naloxone and Brain-Neoplasms

D,L-methadone (MET), an analgesic drug used for pain treatment and opiate addiction, has achieved attention from oncologists and social media as possible chemoensitizing agent in cancer therapy, notably brain cancer (glioblastoma multiforme, GBM). MET has been reported to enhance doxorubicin-induced cytotoxicity in GBM cells via activation of the µ-opioid receptor (MOR). Here, we extended this work and quantified the toxic effect of MET in comparison to other opioids alone and in combination with doxorubicin and the clinically more relevant alkylating drug temozolomide (TMZ), using a set of GBM cell lines and primary GBM cells.. MET alone was cytotoxic in all GBM cell lines and primary GBM cells at high micromolar concentrations (IC. MET was found to be cytotoxic in GBM cells in vitro only at high, clinically not relevant concentrations, where it was effective in inducing apoptosis and necrosis. Sensitizing effects were only observed in combination with doxorubicin, but not with TMZ, and are dependent on cell line and the applied drug concentration. Therefore, our findings do not support the use of MET in the treatment of GBM in combination with TMZ, as no sensitizing effect of MET was observed.

Topics: Analgesics, Opioid; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Cell Line, Tumor; Doxorubicin; Drug Screening Assays, Antitumor; Drug Synergism; Glioblastoma; Humans; Methadone; Morphine; Naloxone; Oxycodone; Receptors, Opioid, mu; Tumor Cells, Cultured

The irreversible opioid receptor antagonists naloxonazine and beta-funaltrexamine have been used to determine whether multiple mu-opioid receptors exist on undifferentiated SH-SY5Y human neuroblastoma cells. Naloxonazine binds irreversibly to the mu 1-opioid receptor subtype and reversibly to the mu 2-opioid receptor subtype. On SH-SY5Y cells naloxonazine afforded a Ki of 3.4 +/- 0.7 nM, and was fully reversible, indicating the mu-opioid receptor population on SH-SY5Y cells was solely of the mu 2-opioid receptor subtype. The alkylating agent beta-funaltrexamine was maximally able to alkylate only 60% of the mu-opioid receptor sites on SH-SY5Y cells, labelled with [3H]diprenorphine or [3H][D-Ala2,MePhe4,Gly(ol)5]enkephalin (DAMGO). The reversible binding of naloxonazine and the insensitivity of a percentage of the mu-opioid receptor sites to alkylation by beta-funaltrexamine suggests that differences do exist in the mu 2-opioid receptor population on undifferentiated SH-SY5Y cells. This may indicate further heterogeneity or the inability of beta-funaltrexamine to alkylate all relevant nucleophilic groups in a single population of receptors.

Topics: Amino Acid Sequence; Animals; Brain Neoplasms; Cerebral Cortex; Diprenorphine; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Humans; Ligands; Molecular Sequence Data; Naloxone; Naltrexone; Neuroblastoma; Rats; Receptors, Opioid, mu; Somatostatin; Tumor Cells, Cultured

Electrical and pharmacological properties of currents induced by compounds having affinities for putative sigma receptors were investigated with NCB20 cells by use of the whole-cell patch-clamp technique. Antipsychotics and naloxone induced inward currents with a decrease in membrane conductance at a holding potential of -60 mV. The rank order of potency for compounds inducing these currents was bromperidol > haloperidol > mosapramine = clocapramine > carpipramine > chlorpromazine > remoxipride > naloxone. Sulpiride, which does not have affinity for sigma receptors, induced inward currents only slightly. Haloperidol-induced currents were not affected by the pretreatments with 10 microM of sulpiride, dopamine, atropine, N-methyl-D-aspartate, 2-amino-7-phosphonoheptanoic acid, morphine or A23187, 100 nM of ICS 205-930, 100 microM of forskolin, 1 microM of phorbol-12,13-dibutyrate, or 100 ng/ml of cholera or pertussis toxins. The reversal potential of the currents induced by haloperidol, naloxone or remoxipride was dependent on the concentration of external or internal potassium. These results indicate that the currents induced by the tested compounds are due to blockade of tonic, outward potassium currents and suggest that these agents act on putative sigma receptors and that the second messenger systems within the cell are not essential for the coupling between the receptors and the channels.

Topics: Animals; Antipsychotic Agents; Brain Neoplasms; Cricetinae; Electrophysiology; Haloperidol; Ligands; Membrane Potentials; Mice; Naloxone; Neuroblastoma; Potassium Channels; Receptors, sigma; Remoxipride; Tumor Cells, Cultured

Effect of dalargin, an opioid peptide (a synthetic analogue of Leu-enkephalin), on proliferation and intensity of DNA synthesis of C6 glioma cells was studied. Specific conditions of cultivation were selected, with a low control value of proliferation, which permitted to assess growth-stimulating effect of the peptide. Growth curves were plotted to assess peptide activity, which demonstrated that reaction was a many-phase process: a significant increase in cell number under peptide effect was observed only at the beginning of the logarithm phase and at the beginning of the prestationary phase of the growth curve. Cell number increased on average by 25-27% in the presence of dalargin as compared to control. Reaction of glioma DNA synthesis to dalargin also demonstrates complexity of the process: the peptide changes DNA synthesis, but as a rule, this process has a three-phase character and is not directly associated with the duration of cultivation in the presence of dalargin. Effect of naloxone, an opiate receptor blocker, was analysed to assess the receptor mechanism. It was found that reaction for naloxone and for combined effect of naloxone and dalargin was not the same.

Topics: Animals; Brain Neoplasms; Cell Division; Cell Line; DNA, Neoplasm; Drug Interactions; Enkephalin, Leucine-2-Alanine; Glioma; Naloxone; Rats; Thymidine; Time Factors; Tritium; Tumor Cells, Cultured

Topics: Adult; Aged; Anesthesia, Intravenous; Brain Neoplasms; Cranial Nerves; Fentanyl; Hemodynamics; Humans; Middle Aged; Naloxone; Neurosurgery; Oxygen; Posture

Topics: Adolescent; Adult; Aged; Atropine; Blood Circulation; Blood Pressure; Brain Neoplasms; Cardiac Volume; Droperidol; Fentanyl; Heart Rate; Humans; Middle Aged; Naloxone; Neuroleptanalgesia; Preanesthetic Medication; Pulse; Respiration