Cloning of a thermostable ascorbate oxidase gene from Acremonium sp. HI-25 and modification of the azide sensitivity of the enzyme by site-directed mutagenesis

Concurrent abuse of cocaine and opioids is frequently observed clinically, and we have developed a model of "speedball" self-administration involving the simultaneous injection of cocaine and heroin combinations in rhesus monkeys (Mello et al. (1995) J Pharmacol Exp Ther 274:1325). In the present study, we evaluated the effects of buprenorphine (0.0075-0.75 mg/kg/day i.v.) and saline on speedball combinations of cocaine [0.001, 0.01 or 0.10 mg/kg/inj] and heroin [0.0001-0.032 mg/kg/inj]. We also examined the effects of buprenorphine (0.075 and 0.237 mg/kg/day i.v.) on self-administration of heroin alone (0.0001-0.01 mg/kg/inj). Drug and food (1-g banana pellets) self-administration were maintained on a second-order FR4 (VR16:S) schedule in four 1-hr sessions each day. Each buprenorphine or saline control treatment was evaluated for 10 consecutive days, and monkeys returned to base-line performance between each treatment condition. Buprenorphine (0.075-0.75 mg/kg/day) selectively reduced self-administration of speedball combinations of low-dose cocaine (0.001 mg/kg/inj) and heroin (0.001 or 0.0032 mg/kg/inj) (P < .05-.01), and buprenorphine (0.237 mg/kg/day) shifted dose-effect curves for speedball combinations of cocaine (0.001 mg/kg/inj) and heroin (0.0001-0.032 mg/kg/inj) downward (P < .05-.01) and approximately 1 log unit to the right. Buprenorphine treatment was less effective in decreasing responding maintained by speedball combinations of heroin and 0.01 and 0.10 mg/kg/inj cocaine. Buprenorphine treatment (0.075 and 0.237 mg/kg/day) also shifted the heroin dose-effect curve downward (P < .01-.001) and to the right. Both speedball and heroin self-administration were associated with dose-dependent decreases in food-maintained responding during saline control treatment. However, food-maintained responding was often higher than control levels during buprenorphine treatment (P < .05-.001), which suggests that buprenorphine antagonized the rate-decreasing effects of speedballs and of heroin. Buprenorphine's selective reduction of speedball and heroin self-administration is consistent with clinical treatment trials in opioid abusers and polydrug abusers. Thus, these primate models of speedball and heroin self-administration should be useful for preclinical evaluation of novel drug abuse treatment medications.     

Buprenorphine antagonism of mu opioids in the rhesus monkey tail-withdrawal procedure

The apparent in vivo dissociation constant (KA) and relative efficacy values for alfentanil, etonitazene, morphine, and nalbuphine were determined by comparing the effects of these agonists in the presence of buprenorphine with the effects of these agonists alone in the rhesus monkey tail-withdrawal procedure. Initial time course studies of buprenorphine alone indicated that 3.2 and 10 mg/kg produced increases in tail-withdrawal latencies when studied with 48 degrees C water for 48 hr. No increases in tail-withdrawal latency were found with either dose studied with 55 degrees C water. Buprenorphine produced dose-dependent shifts to the right for the antinociceptive effects of alfentanil, etonitazene, morphine and nalbuphine 72 hr after administration and decreased the maximal effects of morphine in 48 degrees C water and those of alfentanil and etonitazene in 55 degrees C water. Buprenorphine administration decreased the receptors available for agonist interaction to approximately 2%. The average apparent in vivo dissociation constant (KA) values for alfentanil, etonitazene, morphine and nalbuphine were 3.3, 0.073, 60 and 31 mg/kg, respectively. High efficacy estimates were determined for alfentanil (149-203) and etonitazene (174-203), whereas lower efficacy estimates were determined for nalbuphine (57) and morphine (17). The apparent in vivo dissociation constant of a pseudoirreversible antagonist (KB) value for buprenorphine averaged 0.15 mg/kg across agonists, temperatures and buprenorphine doses. These data extend and emphasize the significance of in vivo estimates of affinity and relative efficacy for drug classification.     

