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N K Mello

Publications and source records attributed to N K Mello.

At least 55 records · Page 3Linked to original sources
PubMed1998

Effects of kappa opioid agonists on cocaine- and food-maintained responding by rhesus monkeys.

There is accumulating evidence that kappa opioid agonists attenuate cocaine's behavioral effects, and we recently reported that the kappa opioid agonists ethylketocyclazocine (EKC) and U50-488 decreased cocaine self-administration by rhesus monkeys. In the present study, we first examined the effects of acute intramuscular administration of six kappa opioid agonists on responding maintained by food under an FR30 schedule. Each kappa agonist produced dose-dependent decreases in schedule controlled behavior, and the relative potencies were enadoline >/= bremazocine > Mr2033 >/= cyclazocine = spiradoline > PD117302. We then studied the effects of chronic administration of these kappa agonists in monkeys responding under a second order schedule of food delivery and cocaine self-administration. The effects of 10 days of intravenous treatment with three arylacetamides [enadoline (0.00032-0.0032 mg/kg/hr), (-) spiradoline (0.0032-0.018 mg/kg/hr), PD117302 (0.032-0.32 mg/kg/hr)] and three benzomorphans [bremazocine (0.00032-0.0032 mg/kg/hr), Mr2033 (0.0032-0.032 mg/kg/hr), cyclazocine (0.001-0.10 mg/kg/hr)] were compared with saline treatment. Enadoline (0.001 and 0.0032 mg/kg/hr), bremazocine (0.0032 mg/kg/hr) and Mr2033 (0.01 and 0.0032 mg/kg/hr) significantly decreased cocaine self-administration (0.01 mg/kg/injection) (P < .05-.01). Cyclazocine (0.001-0.10 mg/kg/hr), (-) spiradoline (0.0032-0.018 mg/kg/hr) and PD117302 (0.032-0.32 mg/kg/hr) had no significant effects on cocaine self-administration across the dose-range studied. When gradually increasing doses of enadoline (0.00032-0.01 mg/kg/hr) or Mr2033 (0.0032-0.032 mg/kg/hr) were administered over 28 consecutive days, cocaine self-administration was dose-dependently decreased in all monkeys. Food-maintained responding was usually decreased at doses that decreased cocaine self-administration. Adverse side effects (emesis and sedation) were transient, and laboratory indices of hematology and blood chemistry were normal throughout chronic enadoline and Mr2033 treatment. These data extend our earlier findings with EKC and U50,488 and suggest that kappa opioid agonists may be a useful approach to the development of new pharmacological treatments for cocaine dependence. The extent to which undesirable side effects may limit their clinical usefulness remains to be determined.

Animals↗
PubMed1997

Cocaine's effects on neuroendocrine systems: clinical and preclinical studies.

This review examines the effects of cocaine on the neuroendocrine system and summarizes findings from clinical studies of cocaine abusers and preclinical studies in rodents and rhesus monkeys. The effects of acute and chronic cocaine administration on anterior pituitary, gonadal, and adrenal hormones are described, and the functional consequences of chronic cocaine exposure are discussed. Many of cocaine's acute effects on the endocrine system are consistent with its actions as a monoamine reuptake inhibitor. Acute cocaine administration stimulates release of gonadotropins, ACTH, and cortisol or corticosterone and suppresses prolactin levels. It has been difficult to detect changes in basal levels of most hormones or alterations in hormone responsiveness to a challenge dose of cocaine or other agents after chronic cocaine treatment. Interpretation of clinical data is often complicated by polydrug abuse involving opiates and alcohol as well as cocaine. However, preclinical studies of the effects of chronic cocaine exposure on integrated neuroendocrine function have revealed disruptions of the estrous cycle in rats and the menstrual cycle in rhesus monkeys. Furthermore, the menstrual cycle disorders observed in rhesus monkeys parallel those reported in women who abuse cocaine. Much remains to be learned about cocaine's interactions with the endocrine system and the consequences of cocaine abuse for reproductive function.

Adrenocorticotropic Hormone↗
PubMed1997

Dopamine infusion does not alter LH levels before or after chronic cocaine exposure in female rhesus monkeys.

