Chronic effects of acetylmethadol and methadone in rhesus monkeys.

Chronic treatment for 12 weeks in rhesus monkeys with α-?-acetylmethadol (LAAM) or methadone failed to cause clinically significant changes in various parameters of blood biochemistry, hemotology, or liver function. However, one of four monkeys showed recurrent episodes of LAAM-induced depression during the 12-week period of chronic treatment.     

Reversal of morphine, methadone and heroin induced effects in mice by naloxone methiodide

Opioid overdose, which is commonly associated with opioid induced respiratory depression, is a problem with both therapeutic and illicit opioid use. While the central mechanisms involved in the effects of opioids are well described, it has also been suggested that a peripheral component may contribute to the effects observed. This study aimed to further characterise the effects of the peripherally acting naloxone methiodide on the respiratory, analgesic and withdrawal effects produced by various opioid agonists. A comparison of the respiratory and analgesic effects of morphine, methadone and heroin in male Swiss-Albino mice was conducted and respiratory depressive ED(80) doses of each opioid determined. These doses (morphine 9 mg/kg i.p., methadone 7 mg/kg i.p., and heroin 17 mg/kg i.p.) were then used to show that both naloxone (3 mg/kg i.p.) and naloxone methiodide (30-100 mg/kg i.p.) could reverse the respiratory and analgesic effects of these opioid agonists, but only naloxone precipitated withdrawal. Further investigation in female C57BL/6J mice using barometric plethysmography found that both opioid antagonists could reverse methadone induced decreases in respiratory rate and increases in tidal volume. Its effects do not appear to be strain or sex dependent. It was concluded that naloxone methiodide can reverse the respiratory and analgesic actions of a variety of opioid agonists, without inducing opioid withdrawal.     

Modulation of delta opioid agonist-induced antinociception by repeated morphine pretreatment in rhesus monkeys

AimsRepeated treatment with morphine increases antinociceptive effects of delta opioid agonists in rodents by a mechanism that may involve increased cell-surface expression of delta receptors. The present study evaluated effects of repeated morphine treatment on behavioral effects of the delta agonist SNC80 and the mu agonist fentanyl in rhesus monkeys.Main methodsIn an assay of schedule-controlled responding, three monkeys responded for food reinforcement under a fixed-ratio 30 schedule. In an assay of thermal nociception, tail-withdrawal latencies were evaluated in three monkeys using thermal stimulus intensities of 48 and 54 °C. In both assays, the effects of SNC80 (0.032–3.2 mg/kg) and fentanyl (0.001–0.056 mg/kg) were evaluated after repeated treatment with saline or a regimen of morphine doses modeled on the regimen that enhanced delta agonist antinociception and apparent delta receptor availability in previous rodent studies.Key findingsBoth SNC80 and fentanyl dose-dependently decreased rates of schedule-controlled responding, and repeated morphine treatment did not significantly alter these effects. In the assay of thermal nociception, SNC80 had little effect on tail-withdrawal latencies from water heated to 48 or 54 °C, whereas fentanyl increased tail-withdrawal latencies at both temperatures. Repeated morphine tended to increase the antinociceptive effects of SNC80 and to decrease the antinociceptive effects of fentanyl, but these effects of repeated morphine were small and were significant only at the higher stimulus intensity (54 °C).SignificanceThese results provide limited support for the proposition that prior stimulation of mu receptors selectively increases the antinociceptive effects of delta agonists in rhesus monkeys.     

Modification of hepatic microsomal oxidative drug metabolism in rats by the opiate maintenance drugs acetylmethadol, propoxyphene, and methadone.

The formation of cytochrome P-450 “metabolic intermediate” complexes $\text{in}$$\text{vivo}$ occurred with acetylmethadol and propoxyphene, but not methadone in both naive and phenobarbital-induced animals. The $\text{in}$$\text{vivo}$ formation correlated with the relative ability of these three compounds to form metabolic intermediate complexes and inhibit mixed-function oxidation reactions $\text{in vitro}$.     

