buprenorphine and 18-19-dihydroetorphine

Buprenorphine is a partial agonist at the micro -opioid receptor with long duration of action and also exhibits delayed antagonist activity. Buprenorphine is finding increasing use as a treatment agent for opioid abuse, though its low efficacy is not well tolerated by all addicts. There is interest in developing a higher efficacy version of buprenorphine and in this mini-review some of the ligands recently discovered, that share with buprenorphine a profile of agonism followed by delayed antagonism, are discussed.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Drug Evaluation, Preclinical; Etorphine; Humans; Hydromorphone; Ligands; Morphinans; Narcotic Antagonists; Receptors, Opioid, mu; Structure-Activity Relationship; Substance-Related Disorders

The extraordinarily strong analgesic dihydroetorphine (DHE) was registered as one of the most strictly controlled narcotic drugs by the United Nations in 1999. However, an effective detection method for DHE in biological samples has not yet been established. We developed a quantitative method for assay of DHE in rat plasma and brain by liquid chromatography-tandem mass spectrometry equipped with an ionspray interface. A 0.5-ml volume of plasma and brain homogenate spiked with buprenorphine (internal standard) was purified by the solid-phase extraction column Bond Elute Certify. DHE produced numerous weak fragment ions by collision induced dissociation. Therefore, collision energy was utilized to decompose the interferences, and the protonated molecular ion was used for both precursor and product ion monitoring. As a result of the method validation, the dynamic concentration range was determined as 0.05-10 ng/ml. DHE in these samples was stable for 2 months at -4 degrees C and for 24 h at ambient temperatures. Using the present method, DHE was detected in rat plasma and brain tissue after intravenous injection (0.5 microg/kg).

Topics: Analgesics, Opioid; Animals; Brain Chemistry; Buprenorphine; Calibration; Chromatography, High Pressure Liquid; Etorphine; Male; Mass Spectrometry; Quality Control; Rats; Reference Standards; Reproducibility of Results; Solutions

This study examines the possibility that oripavine opioid receptor agonists bind equally to both high and low affinity states of the mu-opioid receptor. Studies were performed in C6 cells expressing mu- or delta-opioid receptors; high and low agonist affinity states of the receptors were defined by the absence and presence, respectively of Na+ ions and the GTP analog Gpp(NH)p. At the mu-opioid receptor dihydroetorphine and etorphine were full agonists, buprenorphine had moderate efficacy while diprenorphine was an antagonist. At the delta-opioid receptor, dihydroetorphine, etorphine, and diprenorphine had moderate efficacy while buprenorphine was an antagonist. The binding affinities of the oripavines at the mu-opioid receptor decreased only one to 2-fold in the presence of NaCl and Gpp(NH)p. In contrast, decreases in oripavine affinity at the delta-opioid receptor correlated with delta-opioid receptor efficacy. The ability of oripavine agonists to bind with high affinity to the low agonist affinity state of the nu-opioid receptor may explain the high potencies of these compounds in vivo.

Topics: Analgesics, Opioid; Animals; Benzamides; Binding, Competitive; Buprenorphine; Cloning, Molecular; Diprenorphine; Dose-Response Relationship, Drug; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Etorphine; Fentanyl; Guanosine 5'-O-(3-Thiotriphosphate); Morphine; Naloxone; Piperazines; Radioligand Assay; Rats; Receptors, Opioid, delta; Receptors, Opioid, mu; Sulfur Radioisotopes; Thebaine; Tritium; Tumor Cells, Cultured

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

To test the hypothesis that dihydroetorphine has opioid antagonist properties, we examined the effects of dihydroetorphine on the antinociceptive effect of morphine. The antinociceptive response was evaluated by recording the latency in the tail-flick test using radiant heat as a stimulus. The antinociceptive effect of dihydroetorphine reached its peak 30 min after administration, and remained significant up to 90 min after administration. On the other hand, when dihydroetorphine was injected i.c.v., the antinociceptive effect of dihydroetorphine reached its peak 15 min after administration, and a significant antinociceptive effect disappeared within 90 min after administration. When morphine was administered 30 min after dihydroetorphine, the antinociceptive effect of morphine was significantly enhanced. In contrast, the antinociceptive effect of morphine was significantly reduced when morphine was administered 120 min after either i.p. or i.c.v. administration of dihydroetorphine. This antagonistic effect remained significant up to 6 h after administration of dihydroetorphine, and then gradually decreased. However, dihydroetorphine had no significant effect on the antinociceptive effect of either trans-(+/-)-3,4-dichloro-N-methyl-N-(2(1-pyrrolidinyl) cyclohexyl)-benzeneacetamide (U-50, 488H), a kappa-opioid receptor agonist, or [D-Pen2.5]enkephalin (DPDPE), a delta-opioid receptor agonist. These results suggest that dihydroetorphine may have a reversible antagonist effect for mu-opioid receptors, but not for kappa- or delta-opioid receptors, when its agonistic activity disappears.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Etorphine; Injections, Intraperitoneal; Injections, Intraventricular; Male; Mice; Mice, Inbred ICR; Morphine; Nociceptors; Pain Measurement; Receptors, Opioid, mu