Cocaine stimulates release of luteinizing hormone (LH) in preclinical and clinical studies but the contribution of the indirect dopamine agonist actions of cocaine to its effects on LH are unclear. In the present study, we examined the effects of exogenous dopamine infusions on LH release in drug-naive, normally cycling, female rhesus monkeys. All studies were conducted during the mid-follicular phase (cycle days 6-8). Three successive 80-min dopamine infusions (10 micrograms/kg/min, intravenous) were alternated with 20- or 40-min interruptions of dopamine infusions. There were no significant changes in LH during or following dopamine infusions. Predopamine baseline LH levels averaged 30 +/- 5.4 ng/ml. LH averaged 31.7 +/- 1.3 ng/ml during dopamine infusions and 31.4 +/- 1.3 ng/ml after dopamine infusions stopped. To determine whether chronic cocaine exposure influenced the effect of dopamine on LH, rhesus females were studied after more than 2 years of cocaine self-administration at an average dose of 6.5 +/- 0.2 mg/kg/day. LH averaged 27.3 +/- 3.3 ng/ml during baseline and 26.9 +/- 0.7 ng/ml and 26.1 +/- 0.7 ng/ml during dopamine infusions and interruptions, respectively. Similarly, during withdrawal from cocaine, baseline LH levels averaged 32.1 +/- 4.5 ng/ml, and LH did not change significantly during dopamine infusions (31.2 +/- 1.1 ng/ml) and infusion interruptions (32.1 +/- 1.1 ng/ml). Under the conditions of the present study, dopamine administration did not change LH levels in gonadally intact rhesus monkeys, and these findings are consistent with previous studies in ovariectomized rhesus females. However, these data are not consistent with clinical reports, and some possible implications of this species difference are discussed. Moreover, these data suggest that the stimulation of LH by cocaine may not be explained by its indirect dopamine agonist actions.

Animals↗
PubMed1997

Age-related reduction in functional MRI response to photic stimulation.

Many functional imaging studies have demonstrated age-related alterations in cerebral blood flow during the resting state. However, few studies have addressed possible differences in functional response to cerebral activation. We assessed the response of visual cortex to photic stimulation in 9 normal elderly subjects and 17 normal younger subjects with blood oxygenation level dependent functional magnetic resonance imaging. We found that the amplitude of response in elderly subjects was significantly decreased compared to younger subjects (2.5 +/- 1.0% versus 4.0 +/- 1.6%, p = 0.01), suggesting a reduction in functional activation or an age-related alteration in the coupling of blood oxygenation to focal activation.

Adult↗
PubMed1997

The effects of chronic cocaine self-administration on the menstrual cycle in rhesus monkeys.

Clinical studies suggest that cocaine disrupts reproductive function, but because cocaine abusers often abuse opiates and alcohol, it has been difficult to determine the contribution of cocaine alone. The effects of chronic cocaine self-administration on menstrual cycle duration and basal levels of progesterone were examined in eight female rhesus monkeys and compared with the effects of occasional administration of single cocaine doses (0.4 or 0.8 mg/kg) in six otherwise drug-free controls. All monkeys had normal ovulatory menstrual cycles before cocaine exposure. Monkeys self-administered cocaine (0.10 mg/kg/injection) and food (1 gm banana pellets) in 4 daily sessions on a second-order schedule (fixed ratio 2 [variable ratio 16:S]). Cocaine intake was limited to 8 mg/kg/day. During the first cocaine exposure (256-776 days), monkeys self-administered 3.51 (+/- 0.77) to 7.41 (+/- 0.27) mg/kg/day. During the second cocaine exposure (103-623 days), monkeys self-administered 6.18 (+/- 0.77) to 7.41 (+/- 0.27) mg/kg/day. In these prospective longitudinal studies, 48% of the menstrual cycles were of abnormal duration in the cocaine self-administration group, whereas only 6% of the menstrual cycles were abnormal in the control group. There were 19 episodes of amenorrhea (61-190 days of no menses). During cocaine self-administration, approximately one-third of the menstrual cycles were anovulatory with low mid-luteal progesterone levels of 2.04 (+/- 0.6) to 4.13 (+/- 0.5) ng/ml. Over 25% of menstrual cycles were anovulatory during cocaine withdrawal with mid-luteal progesterone levels below 5 ng/ml. These data indicate that chronic cocaine exposure can disrupt the menstrual cycle in rhesus monkeys and that menstrual cycle abnormalities often persist during cocaine withdrawal. These data are consistent with clinical studies and reports of cocaine-induced disruption of the estrous cycle in rodents.

Adrenocorticotropic Hormone↗
PubMed1997

Effects of kappa opioids on cocaine self-administration by rhesus monkeys.

