heroin and 18-19-dihydroetorphine

To investigate the receptor binding affinity and naloxone-precipitated cAMP overshoot of dihydroetorphine, fentanyl, heroin, and pethidine in Sf9 insect cells expressing human mu-opioid receptor (Sf9-mu cells).. Competitive binding assay of [3H]ohmefentanyl was used to reveal the affinity for mu-opioid receptor in Sf9-mu cells. [3H]cAMP RIA was used to determine cAMP level. Antinociceptive activity was evaluated using degree 55 mouse hot plate test. Naloxone-precipitated withdrawal jumping was used to reflect physical dependence in mice.. All drugs displayed antinociceptive activity and produced physical dependence in mice. The K(i) values of dihydroetorphine, fentanyl, heroin, and pethidine in competitive binding assay were (0.85+/-0.20) nmol, (59.1+/-11.7) nmol, (0.36+/-0.13) micromol, and (12.2+/-3.8) micromol respectively. The binding affinities of these drugs for mu-opioid receptor in Sf9-mu cells were paralleled to their antinociceptive activities in mice. After chronic pretreatment with these drugs, naloxone induced cAMP withdrawal overshoot in Sf9-mu cells. The dependence index in Sf9-mu cells was calculated as K(i) value in competitive binding assay over EC(50) value in naloxone-precipitated cAMP assay. The physical dependence index in mice was calculated as antinociceptive ED(50)/withdrawal jumping cumulative ED(50). There was a good linear correlation between dependence index in Sf9-mu cells and physical dependence index in mice.. The Sf9-mu cells could be used as a cell model to evaluate the receptor binding affinity and physical dependent liability of analgesic agents.

Topics: Analgesics, Opioid; Animals; Baculoviridae; Binding, Competitive; Cells, Cultured; Cyclic AMP; Etorphine; Female; Fentanyl; Heroin; Male; Mice; Opioid-Related Disorders; Receptors, Opioid, mu; Spodoptera; Transfection

The present study was undertaken to compare the neurotoxic effects of three etorphine-like opiates (etorphine, dihydroetorphine, and another derivative of oripavine) and heroin with their ability to activate opiate receptors in human neuroblastoma cell line SK-N-SH as well as in two other neuronal cell lines. Neurotoxicity was measured by using [3H]-thymidine incorporation analysis, cell viability measurement and Cytosensor microphysiometry. It was found that, in spite of the very similar molecular structures of these opiates, they displayed significant differences in cytotoxicity, with etorphine and another derivative of oripavine possessing high potency but dihydroetorphine and heroin little effect. However, neurotoxic potency of the opiates was not directly correlated to their ability to activate opioid receptors, as determined by [35S]-guanylyl-5'-O-(gamma-tho)-triphosphate binding assay. These findings provide clear evidence of differential neurotoxicity of etorphine-like opiates, and suggest that the neurotoxicity is not closely related to the molecular configuration required as opioid receptor agonist but is probably associated with the presence of a double bond in the structure.

Topics: Animals; Cell Survival; Etorphine; Guanosine 5'-O-(3-Thiotriphosphate); Heroin; Humans; Narcotics; Neuroblastoma; Neurotoxins; PC12 Cells; Rats; Receptors, Opioid; Structure-Activity Relationship; Thebaine; Tumor Cells, Cultured

Neuropathic pain has been suggested to be resistant to treatment with opiates. Such perceived lack of opioid responsiveness may be due to the dose-range over which specific opioid compounds have been studied as well as the efficacy of these compounds. Dihydroetorphine is a novel opiate that demonstrates significantly greater analgesic potency compared to morphine, and which also demonstrates diminished capacity for producing physical dependence in laboratory animals. The present study compared the intravenous (i.v.) efficacy, potency and duration of action of dihydroetorphine, fentanyl, heroin and morphine in producing anti-allodynic actions in a rat model of neuropathic pain (ligation of the L5/L6 nerve roots). All compounds produced significant anti-allodynic activity with dihydroetorphine being the most potent (A50 of 0.2 microg kg(-1), i.v.). Morphine was approximately 7440 times less potent than dihydroetorphine while heroin and fentanyl were approximately 163.5 and 6.9 times less potent in producing anti-allodynic actions. Dihydroetorphine also showed a maximal effect at 0.6 microg kg(-1) in all animals tested, while 100 microg kg(-1) was required for heroin to produce a maximal effect. Fentanyl and morphine did not elicit a maximum anti-allodynic response (74 and 76% maximum possible effect (%MPE), respectively). As expected, fentanyl showed a relatively brief duration of action (approximately 20 min at the highest tested dose), while dihydroetorphine and morphine demonstrated anti-allodynic actions for up to 45 min. Heroin had the longest duration of action, producing significant anti-allodynic effects for up to 90 min. These data show that dihydroetorphine and heroin produce potent and long-lasting anti-allodynic actions in this model. Additionally, in contrast to morphine and fentanyl, both dihydroetorphine and heroin were able to achieve a maximal response. The remarkable potency, maximal efficacy and duration of action of these compounds, particularly dihydroetorphine, suggests that these compounds may warrant further examination as potential therapeutic treatments for neuropathic pain states.