Proteomic analysis of the nucleus accumbens in rhesus monkeys of morphine dependence and withdrawal intervention

It has been known that the reinforcing effects and long-term consequences of morphine are closely associated with nucleus accumbens (NAc) in the brain, a key region of the mesolimbic dopamine pathway. However, the proteins involved in neuroadaptive processes and withdrawal symptom in primates of morphine dependence have not been well explored. In the present study, we performed proteomes in the NAc of rhesus monkeys of morphine dependence and withdrawal intervention with clonidine or methadone. Two-dimensional electrophoresis was used to compare changes in cytosolic protein abundance in the NAc. We found a total of 46 proteins differentially expressed, which were further identified by mass spectrometry analysis. The identified proteins can be classified into 6 classes: metabolism and mitochondrial function, synaptic transmission, cytoskeletal proteins, oxidative stress, signal transduction and protein synthesis and degradation. Importantly, we discovered 14 proteins were significantly but similarly altered after withdrawal therapy with clonidine or methadone, revealing potential pharmacological strategies or targets for the treatment of morphine addiction. Our study provides a comprehensive understanding of the neuropathophysiology associated with morphine addiction and withdrawal therapy in primate, which is helpful for the development of opiate withdrawal pharmacotherapies.     

Impaired glucose metabolism in heroin and methadone users

Plasma glucose and insulin responses to both oral and intravenous glucose stimulation were evaluated in heroin and methadone addicts, compared to healthy control subjects. Both groups of addicts had an altered response to oral and intravenous glucose load. These phenomena were linked to a reduced insulin response. Moreover, increased fasting insulin levels in both groups of addicts were observed. These data show that both heroin and methadone addiction may alter glucose metabolism, and, furthermore, stress the findings of similarities between opiate addicts and non-insulin dependent diabetics.     

Correlates of SIV encephalitis in rhesus monkeys.

Necropsy records from 204 SIV-infected rhesus monkeys that had been inoculated with various strains of SIV and had died of SIV-related disease were reviewed. The relationship of SIV encephalitis with other parameters was evaluated. Encephalitis was associated with the presence of syncytial cells in other tissues, with persistent or early recurrent antigenemia, with a selective decrease in CD4+CD29+ blood lymphocytes, and with a shortened time of survival. Monkeys whose lymphocytes produced high levels of virus in culture also had a higher incidence of encephalitis. SIV was more frequently isolated from the brains of animals with encephalitis. No other clear associations were detected.     

Endocardiosis in rhesus monkeys

Endocardiosis was diagnosed as an incidental finding in two rhesus monkeys. The gross and histologic appearance of the lesions was described, and the similarity of this lesion to lesions of endocardiosis as found in dogs and man was discussed.The animals used in this study were handled in accordance with the Guide for Laboratory Animal Facilities and Care established by the National Academy of Science, National Research Council.     

Comparative pharmacokinetics of frusemide in female rhesus monkeys, cynomolgus monkeys and baboons

1. The pharmacokinetics of frusemide have been compared in 3 non-human primate species after single intravenous dose of 3 mg/kg of the drug. 2. Peak mean plasma concentrations of frusemide were 31.6, 33.6, 43.6 micrograms/ml in the rhesus monkey, cynomolgus monkey and baboon respectively, and concentrations declined with a half-life of about 20 min. 3. There were no notable differences in the pharmacokinetic parameters estimated from either a one-compartment or two-compartment open model. 4. There were statistically significant species-related differences in clearance, half-lives and volumes of distribution adjusted for bodyweight. 5. The pharmacokinetics of frusemide in the cynomolgus monkey are closer to those in man than are those in the rhesus monkey, the baboon or other commonly used laboratory animal species.     

Inhibitory effects of TRK-820 on systemic skin scratching induced by morphine in rhesus monkeys

The inhibitory effects of kappa-opioid receptor agonists on systemic skin scratching induced by the intravenous administration of morphine, a micro-opioid receptor agonist, were investigated in rhesus monkeys. Intravenous pretreatment with kappa-opioid receptor agonists, either TRK-820 at 0.25 and 0.5 microg/kg or U-50488H at 64 and 128 microg/kg, inhibited systemic skin scratching induced by morphine at 1 mg/kg, i.v. in a dose-dependent manner. By the intragastric route, apparent inhibitory effects on morphine-induced systemic skin scratching were evident following pretreatment with TRK-820 at 4 microg/kg but not with U-50488H from 512 to 2048 microg/kg. These results suggest that TRK-820 produces antipruritic effects on i.v. morphine-induced systemic skin scratching and is more readily absorbed intragastrically than is U-50488H, resulting in high bioavailability in the intragastric route.     

