned

Raynor K. , et al. 45(2): 330 -334, 1994 Pharmacological characterization of the cloned k-, d-, and m- opioid receptors = Opioid drugs, such as morphine, and the endogenous opioid peptides, namely the enkephalins, endorphins, and dynorphins, exert a wide spectrum of physiological and behavioral effects, including effects on pain perception, mood, motor control, and autonomic functions. These effects are mediated via membrane-bound receptors, of which the best characterized are the kappa, delta, and mu receptors. = The availability of the cloned receptors will facilitate the identification and development of more specific and selective compounds with greater therapeutic potential and fewer undesirable side effects. 1

Exorphins and other biologically active peptides derived from diet, Gardner, M. L. G. ,

Exorphins and other biologically active peptides derived from diet, Gardner, M. L. G. , in Food Allergy and Intolerance, Brostoff and Challacombe eds. , pp 465 -478, Saunders 2002 2

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The role of endogenous opioids and their receptors in the immune system Carr D.

The role of endogenous opioids and their receptors in the immune system Carr D. J. , et al. , 198: 710 -720, 1991 = Opioid peptides appear to be dynamic signaling molecules that are produced within the immune system and are active regulators of an immune response. The receptors for these peptides occurring on immunocyte membranes share characteristics with neuronal opioid receptors, including molecular size, immunogenicity, and the use of specific intracellular signaling pathways. = Recent studies of the interaction of opioids with cytokines have indicated that opioid peptides are intimately involved within the immune system. Specifically, opioids, including 2 -n-pentyloxy-2 -phenyl-4 -methylmorpholine, naloxone, and beta-endorphin, have been shown to interact with IL-2 receptors and regulate production of IL-1 and IL-2. Conversely, IL-1 has been shown to up-regulate opioid peptide binding in brain tissue. = These results seem to typify the intricate association between the immune and neuroendocrine systems through opioid pathways. = It is predicted that future endeavors will use this relationship to diagnose and treat specific diseases that have at their basis neuroendocrine and immunologic imbalances. 7

Interactions of cellular and humoral immunity as defense against invaders 8

Interactions of cellular and humoral immunity as defense against invaders 8

Caroleo M. C. , et al. , 1: 141 -147, 1994 A Reappraisal of

Caroleo M. C. , et al. , 1: 141 -147, 1994 A Reappraisal of the Role of the Various Opioid Receptor Subtypes in Cell-Mediated Immunity = Opioid peptides have been shown by several studies to modulate various parameters of the immune response, but scant experimental findings exist on the role played by specific opioid receptor subtypes in the control of immune mechanisms. = This study focuses on the in vitro influences of [Trp 4, Asn 7] der-morphin, aµselective agonist, [D-Ala 2] deltorphin I, ad-selective agonist and U 50, 488, akselective agonist, on the proliferative response of splenocytes to concanavalin A (Con A). = [Trp 4, Asn 7] dermorphin at low concentrations (10 -11 and 10 -12 M) enhanced the proliferative response to Con A, whereas higher concentrations (10 -6 to 10 -7 M) inhibited it. = Both effects were antagonized by naloxone. = In conclusion, our results clearly indicate that the different opioid receptor subtypes play a different role in the control of immune mechanisms and suggest that immunoenhancing effects of opioid peptides are very likely due to the stimulation of µ- and d-receptors, whereas the immunosuppressive effects are mediated through the stimulation of k-opioid receptors. 9

Boyadjieva N. I. , et al. 26(11): 1719 -1727, 2006 β-Endorphin Modulation of Lymphocyte

Boyadjieva N. I. , et al. 26(11): 1719 -1727, 2006 β-Endorphin Modulation of Lymphocyte Proliferation: Effects of Ethanol =We have previously shown that alcohol suppresses the natural killer (NK) cell activity of splenic lymphocytes partly by reducing the secretion of opioid peptide β-endorphin (β-EP) and its positive influence on NK-cell cytolytic activity in rats. =We investigated whether ethanol treatment for 1 to 4 weeks reduces the proliferation of other lymphocyte subsets and whether β-EP regulates ethanol's effect on lymphocyte proliferation. =Ethanol consumption resulted in a reduction of the number of CD 161+ NK cells, CD 3+ T lymphocytes, CD 4+ T-helper cells, and CD 8 a+ cytotoxic T cells in a time-dependent fashion. Alcohol consumption also suppressed the proliferative response of lymphocyte subsets to Con-A, PHA, and l. LPS. β-EP promoted the lymphocytes' proliferative response to mitogens, whereas naltrindol blocked the effects of the opioid. 10

Matthews P. M. . , et al. , 130(4): 1658 -1662, 1983 Enhancement of

Matthews P. M. . , et al. , 130(4): 1658 -1662, 1983 Enhancement of Natural Cytotoxicity by b-Endorphin =The role of enkephalins, b-endorphin, or other neuropeptides produced by the nervous system in the alteration of immune responsiveness is generally unknown. =The present studies were undertaken to investigate the role of these neuropeptides in the modulation of human spontaneous cytotoxicity induced by natural killer (NK) cells. MOLAR CONCENTRATION OF b. ENDORPHIN =These studies provide new insight into the mechanisms by which neuropeptides produced by the nervous system can alter immune responsiveness. 11

journal of Neuroimmunology Journal of Neuroimmunology 61 (1995) 97 -104 Beta-endorphin enhances the replication

