Summary of growth-promoting and growth-inhibiting effects of opioids
| Cell Type | Opioid | In Vitro Concentration and Time | In Vivo Effects | In Vivo Dose | In Vivo or Ex Vivo Effects | Suggested Mechanism | OR Antagonist Inhibition with: | Other Inhibitors | Reference |
|---|---|---|---|---|---|---|---|---|---|
| Immune cells | |||||||||
| Human blood T-lymphocytes stimulated with concanavalin A | β-endorphin | 10-9—10-10 M for 1 h | Stimulation of Con A-induced proliferation | Increase of IL-2 | No inhibition with Nx 10-6 M | van den Bergh et al., 1991; Navolotskaya et al., 2002a | |||
| Jurkat T-lymphocytes | Morphine DAMGO | 0.01—100 μM for 24—48 h | Apoptosis | Increase of ROS, Bcl2 down- and Bax up-regulation | Ntx (1 μM) | Catalase | Singhal et al., 1999 | ||
| CEMx174 lymphocytic cells | Morphine | 10 μM for 12—42 h | Increase of Erk expression and phosphorylation | Nx (10 μM) | Chuang et al., 1997 | ||||
| Lymphocytes splenocytes of morphine-treated BALB/C mice | Morphine | 3 μM for 24 h | Apoptosis | 50 mg/kg single dose | Reduced number of splenocytes at 24 h | Increase of Fas expression | Nx (100 mg/kg single dose) | Yin et al., 1999 | |
| Spleen, lung and liver tissue of heroin-treated rats | Heroin | 1 mg/kg single dose | Inhibition of LPS-induced iNOS expression | Ntx (0.1 mg/kg) | Fecho and Lysle, 2000; Lysle and How 2000 | ||||
| T- and B-lymphocytes, macrophages in chronically treated mice | Morphine dihydroetorphine | 10—50 mg/kg morphine for 4 days | Atrophy of thymus and spleen decreased Con A/LPS-induced T- and B-cell proliferation decrease of NK cell cytotoxicity | Decreased cytokine production in macrophages | Lu et al., 1996; Wu et al., 1999 | ||||
| Splenocytes from morphine-treated Lewis rats | Morphine | 15 mg/kg single dose | Splenocyte apoptosis decreased Con A-induced splenocyte proliferation | Increase of Con A-stimulated NO release from macrophages | NMMA (NOS antagonist) | Fecho et al., 1994 | |||
| J774 mouse macrophages | Morphine | 0.001—1 μM for 24 h | Apoptosis | 40 mg/kg every 12 h for 24 h | Increased apoptosis of peritoneal macrophages | Increase of Bax and TGFβ release | Anti-TGFβ antibody | Singhal et al., 2000 | |
| J774 mouse macrophages | Morphine | 1—100 μM | Apoptosis inhibition of P-p38 increase of Fas/FasL expression | Inhibition of TGFβ release, iNOS up-regulation and p53 stabilization | Ntx 1 μM vs. 0.01 μM morphine (only P-p38) | Anti-TGFβ antibody apoptosis inhibited with anti-FasL and Casp3, 8, 9 inhibitors | Singhal et al., 2002 | ||
| J774 mouse macrophages peritoneal macrophages from morphine-treated FVB/N mice | Morphine | 1 pM—1 nM for 26 h | Apoptosis | 20 mg/kg/d for 10 days | Inhibition of macrophage migration into peritoneal cavity and apoptosis | Increase of HO-1 activity and expression | Zinc-protoporphyrin | Patel et al., 2003 | |
| Splenocytes from morphine- or heroin-treated C57B1 6 mice | Morphine heroin | 20 mg/kg single dose | Early phase: increase of PHA-stimulated cytokine release (IL-2, TNFα, IL-1β, IFNγ); late phase: inhibition of cytokine release | Early phase: central-mediated immune stimulation; late phase: peripheral immunosuppression | Pacifici et al., 2000b | ||||
| Splenocytes from β-endorphin-treated rats | β-endorphin | 1—10 ng/rat i.t. single dose | Reduction of PHA-stimulated proliferation | Endocrine-mediated mechanism | No inhibition with Nx 5 mg/kg i.p. | Panerai et al., 1995 | |||
