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69. The Effect of Methadone on the Immune Status of B6C3F1 Mice1.

Author

LEVIER, DAVID G., BROWN, RONNETTA D., MUSGROVE, DEBORAH L., BUTTERWORTH, LEON F., MCCAY, J. ANN, WHITE, KIMBER L., HARRIS, LOUIS S., and MUNSON, ALBERT E.

Abstract

Previously, morphine has been shown to elevate corticosterone via the hypothalamic–pituitary–adrenal axis and to suppress the immune system. The present investigation sought to determine if the μ-opiate receptor agonist methadone incurred a similar immune suppression in B6C3F1 mice. Serum methadone and corticosterone levels peaked 1 hr following a single subcutaneous injection of 20 mg/kg methadone HCl. Indeed, the rise in corticosterone levels paralleled that of methadone. After a single injection with 20 mg/kg methadone a pharmacokinetic analysis revealed a serum half-life of ≈2 hr. Following five injections of methadone over a 24-hr period (every 6 hr), methadone levels were elevated as would be expected; however, corticosterone levels did not become elevated. This suggests that the ability of methadone to elevate corticosterone becomes uncoupled following repeated dosing, indicative of either a tolerance or an increased catabolic mechanism. Moreover, dosing every 6 hr for 5 days induced an increase in the catabolism of methadone itself. Therefore, all assays were begun 1 hr after subcutaneous administration of methadone HCl, a time at which both methadone and corticosterone serum levels were elevated. The primary IgM antibody response to sheep red blood cells (sRBC) was suppressed when splenocytes were immunized . In contrast, animals immunized with sRBC and assayed for the primary IgM antibody response 4 days later were not suppressed. The activity of the resident macrophages of the liver and spleen as measured by the uptake of C-sRBC was suppressed in a dose-dependent manner. Previously, it has been demonstrated that morphine suppresses hepatic and splenic phagocytic activity through an opiate receptor-mediated path way that involves the release of corticosterone. It would appear that methadone plays a similar role in the suppression of hepatic and splenic phagocytosis. [ABSTRACT FROM PUBLISHER]

Published
1995

70. Immunotoxicological Profile of Morphine Sulfate in B6C3F1 Female Mice1.

Author

LEVIER, DAVID G., MCCAY, J. ANN, STERN, MALVIN L., HARRIS, LOUIS S., PAGE, DENNIS, BROWN, RONNETTA D., MUSGROVE, DEBORAH L., BUTTERWORTH, LEON F., WHITE, KIMBER L., and MUNSON, ALBERT E.

Abstract

This study was undertaken to investigate a number of immune parameters which may be compromised with exposure to morphine sulfate. Mice were implanted subcutaneously with 8-, 25-, or 75-mg morphine sulfate pellets. Placebo pellets of identical makeup to the 75-mg morphine pellet (without morphine of course) were used as a control. Twenty-four hours after implantation of a 75-mg morphine pellet, blood levels reached a peak of 1610 ng/ml. Corticosterone increased in parallel with morphine and reached a peak level of 966 ng/ml 24 hr after implantation. The dose response of morphine to increase corticosterone, however, was fiat. The weight of the lymphoid organs, spleen and thymus, and the liver were significantly reduced in the morphine-treated groups. Morphine treatment was associated with an increase in serum albumin, SGPT, BUN, and alkaline phosphatase indicative of hepatic damage. In contrast to increased serum proteins, the C3 component of complement was reduced in a dose-dependent manner. Leukocyte number in the peripheral blood was significantly reduced, while erythro-cyte number and hematocrit were both increased. The number of B cells and T cells was decreased in morphine-treated animals. However, the percentage of T cells relative to B cells was increased. The primary IgM antibody response to the T-depen-dent antigen, sheep red blood cells, was decreased. Natural killer cell activity was reduced in response to morphine, as was the phagocytic capacity of Kupffer cells. Host-resistance models of or showed an increased resistance following administration of morphine. This increased host resistance, however, was not due to an increase in antimicrobial action of sera obtained from mice treated with morphine. The majority of morphine's effects on the immune system exhibited a flat dose response, suggesting that these effects may be mediated secondarily through corticosterone. [ABSTRACT FROM PUBLISHER]

Published
1994

74. Derivatives of Apomorphine and of Other N-Substituted Norapomorphines

Author

Atkinson, Edward R., Battista, S.P., Ary, Istvan E., Richardson, Donald G., Harris, Louis S., and Dewey, William L.

Abstract

Derivatives of apomorphine and of N‐n‐propylnorapomorphine were prepared to obtain modified pharmacological activity and enhanced chemical stability. Mouse profile and dog emesis screens were performed, and the activity of various N‐substituted derivatives and their esters was evaluated and compared to the parent compounds. The N‐n‐propyl diacetate derivative and N‐methyl and N‐n‐propyl ascorbate salts were remarkably stable to air; apomorphine etherate was no more stable than the free base. The dimers, the major products formed during the acid‐catalyzed rearrangement of morphines to apomorphines, were all potent emetics. Additionally, two showed a significant antagonism to morphine in mice and dogs.