Clocinnamox antagonism of the antinociceptive effects of mu opioids in squirrel monkeys

The opioid agonists morphine, etorphine, buprenorphine and U50,488 were examined alone and in combination with the insurmountable opioid antagonist clocinnamox (C-CAM) in squirrel monkeys responding under a schedule of shock titration. In this procedure, shock intensity increased every 15 sec from 0.01 to 2.0 mA in 30 increments. Five lever presses during any given 15-sec shock period produced a 15-sec timeout, after which shock resumed at the next lower intensity. When given alone, each of these agonists increased the median intensity at which the monkeys maintained shock [median shock level (MSL)]. At the highest dose examined alone, each agonist produced maximal increases in MSL and, except buprenorphine, decreased response rates. C-CAM dose-dependently antagonized the effects of morphine, etorphine and buprenorphine on MSL. In the presence of the higher C-CAM doses, etorphine, morphine and buprenorphine did not produce maximal effects on MSL. The effects of U50,488 were not systematically altered when tested in combination with the highest C-CAM dose. In general, C-CAM was more potent and the duration of antagonism was slightly longer against buprenorphine than against morphine and etorphine. Quantitative analysis of these data according to an extended model of yielded the following apparent affinity and efficacy estimates, respectively: etorphine (0. 085 mg/kg, 117); morphine (49 mg/kg, 24) and buprenorphine (0.62 mg/kg, 7.1). Determination of the individual q values over time indicated that the receptor population recovers more quickly after C-CAM antagonism of etorphine than from C-CAM antagonism of either morphine or buprenorphine. These data suggest that C-CAM functions as a long-lasting antagonist of mu opioid agonist actions in a shock titration procedure and yields estimates of relative intrinsic efficacy with the rank order of etorphine > morphine > buprenorphine.     

Effects of proposed treatments for cocaine addiction on hemodynamic responsiveness to cocaine in conscious rats

Several agents may treat cocaine addiction and toxicity including bromocriptine, desipramine, GBR 12909 [1-(2-(bis(4-fluorphenyl)-methoxy)-ethyl)-4-(3-phenyl-propyl) piperazine], diazepam, buprenorphine and dizocilpine. In this study, we sought to determine whether these specific therapeutic agents alter cardiovascular responses to cocaine in conscious rats. Arterial pressure responses to cocaine (5 mg/kg, i.v.) were similar in all rats whereas cardiac output responses varied widely. In 26 of 33 rats (named vascular responders), cocaine induced a decrease in cardiac output of 8% or more. The remaining rats with little change or an increase in cardiac output were classified as mixed responders. Pretreatment with bromocriptine (0.1 mg/kg) or desipramine (1 mg/kg) increased cardiac output in mixed responders and increased systemic vascular resistance in vascular responders similar to the differential effects noted with cocaine. GBR 12909 (0.5-10 mg/kg) elicited a decrease in cardiac output at higher doses. Diazepam (0.1 and 0.5 mg/kg) had small, short-lasting effects on cardiovascular parameters. Buprenorphine (0.3 mg/kg) or the NMDA (N-methyl-D-aspartic acid) receptor antagonist, dizocilpine (0.05 mg/kg), increased arterial pressure, heart rate and cardiac output in vascular responders. Bromocriptine and desipramine prevented the difference in cardiac output responses in vascular and mixed responders by reducing the cocaine-induced decrease in cardiac output in vascular responders. Pretreatment with GBR 12909 (1 mg/kg) had little effect on cardiovascular responses to cocaine except to depress the increase in cardiac output noted in mixed responders. Buprenorphine selectively enhanced the increase in systemic vascular resistance whereas dizocilpine enhanced the pressor response. These data suggest that several treatment regimens for cocaine addiction alter the cardiovascular responses to cocaine and that dopamine D2 receptor activation may be necessary for the decrease in cardiac output noted in vascular responders.     

