Opioids,Cannabinoids,Chemokines:Neuroimmune Interactions

Summary

Principal Investigator: Martin Adler
Affiliation: Temple University
Country: USA
Abstract: Opioids and cannabinoids affect not only the nervous, but also the immune system in humans and rodents. Mu, kappa, and delta opioid receptors and CB1 and CB2 cannabinoid receptors have been demonstrated in the immune system. In addition, in rodents, products of the immune system, such as cytokines, have been shown to alter neural function and to modify the effects of opioids on body temperature and analgesia. Chemokines, a subclass of cytokines, are produced by microglia in the brain. In human peripheral blood mononuclear cells, it has been shown that there is an interaction between opioid receptors and chemokine receptors, both being G-protein coupled, seven transmembrane receptors. Selected ligands for each class of receptor can cross-desensitize the other by cross-phosphorylation. Our preliminary results using transfected cell lines support this conclusion as do our recent novel and very exciting results showing that chemokines injected into rat brain PAG block opioid- induced analgesia. The findings suggest the chemokines may alter opioid function in the brain. We have also found super- and sub- additive effects of opioid receptor-selective ligands (mu and delta2) on immune cell function, as well as similar effects between opioids and cannabinoids. Taken together, these results suggest that the opioid, cannabinoid, and chemokine systems interact in the immune system and in the nervous system. It is the purpose of the proposed studies to document the nature of the interactions among these three classes of ligands and their receptors in both the immune and nervous systems. Specifically, we propose to 1) determine the interactions that occur among the classical opioid receptor types and between opioids and cannabinoids in the immune system of mice; 2) determine the cross-regulation of opioid, cannabinoid, and chemokine receptor function in primary human cells and transfected cell lines, and the effect of combinations of these classes of ligands on HIV replication; and 3) examine the effects of Chemokines given supraspinally to rats and mice on morphine- and cannabinoid- mediated analgesia and hypothermia. These studies will explore basic interactions between abused drugs and immune function, and between products of the immune system and these drugs on nervous system function, whether the drugs are used therapeutically or non-therapeutically. Common cellular targets and mechanisms will be sought to elucidate drug interaction pathways. As drug abusers usually use more than one drug, the studies also have public health relevance. Because chemokine receptors are co- receptors for HIV, the studies of how opioids and cannabinoids affect levels and function of chemokine receptors have implications for the effects of drugs of abuse, particularly when taken in combination, on HIV progression.
Funding Period: 1991-03-20 - 2007-06-30
more information: NIH RePORT

Top Publications

  1. pmc A proinflammatory chemokine, CCL3, sensitizes the heat- and capsaicin-gated ion channel TRPV1
    Ning Zhang
    Laboratory of Molecular Immunoregulation, Intramural Research Support Program, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Frederick, MD 21702 1201, USA
    Proc Natl Acad Sci U S A 102:4536-41. 2005
  2. pmc Unresponsiveness of mu-opioid receptor knockout mice to lipopolysaccharide-induced fever
    Khalid Benamar
    Center for Substance Abuse Research, Temple University School of Medicine, 3400 N Broad Street, Philadelphia, PA 19140, USA
    Br J Pharmacol 144:1029-31. 2005
  3. doi Suppression of CCL2/MCP-1 and CCL5/RANTES expression by nociceptin in human monocytes
    David E Kaminsky
    Department of Microbiology and Immunology, Center for Substance Abuse Research, Temple University School of Medicine, 3307 N Broad Street, Philadelphia, PA 19140, USA
    J Neuroimmune Pharmacol 3:75-82. 2008
  4. pmc Opioid and nociceptin receptors regulate cytokine and cytokine receptor expression
    M J Finley
    Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA
    Cell Immunol 252:146-54. 2008
  5. doi First in vivo evidence for a functional interaction between chemokine and cannabinoid systems in the brain
    Khalid Benamar
    Center of Substance Abuse Research, Temple University School of Medicine, 3400 N Broad St, Philadelphia, PA 19140, USA
    J Pharmacol Exp Ther 325:641-5. 2008
  6. doi Endomorphin 1 and endomorphin 2 suppress in vitro antibody formation at ultra-low concentrations: anti-peptide antibodies but not opioid antagonists block the activity
    Benito Anton
    Molecular Neurobiology and Addictive Neurochemistry Laboratory, National Institute of Psychiatry, Mexico City, Mexico
    Brain Behav Immun 22:824-32. 2008
  7. pmc Bi-directional heterologous desensitization between the major HIV-1 co-receptor CXCR4 and the kappa-opioid receptor
    Matthew J Finley
    Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA
    J Neuroimmunol 197:114-23. 2008
  8. doi Elevated level of the proinflammatory chemokine, RANTES/CCL5, in the periaqueductal grey causes hyperalgesia in rats
    Khalid Benamar
    Center for Substance Abuse Research CSAR, Temple University School of Medicine, 3400 N Broad Street, Philadelphia, PA 19140, USA
    Eur J Pharmacol 592:93-5. 2008
  9. doi A new brain area affected by 3,4-methylenedioxymethamphetamine: A microdialysis-biotelemetry study
    Khalid Benamar
    Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA 19140, USA
    Eur J Pharmacol 596:84-8. 2008
  10. pmc Physiological evidence for interaction between the HIV-1 co-receptor CXCR4 and the cannabinoid system in the brain
    Khalid Benamar
    Center for Substance Abuse Research, Temple University School of Medicine, 3400 N Broad Street, Philadelphia, PA 19140, USA
    Br J Pharmacol 157:1225-31. 2009