Kappa opioid agonists attenuate some neurochemical and behavioral effects of cocaine and are being considered as potential treatments for cocaine dependence. The present study examined the effects of two kappa opioid agonists, the benzomorphan ethylketocyclazocine (EKC) and the arylacetamide U50,488, on cocaine self-administration in rhesus monkeys. Monkeys responded for 0.032 mg/kg/injection cocaine (i.v.) and 1 g banana-flavored food pellets during alternating daily sessions of cocaine and food availability. Chronic treatment for 10 consecutive days with EKC (0.0032-0.032 mg/kg/hr) or U50,488 (0.032-0.1 mg/kg/hr) dose-dependently decreased self-administration of cocaine unit doses at the peak of the cocaine dose-effect curve (0.01 and 0.032 mg/kg/injection). These decreases in cocaine self-administration were often sustained throughout the 10 days of treatment. Doses of EKC and U50,488 that decreased cocaine self-administration usually decreased food-maintained responding as well. In addition, EKC and U50,488 often produced emesis and sedation during the first few days of treatment, although tolerance appeared to develop rapidly to these effects. In general, EKC produced fewer undesirable effects than U50,488 at doses that decreased cocaine self-administration. The kappa antagonist norbinaltorphimine (3.2 mg/kg) did not affect responding maintained by cocaine or food. However, both norbinaltorphimine (3.2 mg/kg) and the opioid antagonist naloxone (1.0 mg/kg/hr) blocked the effects of EKC and U50,488. These results indicate that chronic administration of EKC and U50,588 produce a dose-dependent, kappa receptor-mediated and often sustained decrease in cocaine self-administration. However, these kappa agonists also produce undesirable behavioral effects that may complicate their use as treatments for cocaine dependence.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1996

Effects of alcohol ingestion on estrogens in postmenopausal women.

OBJECTIVE: To determine if moderate alcohol drinking increases circulating estradiol levels in postmenopausal women who are taking estrogen replacement. DESIGN: Randomized, double-blind, placebo-controlled crossover study of the effects of alcohol ingestion on plasma estradiol and estrone. SETTING: Inpatient Clinical Research Center. PARTICIPANTS: Twelve healthy postmenopausal women receiving oral estrogen (estradiol, 1 mg/day) and progestin (medroxyprogesterone acetate) replacement therapy were compared with 12 postmenopausal women who were not using estrogen replacement therapy (ERT). INTERVENTION: Each group drank alcohol (0.7 g/kg) and an isoenergetic (isocaloric) placebo (randomized sequence) on consecutive days. Women who were taking ERT were studied during the estrogen-only portion of their replacement cycle, and estrogen was administered each evening at 2100 hours. MAIN OUTCOME MEASURE: The impact of alcohol ingestion on plasma estradiol and estrone levels. RESULTS: Alcohol ingestion lead to a 3-fold increase in circulating estradiol in women on ERT; however, alcohol did not change estradiol significantly in control women who were not on ERT. In women using ERT, estradiol levels increased from 297 to 973 pmol/L (81 to 265 pg/mL) within 50 minutes (P<.001) during the ascending limb of the blood alcohol curve and remained significantly above baseline for 5 hours (P<.001). No significant increase in circulating estrone was detected in either group. However, estrone levels decreased after alcohol and placebo in women on ERT (P<.05). Blood alcohol levels did not differ significantly in women who used ERT and those who did not. Peak blood alcohol levels of 21 mmol/L were attained in each of the 2 groups within 50 to 60 minutes after drinking began. Changes in estradiol were significantly correlated with changes in blood alcohol levels on both the ascending (P<.001) and descending (P<.001) limb of the blood alcohol curve. CONCLUSIONS: Acute alcohol ingestion may lead to significant and sustained elevations in circulating estradiol to levels 300% higher than those targeted in clinical use of ERT. Potential health risks and benefits of the interactions between acute alcohol ingestion and ERT should be further evaluated.

Alcohol Drinking↗
PubMed1996

Naloxonazine antagonism of levorphanol-induced antinociception and respiratory depression in rhesus monkeys.