Buprenorphine-induced alterations of cocaine's reinforcing effects in rhesus monkey: a dose-response analysis

Buprenorphine reduces cocaine self-administration by rhesus monkeys, opiate- and cocaine-dependent men and polydrug abusers, but the mechanisms underlying these cocaine-opiate interactions are not well understood. In the present study, the effects of daily placebo or buprenorphine (0.1, 0.3 and 1.0 mg/kg) treatment on cocaine self-administration (0.001-0.3 mg/kg/inject) were examined in five cocaine-experienced rhesus monkeys. Saline and each of six cocaine doses were available in an irregular order. Responding for cocaine (or saline) and food was maintained on a second order FR4 (VR 16:5) schedule of reinforcement. During placebo treatment, the daily number of cocaine injections increased as the unit dose was increased and then decreased at higher doses. Cocaine doses that maintained the highest rates of responding during placebo treatment were more resistant to buprenorphine's effects. The typical increase in response rate during the first five cocaine injections of a session also was attenuated by buprenorphine. The ascending limb of the cocaine dose-response curve was shifted downward and approximately one log unit to the right during low-dose buprenorphine treatment (0.1 mg/kg/day). In contrast, individual response rates for food pellets were unaffected. We conclude that buprenorphine selectively decreases self-administration of some unit doses of cocaine at doses that have minimal effects on food-maintained responding.     

Aspirin synergistically potentiates isoflurane minimum alveolar concentration reduction produced by morphine in the rat

BACKGROUND: The combination of opioids and nonsteroidal antiinflammatory drugs is more analgesic than the summed effect of each drug administered separately. This synergism has been used to obtain analgesia in the postoperative period at doses at which side effects are minimal. The aim of this study is to evaluate the analgesic interaction between aspirin and morphine in the rat during isoflurane anesthesia. The reduction in minimum alveolar concentration of isoflurane (MAC(ISO)) was used as an objective measure of the analgesic potency of individual drugs and their use in combination. METHODS: Thirty-seven male Wistar rats were anesthetized with isoflurane in oxygen, and the MAC(ISO) was determined before and after the intravenous administration of aspirin and morphine. Rats were administered morphine alone (1, 3, and 10 mg/kg) or morphine (1 and 3 mg/kg) and aspirin (30 mg/kg). The MAC(ISO) was determined from alveolar gas samples at the time of tail clamp. The duration of MAC(ISO) reduction was recorded. RESULTS: Aspirin did not have an effect on MAC(ISO), (average, 1.35+/-0.1%), whereas the combination of morphine (1 and 3 mg/kg) and aspirin (30 mg/kg) produced a reduction in the dose of morphine needed to produce the same degree of MAC(ISO) reduction. Actual MAC(ISO+drug) data were as follows: 1 mg/kg morphine, 1.17+/-0.14%; 3 mg/kg morphine, 0.98+/-0.15%; 1 mg/kg morphine plus aspirin, 0.90+/-0.04%; 10 mg/kg morphine, 0.63+/-0.13%; and 3 mg/kg morphine plus aspirin, 0.64+/-0.06%. CONCLUSIONS: The synergistic effects of aspirin and morphine allow a clinically significant reduction in the requirements of isoflurane and isoflurane plus morphine, and these drug combinations may decrease the side effects associated with the use of single higher, equianalgesic doses of these drugs.     