Scientific Experts

  • Khalid Benamar
  • Xiaohong Chen
  • Martin Adler
  • Toby K Eisenstein
  • Thomas J Rogers
  • Benito Anton
  • Ning Zhang
  • Joseph J Meissler
  • Dessislava I Dimitrova
  • Martin Martinez
  • Maura Matus
  • Alberto Salazar
  • John P Gaughan
  • S Heinisch
  • Phillipe Leff
  • Juan C Calva
  • Rodolfo Acevedo
  • Matthew J Finley
  • David E Kaminsky
  • M J Finley
  • Pu Feng
  • Alan Cowan
  • Joost J Oppenheim
  • Anabel Flores
  • L G Kirby
  • Penny Davey
  • C M Happel
  • Ellen B Geller
  • Lily Zhang
  • Lenin Pavon
  • Guiseppe Bardi
  • T J Rogers
  • D E Kaminsky
  • Rahil T Rahim
  • Xiaohui Peng
  • Michail Sitkovsky
  • Qian Chen
  • Huifang Dong
  • De Yang
  • Lee Yuan Liu-Chen
  • John Gaughan
  • Earl E Henderson
  • Robert J Suhadolnik
  • Xiaowei Yang
  • Michael Caterina
  • Saadet Inan
  • Ronghua Sun
  • Stephanos Karakasidis
  • Ji Ming Wang
  • Richard E Sutton
  • Nancy L Reichenbach
  • Sadeet Inan