The mu-opioid receptor antagonist effects of naloxonazine on levorphanol-induced thermal antinociception and respiratory depression were examined in rhesus monkeys. Levorphanol (0.032-3.2 mg/kg) produced dose-dependent increases in tail-withdrawal latencies from 50 degrees C water in a warm-water tail-withdrawal assay and dose-dependent decreases in ventilation in both air and 5% CO2 mixed in air. Naloxonazine (0.1-3.0 mg/kg) antagonized both the antinociceptive and ventilatory effects of levorphanol to a similar degree, and the antagonist effects of naloxonazine were greater after 1 h than after 24 h. Under all conditions, the antagonist effects of naloxonazine were fully surmountable. Schild analysis of the antagonist effects of naloxonazine after 1 h pretreatment in the antinociception assay yielded a pA2 value of 7.6 and a slope of -0.50; by comparison, quadazocine yielded a pA2 value of 7.5 and a slope of -1.05. These results suggest that naloxonazine acts as a potent and fully reversible mu-opioid receptor antagonist with a moderately long duration of action in rhesus monkeys. In addition, these results suggest that the antinociceptive and ventilatory effects of mu-opioid receptor agonists in rhesus monkeys are mediated by pharmacologically similar populations of mu opioid receptors.

Analgesia↗
PubMed1996

Brain alcohol detectability increase with repeated administration in humans: a proton spectroscopy study.

Proton MRS was used to detect brain alcohol after repeated alcohol exposure in human subjects. MRS detectability measurements were made after administration of an alcoholic drink (0.6 g/kg alcohol) and after an identical drink administrated 6 h later. Between-drink differences in the methyl proton triplet resonance of ethyl alcohol were assessed at statistically equivalent and near-peak blood alcohol concentrations (reflecting brain alcohol concentrations) and statistically equivalent internal standard N-acetyl resonance areas after Drinks 1 and 2, respectively. Brain alcohol detectability was not altered in TE 30-ms spectra but was increased in all five subjects after Drink 2 by an average of 70% in TE 270-ms spectra (p < 0.01). This was accompanied by significant between-drink differences in subjective ratings of alcohol's effects, suggestive of induction of acute alcohol tolerance. These findings suggest increased brain alcohol detectability in TE 270-ms spectra after repeated alcohol exposure that may reflect acute alcohol tolerance.

Adult↗
PubMed1996

Effects of the putative dopamine D3 receptor agonist 7-OH-DPAT in rhesus monkeys trained to discriminate cocaine from saline.

These studies were designed to evaluate the effects of the putative dopamine D3 receptor agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetraline (7-OH-DPAT), alone and in combination with cocaine, in four rhesus monkeys trained to discriminate cocaine (0.4 mg/kg, IM) from saline under a fixed-ratio 30 schedule of food presentation. Under these conditions, cumulative doses of cocaine (0.013-1.3 mg/kg) produced a dose-dependent and complete generalization to the training dose of cocaine in all monkeys, while producing only minimal effects on response rates. The discriminative stimulus effects of cocaine were antagonized by the non-selective dopamine receptor antagonist flupenthixol (0.018 mg/kg, IM) in all four monkeys. The effects of 7-OH-DPAT (0.01-1.8 mg/kg) were inconsistent across monkeys. In two of the four monkeys (monkeys L990 and L958), 7-OH-DPAT consistently and completely generalized to cocaine and decreased response rates in a dose-dependent manner. Both the cocaine-like discriminative stimulus effects and rate-decreasing effects of 7-OH-DPAT were antagonized by flupenthixol in these two monkeys. Pretreatment with low doses of 7-OH-DPAT (0.01-0.032 mg/kg) had no effect on the cocaine dose-effect curve in monkeys L990 and L958; however, higher doses of 7-OH-DPAT (0.032-0.32 mg/kg) shifted the cocaine dose-effect curve to the left. In the other two monkeys (monkeys 150F and 89B036), 7-OH-DPAT produced a dose-dependent decrease in response rates but did not consistently generalize to cocaine. Flupenthixol did not antagonize the rate-decreasing effects of 7-OH-DPAT in these two monkeys, and pretreatment with 7-OH-DPAT (0.1-0.32 mg/kg) produced a decrease in response rates but had no effect on the cocaine dose-effect curve. Time-course experiments revealed that 7-OH-DPAT (0.32 mg/kg) displayed a slower onset and a longer duration of effect than the training dose of cocaine. Finally, the D3/D2 dopamine agonist quinpirole completely generalized to cocaine in three monkeys, and partially in the fourth monkey. Quinpirole showed the highest potency in those monkeys in which 7-OH-DPAT consistently generalized to cocaine. The results of the present study suggest that, in rhesus monkeys, 7-OH-DPAT produces cocaine-like effects and may modulate the discriminative stimulus effects of cocaine in some monkeys.