| Thymocytes from morphine-treated B6C3Fi mice | Morphine | Up to 100 μM for 18 h | No effect | 20 mg/kg for 4 days | Atrophy of thymus and spleen apoptosis of thymocytes particularly CD4+/CD8+ cells | Increased glucocorticoid plasma concentrations | Nx 1/7th of morphine dose | Glucocorticoid receptor antagonist | Freier and Fuchs, 1993; Fuchs and Pruett, 1993; Kim et al., 1999 |
| Macrophages | Morphine | 0.05 and 50 μM for 2 h | 0.05 μM, increase 50 μM decrease of LPS-induced IL-6 and TNFα release | 0.05 μM NF-κB activation, 50 μM NF-κB inhibition | Nx 0.1 and 100 μM | Roy et al., 1998 | |||
| Hematopoietic stem cells | Morphine enkephalin | 1—10 μM for 3—60 min | No effect on proliferation | Increase of MAPK activity (Erk, Elk phosphorylation) | Nx (100 μM) | Rozenfeld-Granot et al., 2002 | |||
| Human neutrophils and monocytes | Morphine Metenkephalin DAMGO | 0.01—100 nM for 1—1.5 h | Inhibition of chemokine-induced (MIP-1α, RANTES, IL-8) chemotaxis | Heterologous desensitization of CXCR1 and CXCR2 through release Gβγ | Nx (equimolar to μ-agonist) | PTX | Grimm et al., 1998a; 1998b | ||
| Human peripheral blood monocytes | DAMGO morphine | 100 nM to 1—100 nM for up to 96 h | Increase of chemokine expression MCP-1, RANTES, and IP-10 and LPS- and PHA-induced TGFβ release | μ-selective antagonist | Chao et al., 1992; Wetzel et al., 2000a | ||||
| Human NK and LAK cells | Morphine | 90—120 mg/kg/day in cancer patients | Reduction of NK cytotoxicity, increase of LAK cell development | Increase of prolactin release | Bromocriptine | Provinciali et al., 1996 | |||
| NK cells and splenocytes of morphine-treated rats with CCI | Morphine | CCI per se had no significant effect | 15 mg/kg/day for 7 days | Reduced ConA and PHA-stimulated NK cell activity and splenocyte proliferation | Central mediated effect | Tsai et al., 2000 | |||
| Splenocytes | β-endorphin deficiency | Increased splenocyte proliferative response and cytokine production in β-endorphin-deficient mice | Refojo et al., 2002 | ||||||
| Neurons and glia | |||||||||
| Primary rat neonatal astrocytes | Morphine | 200 μM for 24 h | Reduction of peroxynitrite-induced cell death | Gi-protein-mediated PI3K activation | Nx | PTX PI3K inhibitor | Kim et al., 2001 | ||
| Isolated rat adult hippocampal progenitors | β-endorphin-selective DOR agonists | 48 h | Increase of mitosis and DNA content | Activation of PI3K/Erk pathway | Nx | Persson et al., 2003 | |||
| Dopaminergic neurons of rat brain neuron-glia cultures | Dynorphin | 10-15 M | Reduction of LPS-induced apoptosis | Protective effect mediated through inhibition of microglial activity | Liu et al., 2001 | ||||
| Primary astrocytes from newborn mouse striatum, hippocampus, and cortex | Morphine | 1 μM for 6 days | Inhibition of proliferation (H3+-thymidine incorporation) | Nx (3 μM) | Stiene-Martin et al., 1991; Stiene-Martin and Hauser, 1993 | ||||
| Neurons (mouse striatum) | Morphine | 0.01—1 μM for 24 h | Increases HIV Tat protein-induced cell death; morphine alone has no effect at 10 μM for 7 days | Nx | Gurwell et al., 2001 | ||||
| U87 astrocytoma cell line and human primary astrocytes | Morphine | 0.01—0.1 μM for 24 h | Down-regulation of IL-8 and MIP-1β, increase of chemokine receptor expression (CCR3, CCR5, and CXCR2) | Funaltrexamine at 1 μM vs. 0.1 μM MOR | Mahajan et al., 2002 | ||||
| Microglia neurons | Morphine | 1 μM for 2—7 days | Apoptosis, astrocytes are resistant | Caspase-3 activation | Nx (10 μM) | Hu et al., 2002 | |||