Buprenorphine's physical dependence potential: antagonist-precipitated withdrawal in humans

Buprenorphine is a partial mu opioid agonist with demonstrated efficacy in the treatment of opioid dependence. One potential advantage of buprenorphine over full mu opioid agonists is its reported low physical dependence profile. This study systematically examined physical dependence produced by maintenance with a clinically relevant dose of buprenorphine using antagonist challenge procedures. In this residential laboratory study, eight opioid-dependent volunteers maintained on 8 mg/day of sublingual buprenorphine were each challenged on independent occasions with placebo, i.m. naloxone (0.3, 1.0, 3.0 and 10.0 mg/70 kg) and p.o. naltrexone (0.3, 1.0 and 3.0 mg/70 kg) 14 hr after their daily buprenorphine dose using a repeated measures, cross-over design. Both naloxone and naltrexone precipitated time- and dose-dependent withdrawal, as evidenced by changes in subject-rated, observer-rated and physiological measures. Significant precipitated withdrawal occurred at 3.0 and 10 mg/70 kg i.m. of naloxone and 3.0 mg/70 kg p.o. of naltrexone. These results indicate that buprenorphine maintenance produces physical dependence and that i.m. naloxone and p.o. naltrexone produce equivalent effects in withdrawal precipitation under these conditions. Findings have implications for selection of antagonist doses for use in formulating combination agonist/antagonist medications and for use in transition of drug abusers from buprenorphine to antagonist maintenance therapies.     

Cocaethylene formation following ethanol and cocaine administration by different routes.

Ethanol alters the hepatic biotransformation of cocaine, resulting in transesterification to a novel active metabolite, cocaethylene. Because of first pass metabolism, oral drug administration might be expected to produce relatively larger concentrations of cocaethylene than would intravenous or smoked administration. We, therefore, compared the effects of route of cocaine administration on the formation and elimination of cocaethylene. Six experienced cocaine users were tested in 6 sessions, approximately 1 week apart. Deuterium-labeled cocaine (d?) was administered in all conditions. Oral cocaine-d? 2.0 mg/kg, intravenous cocaine-d? 1.0 mg/kg, and smoked cocaine-d? (200 mg) were administered after oral ethanol 1.0g/kg or placebo. A small, intravenous dose of deuterated cocaethylene (d?) also was administered with all conditions for determination of cocaethylene formation. Physiologic and subjective effects were recorded and plasma cocaine-d?, cocaethylene-d?, cocaethylene-d?, and benzoylecgonine-d? were measured by gas chromatography-mass spectrometry. About 24% (± 11) of intravenous cocaine was converted to cocaethylene. The oral route (34% ± 20) was significantly greater than from the smoked route (18% ± 11) and showed a trend toward significance for greater formation of cocaethylene compared to the intravenous route. Within each route, the cocaine-ethanol combination produced greater increases in heart rate and rate-pressure product than cocaine alone. Global intoxication effects across time after smoking or intravenous administration were significantly greater when cocaine and ethanol were both given. Administration of cocaine by different routes alters the amount of cocaethylene formed through hepatic first-pass effects. Increased cardiovascular and subjective effects might explain the toxicity and popularity of the combined drugs. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Extent and severity of periodontal destruction based on partial clinical assessments