Detail Information

Publications25

  1. pmc A proinflammatory chemokine, CCL3, sensitizes the heat- and capsaicin-gated ion channel TRPV1
    Ning Zhang
    Laboratory of Molecular Immunoregulation, Intramural Research Support Program, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Frederick, MD 21702 1201, USA
    Proc Natl Acad Sci U S A 102:4536-41. 2005
    ....
  2. pmc Unresponsiveness of mu-opioid receptor knockout mice to lipopolysaccharide-induced fever
    Khalid Benamar
    Center for Substance Abuse Research, Temple University School of Medicine, 3400 N Broad Street, Philadelphia, PA 19140, USA
    Br J Pharmacol 144:1029-31. 2005
    ..p. of LPS did not induce fever during the recording period. Saline by itself, given i.p., did not alter the T(b), either in WT or MOR-KO. These results confirm that the mu-opioid system is involved in LPS-induced fever...
  3. doi Suppression of CCL2/MCP-1 and CCL5/RANTES expression by nociceptin in human monocytes
    David E Kaminsky
    Department of Microbiology and Immunology, Center for Substance Abuse Research, Temple University School of Medicine, 3307 N Broad Street, Philadelphia, PA 19140, USA
    J Neuroimmune Pharmacol 3:75-82. 2008
    ..Finally, these data may provide the initial basis for the development of ORL1 agonists and antagonists for therapeutic treatment of inflammatory disease...
  4. pmc Opioid and nociceptin receptors regulate cytokine and cytokine receptor expression
    M J Finley
    Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA
    Cell Immunol 252:146-54. 2008
    ..These effects suggest a broad role for opioids in the modulation of the function of the immune system, and suggest possible targets for the development of new therapeutics for inflammatory and infectious diseases...
  5. doi First in vivo evidence for a functional interaction between chemokine and cannabinoid systems in the brain
    Khalid Benamar
    Center of Substance Abuse Research, Temple University School of Medicine, 3400 N Broad St, Philadelphia, PA 19140, USA
    J Pharmacol Exp Ther 325:641-5. 2008
    ....
  6. doi Endomorphin 1 and endomorphin 2 suppress in vitro antibody formation at ultra-low concentrations: anti-peptide antibodies but not opioid antagonists block the activity
    Benito Anton
    Molecular Neurobiology and Addictive Neurochemistry Laboratory, National Institute of Psychiatry, Mexico City, Mexico
    Brain Behav Immun 22:824-32. 2008
    ..These studies show that the endomorphins are immunomodulatory at ultra-low concentrations, but the data do not support a mechanism involving the mu-opioid receptor...
  7. pmc Bi-directional heterologous desensitization between the major HIV-1 co-receptor CXCR4 and the kappa-opioid receptor
    Matthew J Finley
    Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA
    J Neuroimmunol 197:114-23. 2008
    ..These results have implications for several essential processes including neuronal and lymphocyte development, inflammatory responses, and pain/sensitivity...
  8. doi Elevated level of the proinflammatory chemokine, RANTES/CCL5, in the periaqueductal grey causes hyperalgesia in rats
    Khalid Benamar
    Center for Substance Abuse Research CSAR, Temple University School of Medicine, 3400 N Broad Street, Philadelphia, PA 19140, USA
    Eur J Pharmacol 592:93-5. 2008
    ....
  9. doi A new brain area affected by 3,4-methylenedioxymethamphetamine: A microdialysis-biotelemetry study
    Khalid Benamar
    Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA 19140, USA
    Eur J Pharmacol 596:84-8. 2008
    ..These data provide the first in vivo evidence that the effects of MDMA extend to preoptic anterior hypothalamus...
  10. pmc Physiological evidence for interaction between the HIV-1 co-receptor CXCR4 and the cannabinoid system in the brain
    Khalid Benamar
    Center for Substance Abuse Research, Temple University School of Medicine, 3400 N Broad Street, Philadelphia, PA 19140, USA
    Br J Pharmacol 157:1225-31. 2009
    ....
  11. pmc Fractalkine/CX3CL1 enhances GABA synaptic activity at serotonin neurons in the rat dorsal raphe nucleus
    S Heinisch
    Department of Anatomy and Cell Biology, Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA 19140, USA
    Neuroscience 164:1210-23. 2009
    ..Therapies targeting CX3CL1 may treat serotonin related mood disorders, including depression experienced by patients with compromised immune systems...
  12. pmc Intrahypothalamic injection of the HIV-1 envelope glycoprotein induces fever via interaction with the chemokine system
    Khalid Benamar
    Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA 19140, USA
    J Pharmacol Exp Ther 332:549-53. 2010
    ..AMD 3100 significantly reduced the gp120-induced fever. The present studies show that the presence of HIV-1 envelope glycoprotein gp120 in the POAH provokes fever via interaction CXCR4 pathway...
  13. ncbi Effects of opioid tolerance and withdrawal on the immune system
    Toby K Eisenstein
    Center for Substance Abuse Research and Department of Microbiology and Immunology, Temple University School of Medicine, 3400 North Broad Street, Philadelphia, PA 19140, USA