| NG108-15 nerve cells | Buprenorphine | 100 μM for 4—12 h | Apoptosis | Caspase-3 activation | Nx no effect | Caspase-3 inhibitor | Kugawa et al., 1998; 2000 | ||
| Spinal cord neurons in rats made tolerant to MOR (GABA-ergic) | Morphine | 10—20 μg i.t. twice daily for 7 days | Apoptosis, reduced antinociception in tolerant rats | Stimulation of NMDA-R-mediated caspase activation, Bcl2 down- and Bax up-regulation | NMDA-R antagonist | Mao et al., 2002 | |||
| Brain tissue | Morphine | Effects of morphine associated with high degree of tolerance and dependence | Increasing doses up to 100 mg/kg every 12 h | Fas up- and Bcl-2 down-regulation decrease of neurofilament | Nx at 10 mg/kg every 12 h vs. equal doses of morphine | Boronat et al., 2001 | |||
| Ciliary ganglion neurons of the chick embryo | Morphine | 100 μM repeatedly | No effect | 70—700 nM/day embryoic day 7—14 | Inhibition of apoptosis, no general effect on growth | Inhibition of synaptic transmission, inhibition of ACh release | Nx at equal doses | Meriney et al., 1985; 1991 | |
| Endothelial cells and fibroblasts | |||||||||
| Kidney fibroblasts | Morphine | 1—100 pM 0.01—100 μM for 48 h | Low dose: increase of proliferation (H3+-thymidine incorporation); high dose: apoptosis | Low dose: induction of c-fos, c-jun, c-myc; high dose: increase of p53 | Singhal et al., 1998 | ||||
| Endothelial cells | Morphine | 200 nM — 1 μM within minutes | Yasodilation (no effect with fentanyl which is no μ3-agonist | μ3-receptor-mediated NO release | Nx | Stefano et al., 1995; Bilfinger et al., 1998; Fimiani et al., 1999b | |||
| HDMEC in vivo: MCF-7 breast cancer cells in nude mice | Morphine | 0.01—100 μM for 48 h (Akt, Erk phosphorylation within minutes) | Increase of proliferation, tube formation and inhibition of apoptosis (cytotoxic effects at ≥1 mM) | 0.714—1.43 mg/kg/day for 38 days | Increase of tumor growth (MCF-7 breast cancer) and angiogenesis | Gβγ/PI3K-mediated activation of Akt and eNOS subsequently NO-induced Erk activation | No inhibition with Nx (equimolar to morphine) | PTX L-NAME (NOS-inhibitor) PD98059 (MEK inhibitor) | Gupta et al., 2002 |
| Glomerular epithelial cell | Morphine | 0.01 pM for 48 h | Increase of proliferation | Increase of heme oxygenase activity | Hemin, antioxidants | Patel et al., 2003 | |||
| Glomerular epithelial cell | Morphine | 1—100 μM for 48 h | Increase of apoptosis | Decrease of heme oxygenase activity | Zinc-protoporphyrin, antioxidants | Patel et al., 2003 | |||
| Tumor cells | |||||||||
| K562 tumor and human peripheral blood mononuclear cells | Morphine | 0.001—1 μM for 24 h | Increase of proliferation of tumor cells, decrease with peripheral blood mononuclear cells (H3+-thymidine incorporation) | Sergeeva et al., 1993 | |||||
| U1690 small cell lung cancer | β-endorphin | 0.001—1 μM for 4 days | Increase of proliferation (cell number) | Not inhibited with Nx | Melzig et al., 1995 | ||||
| PC12 lung cancer, HL-60 leukemia, neuroblastoma, KATO III gastric cancer, SEKI melanoma, SKNO1 leukemia | Morphine | 1500—5000 μM for 1—4 days | Inhibition of proliferation (MTT assay, counting viable cells) | Inhibition of PKC activation and TNFα release | Sueoka et al., 1996 | ||||
| Neuroblastoma, PC-9 lung cancer, U251 glioblastoma, HL-60 colon carcinoma | KT-90 morphine | 50—200 μM 1—10 mM for 48 h | Apoptosis, inhibition of TPA or okadaic acid-induced TNFα release | Inhibition of NF-κB | Sueoka et al., 1996; 1998 | ||||