OBJECTIVES: To evaluate the postoperative analgesic efficacy, side effects and acceptance by patients and nurses of intravenous "patient-controlled analgesia" (PCA) with morphine, metamizole and buprenorphine. MATERIAL AND METHODS: In this randomized double blind prospective study of 150 patients in three groups receiving morphine (group A), metamizole (group B) or buprenorphine (group C), the patients had undergone low abdominal surgery with the same anesthetic protocol. Pain was recorded during the first 48 h after surgery on an orally-communicated scale of none or slight = 0, moderate = 1 and severe = 2. Upon the first report of moderate pain, patients were administered an intravenous bolus containing 5 mg morphine, 1 g metamizole or 0.15 mg buprenorphine. A perfusion pump was then connected and set with one bolus of 1.2 mg morphine, one of 333 mg metamizole or one of 0.04 buprenorphine. The maximum dose allowed in 24 h was 40 mg morphine, 8 g metamizole or 1.2 mg buprenorphine. The minimum interval between doses was 30 min for all three groups. Side effects reported were respiratory depression, sedation, nausea, vomiting, pruritus, perspiration and pain upon administration. Patients and nurses were asked to evaluate the system when the pump was disconnected and the results were then analyzed statistically. RESULTS: The analgesic effect was satisfactory in all three groups, with no significant differences among them. The percentages of patients reaching the maximum allowed dose on the first day were 2% with morphine, 18% (p < 0.05) with metamizole and 8% with buprenorphine. No respiratory depression was observed. Sedation was greater with morphine and buprenorphine than with metamizole (p = 0.0001). Pruritus was also greater with morphine and buprenorphine than with metamizole (p = 0.02) and pain upon infusion was greater with metamizole (p = 0.0002). CONCLUSIONS: Intravenous postoperative PCA was effective with all three drugs studied. Patient and nurse acceptance was good and side effects were few in the three groups. The lower rate of side effects for metamizole makes it the drug of choice.     

Acute participant-rated and behavioral effects of alprazolam and buspirone, alone and in combination with ethanol, in normal volunteers.

The acute behavioral effects of buspirone (15 and 30 mg/70 kg), alprazolam (0.75 and 1.5 mg/70 kg), and placebo, alone and in combination with ethanol (0-0.6 mg/kg), were tested in 13 volunteers. Ethanol alone produced only a few significant behavioral effects. Alprazolam and buspirone produced comparable dose-related increases in participant ratings of sedation, but only alprazolam impaired performance. The buspirone-ethanol and alprazolam-ethanol combinations produced robust sedative-like participant-rated drug effects that were similar in magnitude, but, in general, only the alprazolam ethanol combinations impaired performance. These findings suggest that the participant-rated effects of therapeutic doses of buspirone in combination with moderate doses of ethanol are similar to those of therapeutic doses of alprazolam in combination with ethanol, but the performance-impairing effects of buspirone are distinguishable from those of alprazolam, alone and in combination with ethanol. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Smoked heroin and cocaine based (speedball) combinations in Rhesus monkeys.

The purpose of this investigation was to compare the self-administration of heroin and cocaine base, alone and in combination, in rhesus monkeys (Macaca mulatta) self-administering a combination of heroin (0.1 mg/kg/delivery) and cocaine base (1.0 mg/kg/delivery) via the smoking route. Smoke deliveries were contingent on completion of a chained fixed ratio (FR; lever press), FR 5 (inhalation) schedule. The lever press FR values (64, 128, 256, 512, and 1,024) represented increasing drug price. Demand functions (Consumption x Price) were obtained for the heroin and cocaine combination and compared with previously determined demand functions for smoked heroin and cocaine alone. As the FR increased and the number of responses emitted increased, the number of drug deliveries decreased. The demand functions were not different for heroin versus cocaine alone or for cocaine alone versus the cocaine-heroin combination. However, the demand for heroin alone was significantly less than the demand for the cocaine-heroin combination, suggesting that smoked cocaine base enhances the behavioral effects of smoked heroin. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effect of mu-opioids morphine and buprenorphine on the development of adjuvant arthritis in rats