Topics: Analgesics, Opioid; Animals; Drug Evaluation; Etorphine; Fentanyl; Heroin; Infusions, Intravenous; Ligation; Male; Morphine; Nerve Compression Syndromes; Pain; Rats; Rats, Inbred F344; Spinal Nerves

Dihydroetorphine is a novel opioid that is an extremely potent analgesic in rodents. The reinforcing potency was determined in rats trained to self-administer heroin and compared to those of fentanyl, heroin, 6-acetylmorphine and morphine for assessment of the abuse potential of dihydroetorphine using a procedure that determines the dose-effect curve in individual sessions. Dihydroetorphine produced a bimodal dose-effect curve similar to that of other opioids. Potency ratios were determined with morphine for the ascending and descending limbs of the dose-effect curve, as well as the dose that yielded maximal response rate. Fentanyl, heroin and 6-acetylmorphine were approximately 100, 8 and 2 times more potent than morphine in maintaining self-administration, respectively. Dihydroetorphine was roughly 1500 to 3000 times more potent than morphine, however, depending upon the limb of the dose-effect curve used for comparison. These potency ratios of dihydroetorphine to morphine were somewhat less than has been reported for analgesia assays, and therefore this compound may have some clinical advantages over other opioids. However, these studies indicate significant abuse liability for dihydroetorphine given its potency in maintaining self-administration in these animals.

Topics: Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Etorphine; Fentanyl; Heroin; Male; Morphine; Morphine Derivatives; Rats; Rats, Inbred F344; Substance Withdrawal Syndrome; Substance-Related Disorders

These experiments examined whether dihydroetorphine (DHE) could serve as a reinforcer in rhesus monkeys and evoke the discriminative stimulus effects of heroin (HER) in rats, two procedures useful in predicting the overall abuse potential of compounds. Rhesus monkeys were trained to self-administer i.v. HER (10 micrograms/kg for monkeys M-BA, M-NI, and M-HO; 3 micrograms/kg for monkey M-PO) during daily; 2-h experimental sessions under FR 10 Timeout 4 min schedules. VEH and doses of HER (1-30 micrograms/kg), codeine (COD; 30-1000 micrograms/kg), and DHE (1-100 ng/kg) were then substituted for the HER maintenance doses. Results indicated that DHE served as a reinforcer. The dose of DHE that maintained peak numbers of infusions was 171 and 8571 times smaller than those maintaining peak numbers of infusions of heroin and codeine, respectively. Additionally, male Sprague-Dawley rats were trained to discriminate 0.3 mg/kg HER s.c. from vehicle (VEH) in an FR 10 (fixed-ratio 10), food-reinforced, operant procedure. During tests, HER, morphine (MOR), and DHE dose-dependently evoked heroin-lever responding with ED50s of 0.055, 0.74, and 0.00033 mg/kg, respectively. These results indicate that DHE is self-administered by rhesus monkeys, and potently produces the discriminative stimulus effects of HER in rats, and suggest that DHE would have a substantial potential for abuse.

Topics: Analgesics, Opioid; Animals; Discrimination Learning; Dose-Response Relationship, Drug; Etorphine; Heroin; Macaca mulatta; Male; Rats; Rats, Sprague-Dawley; Reinforcement, Psychology; Self Administration; Substance-Related Disorders

This paper reports the DHE substitution clinical trial in 38 heroin addicts. The CINA (Clinical Institute Narcotic Assessment) scale was used to assess physical dependence potential. The CINA scale contains 10 opioid withdrawal signs (nausea, vomiting, gooseflesh, sweating, restlessness, tremor, larcrimation, nasal congestion, yawning, changes in heart rate and systolic blood pressure) and 3 opiate withdrawal symptoms (abdominal pain, muscle pain and feeling hot or cold). For each subject admitted to the Drug Detoxification and Treatment Center his (her) status on each of the 13 items of CINA were immediately rated. Then, naloxone 0.4 mg was injected iv to precipitate withdrawal symptoms and at 5, 10, 15 min after the naloxone injection, the CINA score of each patient was rated again. The differences among the scores of pre- and post-naloxone injection is a measurement of the degree of withdrawal symptoms. Then, a single dose of DHE was administered sublingually to each patient, all withdrawal symptoms disappeared. These results show that DHE can compete with naloxone for opioid receptors. A good dose-response relationship was found between the 100% suppressive withdrawal sign doses of DHE and the degree of withdrawal sign in heroin addicts. The physical dependence potential of DHE given to heroin addicts sublingually was probably more than that of methadone given to heroin addicts orally by making reference to the report of Dr. Peachy.

Topics: Administration, Sublingual; Adolescent; Adult; Analgesics, Opioid; Etorphine; Female; Heroin; Heroin Dependence; Humans; Male; Methadone; Substance Withdrawal Syndrome; Substance-Related Disorders