| S20Y neuroblastoma in A/Jax mice | Naltrexone | 0.1 mg/kg/day, 10 mg/kg/day | Low dose: decrease of tumor growth and prolonged survival; high dose: increase of tumor growth and reduced survival | Increased sensitivity to endorphin through increase of binding sites with low dose Ntx | Zagon and McLaughlin, 1983 | ||||
| SK-N-SH neuroblastoma cells | Etorphine | 10—100 μM for 24 h | Inhibition of proliferation (H3+-thymidine incorporation) apoptosis no effect with morphine | Involvement of ORL receptors | PTX ICE-inhibitor | Yin et al., 1997 | |||
| SK-N-SH neuroblastoma cells | DAMGO morphine | 0.1—2 (10) μM for 24 h (5—15 min for P-Akt) | Prevention of cell death induced by serum deprivation | Gβγ-mediated PI3K/Akt activation | Inhibition with Nx 50 μM vs. 1 μM DAMGO | Inhibited with PI3K inhibitor LY294002 | Iglesias et al., 2003 | ||
| LCNaP, DU145, PC3 prostate cancer | Morphine, etorphine, various peptides | 0.1—1 nM for 4—5 days | Reduction of metabolically active cells (tetrazolium salt assay) | Binding to atypical binding sites | Diprenorphine 1 μM: potentiation or no effect | Kampa et al., 1997 | |||
| DU145 prostate cancer | κ-agonist dynorphin A | 0.1 pM for 72 h | Increase of proliferation (counting viable cells), morphine: no effect | Subcellular compartment shifts of CaM | No inhibition with Nx | Moon, 1988 | |||
| SCLC and non-SCLC cell lines in vivo: SCLC N417 non-SCLC N466 | D- and S-methadone | 0.1 μM for 5 days | Inhibition of proliferation (MTT assay, counting of viable cells) | 10 mg/kg/day for 20 days | Inhibition of tumor growth (N417 > N466) D, and S isomer equally active | Atypical binding sites, mRNA, and protein de novo synthesis involved | Nx (0.1 μM) only for short term exposure (6 h) | Cycloheximide actinomycin D PTX no effects | Maneckjee and Minna, 1992 |
| H69, N417 SCLC, H157 non-SCLC | Morphine | 0.01—1 μM for 24 h | Inhibition of proliferation (MTT assay) | Inhibition of protein kinase C | Nx (100 nM vs. 10 nM morphine) | Nicotine | Maneckjee and Minna, 1990, 1994 | ||
| Lung cancer tissue specimens | Morphine | 1 μM within minutes | μ3-receptor-mediated NOS activation, NO release | Nx | Fimiani et al., 1999a | ||||
| T47D breast cancer | κ-agonists | 0.01—1 μM for 1 h | Inhibition of NOS activity and NO release (no effect with specific μ and δ agonists) | Direct interaction of internalized opioid with NOS | Diprenorphine no effect (1 μM) | Kampa et al., 2001 | |||
| MCF-7 breast cancer | Morphine DADLE (δ-agonist) cyclazocine (κ-agonist) | 0.01—0.1 μM for up to 6 days | Inhibition of proliferation (tetrazolium salt assay, counting viable cells) | Nx (100 nM) | Lack of estrogen in culture | Maneckjee et al., 1990 | |||
| MCF-7, MDA-MB231 breast cancer HT-29 colon cancer in vivo: cells injected s.c. in nude mice | Morphine DAMGO | 10—2000 μM for 24 h | G1 cell cycle arrest, inhibition of proliferation (counting of viable cells) and apoptosis | 10—30 mg/kg/day for 3 weeks | Inhibition of tumor growth (MCF-7 and MDA-MB231) no effect on HT-29 tumors | p53 phosphorylation and stabilization, up-regulation of p53-dependent p21, Bax, Fas | Nx no effect (equimolar concentrations in vitro and 1/10th of morphine dose in vivo) | No effect with PTX, forskolin, 8-Br-cAMP; inhibition of apoptosis with inhibitors of caspase 3, 8, 9, and FasFusion protein | Tegeder et al., 2003 |