Animals↗
PubMed1996

Preclinical evaluation of pharmacotherapies for treatment of cocaine and opioid abuse using drug self-administration procedures.

Drug abuse is a major public health problem, and the relationship between intravenous drug abuse and AIDS underscores the need for more effective treatment medications. Animal models of drug self-administration are useful to systematically evaluate new treatment medications and predict clinical efficacy. This review summarizes the status of preclinical evaluations of medications for treatment of cocaine and opiate abuse. The basic drug self-administration methodology and the rationale for experimental designs and outcome criteria are described. Studies of the effects of dopamine or opioid receptor agonists and antagonists as well as medications used clinically for other indications on drug self-administration are critically examined. Where possible, the degree of concordance between clinical and preclinical studies of drug abuse treatment medications is discussed. We conclude that drug self-administration models are valuable for preclinical assessment of medication efficacy, and we recommend some strategies to further improve evaluation procedures. The discovery of more effective medications for substance abuse treatment should be facilitated by recent advances in behavioral science, pharmacology, neurobiology and medicinal chemistry.

Animals↗
PubMed1996

Impact of maternal alcoholism on separation of children from their mothers: findings from a sample of incarcerated women.

Patterns of maternal child co-residence among 25 alcoholic women incarcerated for drunk driving are examined. Two-thirds of these mothers reported significant periods of time, not due to incarceration, when minor children did not reside with them. Fewer than half of the placements were mandated by child-protective services. Having two or more children while actively alcoholic or residing with a substance abuser correlated strongly with separate residence.

Adult↗
PubMed1996

Effects of cocaine on pulsatile activity of hypothalamic-pituitary-adrenal axis in male rhesus monkeys: neuroendocrine and behavioral correlates.

Cocaine stimulates the hypothalamic-pituitary-adrenal (HPA) axis in rodents and in humans. This study examined the acute effects of cocaine (0.4 and 0.8 mg/kg) and saline placebo on pulsatile adrenocorticotropic hormone (ACTH) and cortisol release in seven male rhesus monkeys. Pulsatile ACTH and cortisol release were evaluated with an intensive (2-min) venous blood sampling procedure and cluster analysis. In addition, the behavioral responses to cocaine were analyzed to assess the relationship between HPA axis activation and behavior. Although analysis of group data revealed significant (P < .05) increases in pulse amplitude and incremental peak height of ACTH and cortisol release after cocaine (0.8 mg/kg) administration, examination of individual data indicated that this effect was not consistent across all monkeys. Cocaine (0.8 mg/kg) increased ACTH plasma levels within 4.7 +/- 1.3 min (P < .05) and amplitude-related characteristics (P < .05) of pulsatile ACTH and cortisol release only in those animals that subsequently showed behavioral stimulation (high responders: n = 3). The frequency of pulsatile ACTH and cortisol remained unchanged by cocaine. Cocaine (0.8 mg/kg) decreased the mean amplitude of ACTH peaks with no changes in pulsatile cortisol release in the four monkeys that showed no behavioral stimulation (low responders). These differences in pulsatile ACTH and cortisol release patterns after cocaine could not explained by different plasma cocaine levels. Peak plasma cocaine levels averaged 63.1 +/- 13.4 and 78.0 +/- 21.4 ng/ml within 2 min after lower dose and 183.3 +/- 52.3 and 204.3 +/- 50.8 ng/ml after higher dose of cocaine in high- and low responder groups, respectively (P > .05; N.S.). Base-line cortisol, but not ACTH, levels were higher (P < .05) in low responders before administration of 0.8 mg/kg of cocaine. Peak and valley characteristics of base-line cortisol release were higher in low responders than in high responders and an inverse relationship was found between basal cortisol levels and postcocaine ACTH release and behavior. In summary, cocaine stimulated the pulsatile ACTH and cortisol release by increasing the amplitude of secretory episodes in behaviorally responsive monkeys.

Adrenocorticotropic Hormone↗
PubMed1996

Acute and chronic effects of flupenthixol on the discriminative stimulus and reinforcing effects of cocaine in rhesus monkeys.