OBJECTIVE AND DESIGN: On the basis that endogenous opioids play a role in the physiological response to inflammation, this study tests the anti-arthritic effects of a mu-opioid agonist, morphine and the partial mu-agonist, buprenorphine. MATERIAL: Male Lewis rats were used. TREATMENT: Rats were inoculated subcutaneously with 0.05 ml of Freund's complete adjuvant (5 mg/ml) into the right hind paw to produce adjuvant arthritis. Morphine (either 10 to 60 mg/kg/day s.c. bolus or 60 mg/kg/day s.c. infusion) and buprenorphine (0.65 +/- 0.06 mg/kg/day, orally), respectively, were administered for 3 days during the primary inflammatory phase of adjuvant arthritis. METHODS: The progression of adjuvant arthritis was monitored every three days by body weight change and hind limb oedema (ipsilateral and contralateral). On day 21 the animals were sacrificed and histology and radiography of the contralateral limb were performed. In rats receiving Freund's adjuvant and no drug treatment, the incidence of arthritis was 89%. Effect was expressed as the pooled severity index (PSI) derived from the arithmetic average of the volume, histology and radiography scores in the contralateral hind limb. RESULTS: Buprenorphine had no effect on experimental arthritis (PSI control vs treated: 242 +/- 28 vs 253 +/- 28%). In contrast, morphine by subcutaneous injection twice daily (10 to 60 mg/kg/day) but not by subcutaneous infusion (60 mg/kg/day) was found to attenuate the progression of adjuvant arthritis in a dose-dependent manner. This indicates that the anti-arthritic effects of morphine are opioid receptor mediated (ED50, 58 +/- 9 mg/kg) and suggests that the local concentration reached effective levels only after subcutaneous injection. It is also possible that the high doses of morphine were anti-inflammatory through effects at the kappa receptor. However, these high doses of morphine produced death in one third of the rats, the calculated lethal dose (LD50, 63 +/- 2 mg/kg) being close to the effective dose. CONCLUSION: Anti-arthritic effects of morphine are opioid receptor mediated but morphine use for this indication is restricted by its adverse effects.     

Blood lead of intravenous drug users

Ethanol, morphine, cocaine and amphetamine were examined in place conditioning. After determination of initial preferences, animals were conditioned with ethanol (1 g/kg), morphine (5 mg/kg), cocaine (5 mg/kg) and amphetamine (5 mg/kg) alone or with combinations of these drugs plus naloxone (1 mg/kg). Naloxone prevented the ability of all drugs used to produce a place preference. The reinforcing properties of ethanol and morphine were reduced by sodium nitroprusside at a dose equal to 1/10 of LD50 given before preference testing. Molsidomine (1/10 LD50 and 1/20 LD50) altered the expression of the conditioned place preference produced by ethanol but not by morphine. Results of the present study suggest the involvement of endogenous opioids and probably of nitric oxide in the rewarding actions of drugs of abuse.     

Combined effects of buprenorphine and an alternative nondrug reinforcer on phencyclidine self-administration in rhesus monkeys.

Six rhesus monkeys self-administered orally delivered phencyclidine (PCP; 0.35 mg/ml) with saccharin (0.3 or 0.03 % wt/vol) or water under concurrenl fixed-ralio (FR) schedules. During daily 3-hr sessions, subjects had concurrent access to liquids: PCP versus water, PCP versus saccharin. or saccharin versus water. The FR of both liquids was varied (4, 8, 16, 32, and 64) in nonsystematic order and when behavior was stable at each FR, buprenorphine (0.005 mg/kg) was injected intramuscularly for 5 days. Buprenorphine treatment decreased PCP deliveries by 16–65% across the range of FR values when compared with the no-treatment baseline, and concurrent saccharin reduced PCP deliveries from 34 to 63%. Combining buprenorphine treatment and concurrent availability of saccharin produced decreases in PCP deliveries of 70–87% from the no-trealmenl baseline across the FR values. Greater reductions were found at the highest FR values. Pmax values were shifted to the left under all treatment conditions, suggesting that the reinforcing efficacy of the drug was reduced. These findings suggest that pharmacological and behavioral treatments produce additive reductions in drug self-administration. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Acute behavioral effects of triazolam and caffeine, alone and in combination, in humans.