Published
1976
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75. δ9-Tetrahydrocannabinol: Effects of route of administration on onset and duration of activity and tolerance development

Author

Abel, E. L., McMillan, D. E., and Harris, Louis S.

Abstract

Pigeons trained to key-peck for food reinforcement on a VI 3', were injected either orally, intramuscularly, or intravenously with d9-tetrahydrocannabinol and the onset and duration of this drug were determined. Onset of action was much faster for the intravenous route than the other two routes. Speed of and duration of effect were also affected by drag dosage. Using the same methods, the development of tolerance to the behavioral effects were investigated. Tolerance occurred with all three routes at about the same rate.

Published
1974
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76. Measurements of weight and activity in male mice following inhalation of cannabis smoke in a controlled smoke exposure chamber

Author

Weinberg, Andrew D., Dimen, Edward M., Simon, Glenn Stuart, Harris, Louis S., and Borzelleca, Joseph F.

Abstract

A smoke exposure device delivering marijuana smoke to mice is described. Standardized smoking conditions were achieved with this unit yielding a concentration of 0.123 mg/liter of delta-9-tetrahydrocannabinol in air. A significant (p< 0.05) decrease in locomotor activity in treated animals was seen following the fourth treatment in a 21-day study where animals were exposed three times weekly for 3 weeks. A significant decrease in body weight for marijuana-exposed animals was also noted. In another study, animals were exposed daily for 7 days. Locomotor activity was significantly decreased in marijuana-exposed animals on Days 6 and 7. There was no significant change in body weight. Following removal from the exposure chamber, the marijuana-exposed animals showed transient hyperactivity (1–3 min) followed by a period of depressed activity lasting 1 hr. Some tolerance to the placebo smoke was seen after the fourth treatment in both studies. Cumulative effects were seen following repeated exposures. These preliminary data suggest that inhalation of marijuana smoke will initiate behavioral changes in mice.

Published
1977
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77. 2,5-Dimethyl-2′-hydroxy-9α- and 9β-(3-Methylbutyl)-6,7-benzomorphans and N-Substituted Compounds in the 9α-(3-Methylbutyl) Series: Chemistry, Pharmacology, and Biochemistry

Author

Jacobson, Arthur E., Rice, Kenner C., Burke, Terrence R., Lupinacci, Lillian, Mattson, Mariena V., Aceto, Mario D., and Harris, Louis S.

Abstract

2,5-Dimethyl-2′-hydroxy-9α-(3-methylbutyl)-6,7-benzomorphan, the 9β-analogue, and 9α-N-substituted (N-ethyl, propyl, butyl, pentyl, hexyl, phenylethyl, allyl, and cyclopropylmethyl) compounds were synthesized and evaluated biochemically and pharmacologically. The 9β N-methyl compound was found to be as potent as morphine in the mouse hot plate assay and had one-seventh the affinity of morphine for the opioid receptor. The N-alkyl and N-phenethyl 9α-substituted compounds were either inactive or relatively ineffective as antinociceptive agents. None of the examined compounds substituted for morphine in single-dose suppression studies in the rhesus monkey. The N-cyclopropylmethyl compound in the 9αseries had half the narcotic antagonist potency of nalorphine and one-eighth of its affinity for the opioid receptor. The 9α-(3-methylbutyl) moiety, unlike bulky substituents in the 9βposition of 6,7-benzomorphans, generally lowers affinity for the μ opioid receptor and diminishes their in vivo activity as agonists or antagonists.

Published
1987
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78. Excretion of trans-Δ9-Tetrahydrocannabinol and Its Metabolites in Intact and Bile Duct-Cannulated Rats

Author

Turk, Robert F., Harris, Louis S., and Dewey, William L.

Abstract

Tritiated Δ9-tetrahydrocannabinol (I) was administered both orally and intravenously to groups of bile duct-cannulated rats and those with their bile duct intact. From 55.8 to 66.9% of the total radioactivity was excreted during the 96-hr. period following administration. The excretion of radioactivity was minimal in each group beyond 48hr. after drug administration. The major route of excretion following the intravenous administration in bile duct-cannulated rats was by way of bile (59.4%; feces, 2.7%), whereas more radioactivity was excreted in feces (41.5%) than bile (21.5%) when the drug was given orally. The radioactivity excreted in the feces of the orally medicated rats was mainly extractable in petroleum ether. This extract was found to contain I by TLC and GLC analysis. After intravenous administration, the radioactivity in the feces was not extractable in petroleum ether but appeared in ether, methanol, and water extracts. TLC confirmed that the radioactivity in these solvents was associated with metabolites of I. Bile contained mainly metabolites of I, as did the urine. Less than 10% of the radioactivity was excreted in the urine of each group of rats.

Published
1973
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