Opioids and cannabinoids are both associated with analgetic, psychotropic, and immunomodulatory effects. It has been suggested that both systems interact on multiple levels. We hypothesized that cannabinoids induce opioid receptors and investigated cannabinoid-dependent expression of the μ-opioid receptor subtype in a human T cell model. We report that activation of the peripheral cannabinoid receptor type 2 leads to a de novo induction of μ-opioid receptor transcription in Jurkat E6.1 cells. We show that interleukin-4 is transcriptionally induced in response to cannabinoids and that an interleukin-4 receptor antagonist blocks cannabinoid-dependent induction of μ-opioid receptors, indicating that induced expression of interleukin-4 is required in this process. Induction of interleukin-4 is blocked by decoy oligonucleotides directed against STAT5, indicating the requirement of this transcription factor. In addition, we show cannabinoid-dependent phosphorylation of STAT5. Further experiments demonstrate that interleukin-4 then induces phosphorylation of STAT6, which directly transactivates the μ-opioid receptor gene. In addition, STAT6 induces expression of the transcription factor GATA3, which also contributes to μ-opioid receptor gene transcription. The responsive promoter region of the human μ-opioid receptor gene with the binding sites for both factors was mapped to nt -1001 to -950. To demonstrate functional μ-opioid receptor proteins, morphine-mediated phosphorylation of mitogen-activated protein kinase was investigated. We show that phosphorylation of mitogen-activated protein kinase occurs only in cannabinoid-prestimulated Jurkat E6.1 cells and that it is blocked by the μ-opioid receptor antagonist d-Phe-Cys-Tyr-d-Trp-Orn-Thr-Pen-Thr-NH2. In summary, these findings provide a first example for cannabinoid-opioid-interactions in cells of the immune system.
- Received August 19, 2005.
- Accepted January 24, 2006.
- The American Society for Pharmacology and Experimental Therapeutics