It has been proposed that the relatively nonselective dopamine receptor antagonist flupenthixol may be useful in the treatment of cocaine dependence. Drugs used in the treatment of cocaine dependence are administered chronically; however, most preclinical studies have examined only the acute effects of flupenthixol treatment on the effects of cocaine. Consequently, the purpose of the present study was to compare the effects of acute and chronic treatment with flupenthixol (0.0032-0.032 mg/kg) on the discriminative stimulus and reinforcing effects to cocaine in rhesus monkeys. One group of six monkeys was trained to discriminate 0.4 mg/kg cocaine (i.m.) from saline in a two-lever, food-reinforced, drug discrimination procedure. A second group of four monkeys was trained to respond for 0.032 mg/kg/injection cocaine (i.v.) and 1-g banana-flavored food pellets during alternating daily cycles of cocaine and food availability. Neither acute nor chronic treatment with a low dose of flupenthixol (0.0032 mg/kg) significantly altered the discriminative stimulus or reinforcing effects of cocaine. Higher doses of flupenthixol (0.01-0.032 mg/kg) produced a surmountable blockade of both the discriminative stimulus and reinforcing effects of cocaine, shifting the dose-effect curves for both cocaine discrimination and cocaine self-administration up to 0.5 log unit to the right. However, doses of flupenthixol that altered cocaine discrimination also decreased response rates. Similarly, doses of flupenthixol that decreased cocaine self-administration also often decreased rates of food-maintained responding. Consequently, nonselective behavioral effects of flupenthixol may have contributed to its effects on cocaine discrimination and self-administration. Moreover, the effects of flupenthixol on cocaine discrimination and self-administration diminished over time. After only 3 to 5 days of chronic treatment, flupenthixol did not consistently shift the cocaine discrimination dose-effect curve to the right. Similarly, rates of cocaine self-administration that were initially decreased by flupenthixol often recovered partially or completely during a 10-day regimen of chronic flupenthixol treatment. These results suggest that flupenthixol may have limited utility in the long-term treatment of cocaine dependence.

Animals↗
PubMed1996

Effects of the structurally novel opioid 14 alpha, 14' beta-[dithiobis [(2-oxo-2,1-ethanediyl)imino]]bis(7,8-dihydromorphinone) on schedule-controlled behavior and thermal nociception in rhesus monkeys.

The in vivo pharmacology of the structurally novel opioid 14 alpha, 14' beta-[dithiobis[(2-oxo-2,1-ethanediyl)imino]]bis(7,8-dihydromorphinon e) (TAMO) was examined in rhesus monkeys with assays of schedule-controlled behavior and thermal nociception. TAMO (0.032-1.8 mg/kg) produced dose-dependent decreases in response rates maintained under a fixed-ratio 30 schedule of food delivery (n = 3) and increases in tail-withdrawal latencies in a warm-water tail-withdrawal procedure (n = 3). Both the rate-decreasing and antinociceptive effects of TAMO (1.0 mg/kg) were maximal after 40 to 80 min and lasted at least 160 min. Pretreatment with the mu-selective opioid antagonist quadazocine (0.001-0.1 mg/kg) antagonized the effects of TAMO and shifted the TAMO dose-effect curves to the right. Schild analysis yielded in vivo apparent pA2 values (mean +/- S.E.M.) of 8.8 +/- 0.072 and 8.7 +/- 0.40 for quadazocine antagonism of the rate-decreasing and antinociceptive effects, respectively, of TAMO, which suggests that the effects of TAMO were mediated by mu-opioid receptors. In addition, quadazocine (0.1-1.0 mg/kg) reversed the behavioral effects of TAMO (1.0 mg/kg) when quadazocine was administered immediately after TAMO had attained its maximal effect. Twenty-four-hour pretreatment with 1.0 mg/kg TAMO did not significantly after the rate-decreasing or antinociceptive effects of fentanyl or the rate-decreasing effects of morphine. The dose-effect curve for morphine antinociception was shifted 4-fold to the right 24 hr after pretreatment with 1.0 mg/kg TAMO. However, 24-hr pretreatment with an equiactive dose of morphine (10.0 mg/kg) also produced a small (2-fold) but significant rightward shift in the dose-effect curve for morphine antinociception. Twenty-four-hour pretreatment with 1.8 mg/kg TAMO had no effect on the antinociceptive effects of U69,593 (0.0032-0.1 mg/kg). These results suggest that TAMO acts as a reversible mu agonist with a relatively slow onset and a duration of action and relative efficacy similar to those of morphine in rhesus monkeys. Twenty-four hours after TAMO administration, the highest doses of TAMO that could be safely administered produced little or no mu antagonist effects and no kappa antagonist effects.

Analgesics↗