journal of Neuroimmunology Journal of Neuroimmunology 61 (1995) 97 -104 Beta-endorphin enhances the replication of neurotropic human immunodeficiency virus in fetal perivascular microglia Sundar K. S. , et al. =The effect of an endogenous opiate, b-endorphin, on the replication of HIV was investigated in brain perivascular microglia. =Beta-endorphin enhanced the synthesis of p-24 antigen and transactivation of HIV promoter. =Dialysed culture supematants of endorphin-treated microglia re-activated latent HIV infection. =These culture supernatants showed elevated levels of interleukin-l b, IL-6 and tumor necrosis factor a. =Sub-optimal concentration of b-endorphin potentiated GP-120 -induced synthesis of these cytokines. =Nalaxone reversed b-endorphin-induced, but not GP -120 -induced, cytokine production and enhanced HIV replication. =These results suggest that endogenous opiates may contribute to the progression of AIDS dementia complex.

Binding of naloxone to human T lymphocytes Madden J. J. . , et al.

Binding of naloxone to human T lymphocytes Madden J. J. . , et al. , 36(23): 4103 -4109 =Purified T lymphocytes have a specific binding site for naloxone. =The bound naloxone was partially displaceable by various opiate agonists including morphine (56%), beta-endorphin (61%), met 5 - and leu 5 -enkephalin (40% each), [D-ala 2, D-leu 5]-enkephalin (78%) and [D-ala 2, D-leu 5]-enkephalinamide (66%). =There was great interindividual variability in Bmax between samples, suggesting a possible mechanistic basis for the variability in drug action seen between different individuals. 13

Nadka I, et al. , 2004, 173: 42 -49 = Naltrexone, an opioid antagonist,

Nadka I, et al. , 2004, 173: 42 -49 = Naltrexone, an opioid antagonist, has been used in clinical trials to treat alcoholism. = As the opioid peptides b-endorphin and enkephalin increase splenic NK cell function in laboratory animals, it is anticipated that naltrexone treatment will cause immunosuppression. = However, we report in this study that chronic naltrexone administration in laboratory rats increases the cytolytic activity of NK cells. It also prevents alcohol’s suppressive effect on these cells. = We identified that, in the splenocytes, d opioid receptor expression is tightly controlled by negative feedback regulation of m opioid receptors. = Naltrexone disrupts this feedback control by reducing m opioid receptor function, thereby up-regulating d opioid receptor binding, which results in an enhanced NK cell cytolytic response to d opioid receptor ligands. = We conclude that naltrexone, which has been shown to be a promising agent for the clinical management of alcoholism, may have potential use in the treatment of immune deficiency in alcoholic and nonalcoholic patients. 14

Schematic representation of the proposed mechanisms by which naltrexone and ethanol affect negative interaction

Schematic representation of the proposed mechanisms by which naltrexone and ethanol affect negative interaction between d opioid receptor (DOR) and m opioid receptor (MOR). We propose that a negative interaction between MOR and DOR exists in the spleen, possibly due to heterodimerization of MOR and DOR or other unknown mechanisms. We also propose that an increased negative interaction between DOR and MOR might be a mechanism by which ethanol alters the NK cell response to the endogenous opioid peptide (OP). Nadka et al. , J Immunol, 173: 42– 49, 2004 15

Schematic representation of the proposed mechanisms by which naltrexone and ethanol affect negative interaction

Schematic representation of the proposed mechanisms by which naltrexone and ethanol affect negative interaction between d opioid receptor (DOR) and m opioid receptor (MOR). We propose that the action of naltrexone on NK cells might be related to prevention of the negative interaction between MOR and DOR, because the antagonist prevents MOR binding. Nadka et al. , J Immunol, 173: 42– 49, 2004 16

International Immunopharmacol ogy Buprenorphine produces naltrexone reversible alterations of immune status - Carrigan K.

International Immunopharmacol ogy Buprenorphine produces naltrexone reversible alterations of immune status - Carrigan K. A. et al. Substantial evidence demonstrates that administration of high efficacy m opioid agonists such as morphine modulate the immune response in a dose-dependent and pharmacologically specific manner, indicating functional interactions between the opioid and immune systems. In contrast to the well-characterized immunomodulatory effects of high efficacy m opioids, little is known about how these effects generalize to other clinically employed opioids and agonists of varying degrees of A opioid receptor stimulation. Buprenorphine is a m opioid agonist of intermediate efficacy that is used clinically for pain management and has recently been approved for the treatment of opioid dependence. Recent evidence indicates pharmacological and mechanistic differences between buprenorphine and morphine. that Therefore, the aim of the present study was The results demonstrate buprenorphine dose-dependently to investigate whether also possesses immunomodulatory suppresses splenicbuprenorphine natural killer cell activity, lymphocyte properties. Theand results demonstrate buprenorphine dose-dependently proliferation IFN-g productionthat in rats in a naltrexone reversible suppresses natural killer cell activity, lymphocyte proliferation and manner, splenic demonstrating pharmacological specificity of IFN-g production in rats in aimmune naltrexone reversible manner, demonstrating buprenorphine-induced alterations. 17 pharmacological specificity of buprenorphine-induced immune alterations.

Splenic natural killer cell cytotoxic activity is reduced following s. c. administration of buprenorphine.

Splenic natural killer cell cytotoxic activity is reduced following s. c. administration of buprenorphine. K. A. Carrigan et al. , Int Immunopharmacol 2004, 4: 419 -428 18