| T47D breast carcinoma | Morphine, etorphine, DADLE | 0.001—0.1 μM for 5 days | Inhibition of proliferation (H3+-incorporation) | δ and κ-opioid receptor-mediated effects | Diprenorphine 1 μM (except for effects of morphine) | Hatzoglou et al., 1996 | |||
| EL-4 leukemia in C57B16 mice, sarcoma 180 in ddY mice | Morphine | 500—1000 μM (EL-4, P388, Meth-A, MM-46 cells) for 48—72 h | Decrease of viability/proliferation (MTT assay) of tumor cells attenuated ConA-induced lymphocyte proliferation | 10 mg/kg/day for 10 days | Increase of tumor growth | General immunosuppression with morphine or alterations of hormone secretion | Nx (1 mg/kg/day for 10 days) | Ishikawa et al., 1993 | |
| Walker 256 carcinosarcoma cells injected i.v. in SD rats | Morphine | 5 mg/kg single dose | Increase of metastatic tumor growth | Short lasting suppression of NK cell cytotoxicity | Nx (5 mg/kg single dose) | Pentacozine | Simon and Arbo, 1986 | ||
| Colon 26-L5 carcinoma cells in vivo: BALB/c mice injected i.v. | Morphine | 0.035—0.35 μM for 24 h | No effect on cell proliferation, inhibition of adhesion and invasion | 10 mg/kg/day for 6 days | Reduced lung metastases | Inhibition of MMP-2 and 9 production (not inhibited with naloxone) | Nx (equimolar concentrations to MOR) | Harimaya et al., 2002 | |
| MADB100 mammary adenocarcinoma cells injected i.v. in Fisher 344 rats 5 h after surgery | Morphine | 5 mg/kg 3 doses (pre, post and 5 h post surgery) | Attenuated surgery-induced enhancement of metastatic growth | Inhibition of post-surgical pain, thereby reduction of stress and stress induced immunosuppression | Page et al., 1993 | ||||
| Colon cancer cells i.p. in Fisher 344 rats | Morphine | 20 mg/kg/day for 3 days | Reduced liver metastasis | Enhanced NK cell activity at the time of tumor cell injection | Yeager and Colacchio, 1991 | ||||
| B16-16 melanoma cells injected into hindpaw in C57Bl mice | Morphine | 0.35—3500 μM for 48 h | No effect up to 350 μM, inhibition of proliferation at 3500 μM | 10 mg/kg/day for 6 days | Inhibition of local tumor growth and lung metastasis, similar effect achieved with nerve ligation | Pain reduction prevents stress-induced alterations of anti-tumor immune response | Sasamura et al., 2002 | ||
| HSC-2 and HSG human oral cancer cell lines | Codeinone, morphine | 10—500 μM for 24 h | Inhibition of proliferation (MTT assay), apoptosis | Acetyl-cysteine | Kawase et al., 2002 | ||||
| Transfected cells | |||||||||
| CHO stably transfected with MOR | DAMGO | 0.1—10 μM within minutes | Gβ/γ/PI3K mediated Akt and p70S6 kinase activation | Nx (10 μM) | PTX | Polakiewicz et al., 1998b | |||
| CHO stably transfected with MOR | Morphine | 0.1—10 μM within 1 h (mRNA) | Increase of c-fos and junB expression and AP-1 DNA binding activity | Gβγ/PI3K mediated Erk activation | PTX PD98059 (MEK-inhibitor) | Shoda et al., 2001 | |||
| HEK293 cells stably transfected with MOR or mutant MOR | DAMGO | 1 μM 5—60 min | Erk phosphorylation | Transactivation of EGFR through release of membrane bound EGF, requires direct interaction of μ- or δ-OR with CaM | No effects with MOR-mutant that cannot bind CaM | Inhibition with inhibitors of PKC and CaMK | Belcheva et al., 2001 |
ConA, concanavalin A; LPS, lipopolysaccharide; Nx, naloxone; Ntx, naltrexone; CCI, chronic constriction injury; ICE, interleukin-converting enzyme; CHO, chinese hamster ovary; iNOS, inducible NOS; eNOS, endothelial NOS; DADLE, [d-Ala2,d-Leu5]-enkephalin.