The acute behavioral effects of triazolam (0, 0.375, and 0.75 mg/70 kg) and caffeine (0, 250, and 500 mg/70 kg), alone and in combination, were assessed in 9 male volunteers. Ss received all possible dose combinations according to a Latin square design. Triazolam administered alone dose dependently disrupted learning and performance on the Repeated Acquisition and Performance procedure and the Digit Symbol Substitution Test and increased S ratings of sedation. Caffeine administered alone did not significantly affect learning or performance measures, but it did dose dependently increase S ratings of drug strength. Caffeine significantly attenuated triazolam-induced decrements in learning and performance. Consistent with effects on learning and performance, caffeine offset triazolam-induced increases in S ratings of sedation. Combining caffeine and triazolam did not significantly alter increases in S ratings of drug strength observed with caffeine alone. These effects are qualitatively similar to those observed with other benzodiazepines (e.g., lorazepam) and document a high degree of consistency in the behavioral pharmacology of benzodiazepine-caffeine combinations in humans. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Mu opioid agonists potentiate amphetamine- and cocaine-induced rotational behavior in the rat

Opioids modulate brain dopaminergic function in various experimental paradigms. This study used the rotational model of behavior in rats with unilateral 6-hydroxydopamine-induced lesions of the nigrostriatal pathway to investigate this interaction. Doses of two presynaptically acting dopaminergic drugs, amphetamine and cocaine, were coadministered with several doses of the mu opioid agonist, morphine. Morphine, at 3.0 mg/kg, potentiated rotational behavior induced by each dose of the stimulants. To determine the receptor specificity of the actions of morphine, the mu opioid agonists buprenorphine, fentanyl, levorphanol, meperidine, and methadone, and dextrorphan, the non-opioid isomer of levorphanol, were administered alone and with 1.0 mg/kg amphetamine. Each of these drugs, as well as morphine, produced circling behavior on its own. All of the mu opioid agonists and dextrorphan increased amphetamine-induced turning; the coadministration of dextrorphan, levorphanol, meperidine, methadone and morphine with amphetamine produced turning greater than predicted by simple additivity. To determine whether an opioid receptor was involved in these interactions, the opioid antagonist, naltrexone, was administered before the amphetamine/mu opioid receptor agonist combination. Naltrexone blocked the potentiating effects of morphine, but not those of the other drugs. Moreover, naltrexone alone dose-dependently increased amphetamine-induced rotational behavior. These studies show that some mu opioid receptor agonists can potentiate stimulant-induced rotational behavior and that blockade of opioid receptors can also produce a potentiation. The role of mu opioid receptors in these effects remains unclear.     

Effects of oral cocaine on intravenous cocaine discrimination in humans.

This study was designed to evaluate the drug discrimination paradigm as a model for assessing the ability of potential agonist medications to block the effects of intravenous cocaine. Previous research has demonstrated that oral cocaine attenuated the subjective and physiological effects of intravenous cocaine injections, and in the absence of a known efficacious medication for cocaine use disorders, a proof-of-concept approach was used in which cocaine was acutely administered orally to block intravenous cocaine's discriminative-stimulus effects. During training, 11 cocaine-dependent participants were able to discriminate between intravenous saline and 20 mg/70 kg iv cocaine, and 8 of these participants completed the study. After training, participants ingested capsules containing either placebo or 300 mg/70 kg cocaine 60 min prior to the intravenous injection of different doses of cocaine during test sessions with no contingencies in place. Each cocaine dose was administered twice, once under each oral pretreatment condition. Training sessions were interspersed among the test sessions. Physiological and subjective effects were measured throughout each session. Oral cocaine moderately increased some of the subjective and physiological effects of the lower doses of intravenous cocaine, whereas effects at the higher doses were unaltered. Similar changes were seen for the discrimination results. Thus, although oral cocaine given acutely likely is not a viable treatment medication for cocaine dependence, the usefulness of the drug discrimination model in the evaluation of agonist treatment medications remains unclear. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Discriminative stimulus effects of a cocaine/heroin "speedball" combination in rhesus monkeys

