Transcript Document

Mechanisms
associated with
Low Dose
Naltrexone
Therapy
in Autism and HIV
Aristo Vojdani, Ph.D., M.T.
Immunosciences Lab., Inc.
[email protected]
LDN Conference, USC
October 11, 2008
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.
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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
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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.
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Interactions of cellular and humoral immunity as defense against invaders
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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 [Trp4,Asn7] der-morphin, aµselective agonist, [D-Ala2] deltorphin I, ad-selective agonist and U50,488, akselective agonist, on the proliferative response of splenocytes to concanavalin
A (Con A).
 [Trp4, Asn7] dermorphin at low concentrations (10-11 and 10-12M)
enhanced the proliferative response to Con A, whereas higher
concentrations (10-6 to 10-7M) 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.
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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 CD161+ NK cells, CD3+ T lymphocytes, CD4+ T-helper
cells, and CD8a+ cytotoxic T cells in a time-dependent
fashion. Alcohol consumption also suppressed the
proliferative response of lymphocyte subsets to Con-A,
PHA, and lLPS. β-EP promoted the lymphocytes'
proliferative response to mitogens, whereas naltrindol
blocked the effects of the opioid.
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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.
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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., 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%), met5- and leu5-enkephalin
(40% each), [D-ala2, D-leu5]-enkephalin (78%) and
[D-ala2, D-leu5]-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.
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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.
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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
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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
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International
Immunopharmacology
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. Therefore,
the aim of the
present study was
The results demonstrate
that 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, lymphocytespecificity
proliferation and
manner, splenic
demonstrating
pharmacological
of
IFN-g
production in rats in aimmune
naltrexone
reversible manner, demonstrating
buprenorphine-induced
alterations.
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pharmacological specificity of buprenorphine-induced immune alterations.
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
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