Long-term interactions between opioid and cannabinoid agonists at the cellular level: cross-desensitization and downregulation

Long-term interactions between opioid and cannabinoid agonists at the cellular level:... In the present study we investigated long-term interactions between opioid and cannabinoid drugs at several steps along their cellular signal transduction pathways. For this purpose we co-transfected HEK-293 and COS-7 cells with δ-opioid (DOR) and CB1-cannabinoid receptors, and examined the effect of prolonged exposure to either opioid (etorphine) or cannabinoid (DALN) agonists on DOR and CB-1 receptor density and on the ability of subsequent application of the agonists to activate G-proteins (as measured by ( 35 S)GTPγS binding) and to inhibit cAMP production. In HEK-293 cells, etorphine induced both homologous and heterologous desensitization, while DALN induced only homologous desensitization. This asymmetric cross-desensitization coincided with asymmetric cross downregulation: etorphine downregulated the binding of the cannabinoid ligand ( 3 H)CP55,940, while DALN failed to reduce the binding of the opioid ligand ( 3 H)diprenorphine. In contrast to the asymmetric desensitization in HEK-293 cells, COS-7 cells presented a two-way cross-desensitization between opioid and cannabinoid agonists, and DALN downregulated the binding of ( 3 H)diprenorphine in these cells. Thus, a complete correlation was found between downregulation and reduction in cell responsiveness (‘desensitization’). Moreover, when opioid downregulation in HEK-293 cells was inhibited by either hypertonic sucrose solution or protein kinase inhibitors, desensitization was suppressed to the same extent. These results suggest that, under the present experimental conditions, the reduction in cell responsiveness resulted primarily from downregulation of the receptors. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Brain Research Elsevier

Long-term interactions between opioid and cannabinoid agonists at the cellular level: cross-desensitization and downregulation

Brain Research, Volume 960 (1) – Jan 17, 2003

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Publisher
Elsevier
Copyright
Copyright © 2002 Elsevier Science B.V.
ISSN
0006-8993
DOI
10.1016/S0006-8993(02)03842-8
Publisher site
See Article on Publisher Site

Abstract

In the present study we investigated long-term interactions between opioid and cannabinoid drugs at several steps along their cellular signal transduction pathways. For this purpose we co-transfected HEK-293 and COS-7 cells with δ-opioid (DOR) and CB1-cannabinoid receptors, and examined the effect of prolonged exposure to either opioid (etorphine) or cannabinoid (DALN) agonists on DOR and CB-1 receptor density and on the ability of subsequent application of the agonists to activate G-proteins (as measured by ( 35 S)GTPγS binding) and to inhibit cAMP production. In HEK-293 cells, etorphine induced both homologous and heterologous desensitization, while DALN induced only homologous desensitization. This asymmetric cross-desensitization coincided with asymmetric cross downregulation: etorphine downregulated the binding of the cannabinoid ligand ( 3 H)CP55,940, while DALN failed to reduce the binding of the opioid ligand ( 3 H)diprenorphine. In contrast to the asymmetric desensitization in HEK-293 cells, COS-7 cells presented a two-way cross-desensitization between opioid and cannabinoid agonists, and DALN downregulated the binding of ( 3 H)diprenorphine in these cells. Thus, a complete correlation was found between downregulation and reduction in cell responsiveness (‘desensitization’). Moreover, when opioid downregulation in HEK-293 cells was inhibited by either hypertonic sucrose solution or protein kinase inhibitors, desensitization was suppressed to the same extent. These results suggest that, under the present experimental conditions, the reduction in cell responsiveness resulted primarily from downregulation of the receptors.

Journal

Brain ResearchElsevier

Published: Jan 17, 2003

References

  • An assessment of the role of opioid receptors in the response to cannabimimetic drugs
    Devane, W.A.; Spain, J.W.; Coscia, C.J.; Howlett, A.C.
  • Opiate tolerance and dependence: receptors, G-proteins, and antiopiates
    Harrison, L.M.; Kastin, A.J.; Zadina, J.E.
  • Hypertonic media inhibit receptor-mediated endocytosis by blocking clathrin-coated pit formation
    Heuser, J.E.; Anderson, R.G.W.
  • Cellular signal transduction by anandamide and 2-arachidonoylglycerol
    Howlett, A.C.; Mukhopadhyay, S.
  • Molecular mechanisms and regulation of opioid receptor signaling
    Law, P.Y.; Wong, Y.H.; Loh, H.H.
  • Two distinctive antinociceptive systems in rats with pathological pain
    Mao, J.; Price, D.D.; Lu, J.; Keniston, L.; Mayer, D.J.
  • Independence of, and interactions between, cannabinoid and opioid signal transduction pathways in N18TG2 cells
    Shapira, M.; Gafni, M.; Sarne, Y.
  • Opioid and cannabinoid receptors share a common pool of GTP-binding proteins in cotransfected cells, but not in cells which endogenously coexpress the receptors
    Shapira, M.; Vogel, Z.; Sarne, Y.
  • Synergistic interactions of endogenous opioids and cannabinoid systems
    Welch, S.P.; Eads, M.

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