Self-agency in rhesus monkeys

Rhesus monkeys (Macaca mulatta) have shown the ability to monitor their own mental states, but fail the mirror self-recognition test. In humans, the sense of self-agency is closely related to self-awareness, and results from monitoring the relationship between intentional, sensorimotor and perceptual information. Humans and rhesus monkeys were trained to move a computer icon with a joystick while a distractor icon partially matched their movements. Both humans and monkeys were able to monitor and identify the icon they were controlling, suggesting they have some understanding of self-agency.     

Enhancement of tolerance development to morphine in rats prenatally exposed to morphine,methadone, and buprenorphine

Background  

Abuse of addictive substances is a serious problem that has a significant impact on areas such as health, the economy, and public safety. Heroin use among young women of reproductive age has drawn much attention around the world. However, there is a lack of information on effects of prenatal exposure to opioids on their offspring. In this study, an animal model was established to study effects of prenatal exposure to opioids on offspring.     

Self-administration of morphine contingent on heart rate in the rat

The tendency to associate a given response-reinforcement combination reflects the adaptive significance of the association. Biologically relevant reinforcement can be much more effective in modifying certain responses. For example, treatments that result in various types of illness readily condition aversions to novel flavors, but electric shock is relatively ineffective. While opioid self-administration contingent on lever pressing has been extensively studied, the potential for opioids to reinforce visceral responses remains to be determined. An approach to reinforcing changes in heart rate with drug infusions is described. Methods to control for unconditioned drug effects include reversing the direction of change in heart rate required for infusions and addition of a yoked control subject. In several instances, rats exposed to .1 mg/kg infusions of morphine sulfate contingent on tachycardia showed trends for elevated heart rate, with increased locomotor and grooming activity preceding infusions. Increases in heart rate were most pronounced during daytime, normally inactive periods.     

SIV vaccine protection of rhesus monkeys.

Rhesus macaques (M. mulatta), immunized with an inactivated whole SIVmac vaccine and muramyl dipeptide or Freund's incomplete adjuvant, were protected against IV challenge infection with 10 animal infectious doses of the homologous virus. The protection in these animals appeared to be complete, with no breakthrough of latent virus infection over a 10-month period. Vaccine protection in this model was correlated generally with a high level of SIVmac envelope antibody by ELISA and immunoblot, high titers of syncytial inhibiting antibody, and, more specifically, with the presence of antibodies binding to a putative V3 loop synthetic peptide of the SIVmac outer envelope. This model can now be used for further identification of the protective epitopes and protective host immune responses as well as for development of novel and better AIDS vaccines.     

Chylothorax in rhesus monkeys with intravenous catheters.

Chylothorax associated with the use of indwelling intravenous catheters was diagnosed in 13 Macaca mulatta. Clinical signs were marked respiratory embarrassment or sudden death. Lesions at necropsy included large quantities of sterile pleural fluid, pulmonary atelectasis and chronic fibrinous pleuritis. Lipid was present in the effusion and in tissue sections of visceral pleura.     

Genomic diversity and evolution of papillomaviruses in rhesus monkeys.

We are studying the diversity of and relationships among papillomaviruses (PVs) to understand the modes and timescales of PV evolution and in the hope of finding animal PVs that may serve as model systems for disease caused by human PVs (HPVs). Toward this goal, we have examined 326 genital samples from rhesus monkeys and long-tailed macaques with a PCR protocol optimized for detecting genital HPV types. In 28 of the rhesus monkey samples, we found amplicons derived from 12 different and novel PV genomes, RhPV-a to RhPV-m, with the likely taxonomic status of "type." The frequency with which novel RhPVs were detected suggests that rhesus monkeys may play host to PVs with a diversity similar to that of humans. In phylogenetic trees, all 12 of the different RhPVs and the previously described type RhPV-1 were members of the genital HPV supergroup and formed three minor branches distinct from the 11 branches formed by genital HPVs. We also identified a novel PV amplicon, MfPV-a, from a long-tailed macaque, a species belonging to the same genus as rhesus monkeys. MfPV-a turned out to be a close relative of five RhPVs. It appears that the evolution of primate lineages leading to the genus Macaca and to humans created transmission barriers for PVs, resulting in viral evolution closely linked to the host. Additional support for the linked-evolution hypothesis comes from considering the phylogenetic association of two other ape and monkey PVs with the genital HPVs, the supergroup formed by at least seven ungulate PVs, and the isolated phylogenetic position of the only known bird PV.