buprenorphine and Neuroblastoma

Opioids are the most effective drugs used for the management of moderate to severe pain; however, their chronic use is often associated with numerous adverse effects. Some results indicate the involvement of oxidative stress as well as of proteasome function in the development of some opioid-related side effects including analgesic tolerance, opioid-induced hyperalgesia (OIH) and dependence. Based on the evidence, this study investigated the impact of morphine, buprenorphine or tapentadol on intracellular reactive oxygen species levels (ROS), superoxide dismutase activity/gene expression, as well as β2 and β5 subunit proteasome activity/biosynthesis in SH-SY5Y cells. Results showed that tested opioids differently altered ROS production and SOD activity/biosynthesis. Indeed, the increase in ROS production and the reduction in SOD function elicited by morphine were not shared by the other opioids. Moreover, tested drugs produced distinct changes in β2(trypsin-like) and β5(chymotrypsin-like) proteasome activity and biosynthesis. In fact, while prolonged morphine exposure significantly increased the proteolytic activity of both subunits and β5 mRNA levels, buprenorphine and tapentadol either reduced or did not alter these parameters. These results, showing different actions of the selected opioid drugs on the investigated parameters, suggest that a low µ receptor intrinsic efficacy could be related to a smaller oxidative stress and proteasome activation and could be useful to shed more light on the role of the investigated cellular processes in the occurrence of these opioid drug side effects.

Topics: Analgesics, Opioid; Buprenorphine; Humans; Morphine; Neuroblastoma; Proteasome Endopeptidase Complex; Tapentadol

To study the mechanism underlying the difference in physical dependence potential of morphine (Mor), methadone (Met), buprenorphine (Bup), etorphine (Eto), and dihydroetorphine (DHE).. Adenylate cyclase of NG108-15 cells were used for studying the effects of different opiates on cAMP second messenger system.. Bup, DHE, and Eto were distinct from Mor in naloxone-precipitated rebound response of cAMP in NG108-15 cells chronically treated with these opiates. Naloxone given to NG108-15 cells treated with Mor for 24 h produced marked rebound response of adenylate cyclase. While no such rebound response was detected when the cells were treated with Bup, DHE, and Eto for 24 h. The naloxone-induced rebound response of cAMP in chronic Met-treated NG108-15 cells was also lower than that in chronic Mor-treated NG108-15 cells. Following a prolonged exposure to Bup, DHE, and Eto for 72 h, the naloxone-induced rebound response of cAMP in these cells was still markedly lower than that in Mor-treated cells. The substitution of Mor with Bup, Met, DHE, and Eto inhibited naloxone-induced rebound response of cAMP in chronic Mor-treated NG108-15 cells.. There were distinct differences among these opiates in regulating cAMP second messenger system, which was related to their physical dependence potential.

Topics: Adenylyl Cyclases; Analgesics, Opioid; Buprenorphine; Cyclic AMP; Etorphine; Glioma; Humans; Hybrid Cells; Methadone; Morphine; Neuroblastoma; Opioid-Related Disorders; Receptors, Opioid; Receptors, Opioid, delta; Tumor Cells, Cultured

To study the mechanism of opioid agonists in regulation of cAMP second messenger system.. Low-pH treatment was used to deplete the stimulatory G protein (Gs) function. The effects of some opiates on adenylate cyclase were compared between control and low-pH treatment membranes.. In contrast to dehydroetorphine (DHE), etorphine (Eto), morphine (Mor) and methadone (Met) substantially increased the inhibitory effects on adenylate cyclase in membranes prepared from naive and chronic Mor- or Met-treated NG108-15 cells by low-pH treatment. In contrast to Mor, DHE and Eto did not result in significant decrease in the inhibitory effects on adenylate cyclase in membranes from the cells treated chronically with DHE or Eto. Marked rebound of adenylate cyclase was also not observed in membranes from chronic DHE or Eto-treated cells when precipitated with naloxone. Low-pH treatment eliminated naloxone-induced rebound of adenylate cyclase in chronic Mor-treated cells.. The difference in opiate-induced functional adaptive alteration of Gs is at least one biochemical mechanism of developing opiate tolerance and dependence.

Topics: Adenylyl Cyclases; Analgesics, Opioid; Buprenorphine; Cyclic AMP; Etorphine; Glioma; Humans; Hybrid Cells; Hydrogen-Ion Concentration; Methadone; Morphine; Neuroblastoma; Opioid-Related Disorders; Receptors, Opioid, delta; Tumor Cells, Cultured

Buprenorphine is an opiate drug with a mixed agonist-antagonist profile and has therapeutic efficacy in attenuating drug craving and addiction. Because the adenylyl cyclase system has been implicated in the biochemical basis of opiate withdrawal phenomena, we have compared the acute and chronic effects of buprenorphine with the full opiate agonist etorphine on cyclic AMP (cAMP) synthesis in the human neuroblastoma cell SK-N-SH. Both drugs acutely inhibited prostaglandin (PG)E1-stimulated cAMP accumulation; the inhibition caused by either drug was prevented by pretreatment with the opiate antagonist naltrexone or with pertussis toxin. Chronic treatment of the cells with etorphine induced an increase in PGE1-stimulated cAMP synthesis which was observed after withdrawal of the inhibitory drug. Chronic treatment with buprenorphine appeared to have the opposite effect, resulting in an attenuated PGE1 stimulation; additionally, buprenorphine prevented the etorphine-induced enhancement in cAMP synthesis, whether administered before or after prolonged incubation of the cells with etorphine. The attenuating effect of buprenorphine occurred within 5 min and was prevented by a prior application of naltrexone, but could not be reversed by a subsequent treatment with antagonist. These findings suggest that buprenorphine was binding (pseudo)irreversibly to the opiate receptor, resulting in a persistent inhibition of cAMP synthesis which masks the etorphine-induced enhancement of adenylyl cyclase activity. This hypothesis was confirmed by experiments demonstrating that treatment of the cells with buprenorphine significantly reduced available opiate receptor binding sites despite extensive washing of the cells to remove unbound buprenorphine. These pharmacodynamic actions of buprenorphine may be relevant to its therapeutic efficacy in treating drug abuse and addiction.

Topics: Adenylyl Cyclases; Alprostadil; Buprenorphine; Cell Differentiation; Cyclic AMP; Drug Interactions; Etorphine; Humans; Neuroblastoma; Receptors, Opioid, mu; Sensitivity and Specificity; Stimulation, Chemical; Time Factors; Tretinoin; Tumor Cells, Cultured