Cocaine and heroin often are abused together in a combination known as a "speedball," but relatively little is known about ways in which cocaine and heroin may interact to modify each other's abuse-related effects. The present study evaluated the discriminative stimulus effects of a speedball combination of cocaine and heroin. Three rhesus monkeys were trained to discriminate vehicle from a 10:1 ratio of cocaine (0.4 mg/kg) in combination with heroin (0.04 mg/kg). Both cocaine alone and heroin alone substituted completely for the cocaine/heroin combination, although cocaine and heroin were more potent when administered together than when administered alone. Combined pretreatment with the dopamine antagonist flupenthixol and the opioid antagonist quadazocine dose-dependently antagonized the discriminative stimulus effects of the cocaine/heroin combination, but pretreatment with either antagonist alone was less effective. These findings suggest that either cocaine or heroin alone was sufficient to substitute for the cocaine/heroin training combination. To characterize the discriminative stimulus properties of this speedball more fully, a series of cocaine-like and heroin-like agonists were studied in substitution tests. The indirect dopamine agonists CFT, amphetamine and bupropion and the mu opioid agonists alfentanil, fentanyl and morphine produced high levels of speedball-appropriate responding. However, the indirect dopamine agonist GBR12909, the D1 dopamine agonist SKF82958, the D2 dopamine agonist quinpirole and the partial mu opioid agonist nalbuphine did not substitute for the cocaine/heroin combination. Because these compounds produce discriminative stimulus effects similar to either cocaine or mu opioid agonists alone, these findings suggest that the discriminative stimulus effects of the cocaine/heroin combination do not overlap completely with the effects of cocaine and heroin alone. Finally, a series of compounds that produce partial or no substitution for cocaine or mu agonists alone also did not substitute for the cocaine/heroin combination, which indicates that the discriminative stimulus effects of the combination were pharmacologically selective. Taken together, these findings suggest that a combination of cocaine and heroin produces a pharmacologically selective discriminative stimulus complex that includes aspects of both component drugs.     

Effects of oral caffeine pretreatment on response to intravenous nicotine and cocaine.

Previous research suggests that under conditions of chronic daily caffeine administration, caffeine increases the effects of nicotine. Little is known about the effects of caffeine pretreatment on response to nicotine under infrequent caffeine administration conditions. The present study examined whether infrequent (not on consecutive days) acute oral caffeine administration alters subject-rated, physiological, and monetary value effects of intravenous nicotine in regular users of caffeine, tobacco, and cocaine. To determine the specificity of effects of caffeine on response to nicotine, the effects of caffeine administration on response to intravenous cocaine (another short-acting stimulant) were also studied. Fourteen (1 woman) volunteers participated in this 3–4 week, double-blind, inpatient study. Volunteers participated in 10 experimental conditions in pseudo-randomized order, in which oral caffeine (250 mg/70 kg) or placebo was administered 1 hr before an intravenous injection, consisting of nicotine (1 or 2 mg/70 kg), cocaine (15 or 30 mg/70 kg), or saline. Infrequent acute caffeine pretreatment attenuated the increase resulting from 2 mg/70 kg nicotine administration on ratings of “rush,” “good effects,” “liking,” “high,” and “drowsy/sleepy.” Caffeine had no significant effect on physiological response to nicotine. Caffeine had no significant effect on subject-rated and physiological response to cocaine, with the exception that caffeine significantly augmented blood pressure response to cocaine. In contrast to the previous research using chronic caffeine maintenance, these data suggest that infrequent acute caffeine administration may attenuate nicotine effects. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Pain therapy in dogs and cats--clinical experiences with buprenorphine (Temgesic)

Buprenorphine was used as a post-operative analgesic drug in 40 dogs and 30 cats. The analgesic properties of buprenorphine failed in 20% (dogs) respectively 23.3% (cats) of the cases even after high doses of 0.1 mg/kg in dogs and 0.01 mg/kg in cats. The unsatisfactory results were seen in fracture-patients with a concurrent severe tissue damage. Side effects even after high doses were of no clinical relevance.