    J Neuroimmune Pharmacol 1:237-49. 2006
    ..As episodes of withdrawal are common among drug abusers, more intensive investigation is warranted on the effects of withdrawal on immune function, on mechanisms of immune modulation, and on sensitization to infection...
  14. ncbi Deletion of mu-opioid receptor in mice alters the development of acute neuroinflammation
    Khalid Benamar
    Center of Substance Abuse Research, Temple University School of Medicine, 3400 N Broad St, Philadelphia, PA 19140, USA
    J Pharmacol Exp Ther 323:990-4. 2007
    ....
  15. pmc Anandamide and Delta9-tetrahydrocannabinol directly inhibit cells of the immune system via CB2 receptors
    Toby K Eisenstein
    Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA 19140, United States
    J Neuroimmunol 189:17-22. 2007
    ....
  16. ncbi Lentivirus-mediated transduction of PKR into CD34(+) hematopoietic stem cells inhibits HIV-1 replication in differentiated T cell progeny
    Dessislava I Dimitrova
    Departments of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA
    J Interferon Cytokine Res 25:345-60. 2005
    ..These results provide support for application of the innate antiviral defense pathway in a gene therapy setting to the treatment of HIV-1 infection...
  17. ncbi Are chemokines the third major system in the brain?
    Martin W Adler
    Center for Substance Abuse Research, Department of Pharmacology, Temple University School of Medicine, 3400 N Broad Street, Philadelphia, PA 19140, USA
    J Leukoc Biol 78:1204-9. 2005
    ..The chemokine system can thus be thought of as the third major transmitter system in the brain...
  18. ncbi Effects of mu, kappa or delta opioids administered by pellet or pump on oral Salmonella infection and gastrointestinal transit
    Pu Feng
    Department of Microbiology and Immunology, Temple University School of Medicine, 3400 North Broad Street, Philadelphia, PA 19140, USA
    Eur J Pharmacol 534:250-7. 2006
    ..A delta1 opioid receptor agonist did not sensitize to infection, and a delta2 and a kappa opioid receptor agonist had minimal effects on either parameter...
  19. pmc Adenosine A2a receptors induce heterologous desensitization of chemokine receptors
    Ning Zhang
    Laboratory of Molecular Immunoregulation, Center for Cancer Research and Basic Research Program, Science Applications International Frederick, National Cancer Institute at Frederick, Frederick, MD 21702, USA
    Blood 108:38-44. 2006
    ....
  20. pmc Viewing chemokines as a third major system of communication in the brain
    Martin W Adler
    Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA 19140, USA
    AAPS J 7:E865-70. 2005
    ..In this review, we propose that the endogenous chemokine system in the brain acts in concert with the neurotransmitter and neuropeptide systems to govern brain function. It can thus be thought of as the third major system in the brain...
  21. pmc Rapid heterologous desensitization of antinociceptive activity between mu or delta opioid receptors and chemokine receptors in rats
    Xiaohong Chen
    Center for Substance Abuse Research, Temple University School of Medicine, 3400 N Broad Street, Philadelphia, PA 19140, USA
    Drug Alcohol Depend 88:36-41. 2007
    ....
  22. pmc Nociceptin/orphanin FQ blocks the antinociception induced by mu, kappa and delta opioid agonists on the cold water tail-flick test
    Xiaohong Chen
    Center for Substance Abuse Research, Temple University School of Medicine, 3400 N Broad Street, Philadelphia, PA 19140, United States
    Eur J Pharmacol 557:32-6. 2007
    ..5 microg), respectively. These results indicate that N/OFQ may be an endogenous anti-opioid peptide in the brain of rats in the CWT test...
  23. ncbi A novel role of cannabinoids: implication in the fever induced by bacterial lipopolysaccharide
    Khalid Benamar
    Center of Substance Abuse Research, Temple University School of Medicine, 3400 North Broad Street, Philadelphia, PA 19140, USA
    J Pharmacol Exp Ther 320:1127-33. 2007
    ..The present results show that cannabinoids interact with systemic bacterial LPS injection and indicate a role of the CB1 receptor subtype in the pathogenesis of LPS fever...
  24. pmc The chemokine CX3CL1/fractalkine interferes with the antinociceptive effect induced by opioid agonists in the periaqueductal grey of rats
    Xiaohong Chen
    Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA 19140, USA
    Brain Res 1153:52-7. 2007
    ..These results demonstrate that activation of the CX3CL1 receptor diminishes the effect of mu, delta and kappa opioid agonists on their receptors in the PAG of rats...
  25. doi Nociceptin/orphanin FQ suppresses adaptive immune responses in vivo and at picomolar levels in vitro
    Benito Anton
    Molecular Neurobiology and Addictive Neurochemistry Laboratory, National Institute of Psychiatry, Mexico City, Mexico
    J Neuroimmune Pharmacol 5:143-54. 2010
    ..These studies show that nociceptin directly inhibits an adaptive immune response, i.e., antibody formation, both in vitro and in vivo...