Effect of chemical sympathectomy on morphine antinociception and tolerance development in the rat

Bhargava, Hemendra N.; Afifi, Abdel-Halim M.; Way, E. Leong

doi:10.1016/0006-2952(73)90139-1

Cited by 31 publications

(5 citation statements)

References 6 publications

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“…Currently, therefore, we see no apparent correlation between the effects of these peptides on morphine addiction and dopaminergic mechanisms in the extrapyramidal system. These conclusions are in line with our contention that dopamine is involved in the expression of symptoms of physical dependence but not in the development of the physical dependence process (15,16). In summary, in our hands MIF and cyclo(Leu-Gly) are the most potent peptides to date in blocking physical dependence on morphine in mice, and several additional structural analogues of MIF were found to exhibit a substantial degree of potency.…”

Section: Resultssupporting

confidence: 91%

Prolyl-leucyl-glycinamide, cyclo(leucylglycine), and derivatives block development of physical dependence on morphine in mice.

Walter¹,

Ritzmann²,

Bhargava³

et al. 1979

Proc. Natl. Acad. Sci. U.S.A.

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Pro-Leu-Gly-NH2 (MIF) and several structural analogues, all injected in 50jsg doses daily in mice receiving morphine chronically, were found to prevent development of physical dependence as measured by changes in body temperature associated with naloxone-induced withdrawal. Doseresponse studies, using again a protocol of daily injections of peptide at 50, 5, 0.5, 0.05, or 0.005 ,ug per mouse revealed MIF and cyclo(Leu-ly) to be the most potent peptides and to be effective In lockng physical dependence to morphine at a dose as low as 0.5 and 0.05 ,g per mouse, respectively. The benzyloxycarbonyl derivative of MIF, Pro-Leu, and Pro--Leu exhibited significant activities down to a dose of 5 1Ag of peptide per mouse.Recent evidence (1) indicates that the dipeptide benzyloxycarbonyl-Pro-D-Leu is capable of blocking the development of tolerance to and physical dependence on morphine in mice; these effects were achieved without altering the analgesic potency of morphine.In light of the potential clinical importance of these observations and their significance for the study of the mechanism of action of central nervous system-active peptides, it was decided to investigate whether more potent inhibitors could be found. The inhibitory properties of a selected number of peptides was evaluated over a broader dose range. Because, in our original studies, Z-Pro-D-Leu was equally effective in blocking tolerance, abrupt withdrawal, or naloxone-precipitated withdrawal (1), it was decided to use naloxone-precipitated withdrawal in mice as the bioassay in the current investigation for an evaluation of structure-function and dose-response relationships.MATERIAL AND METHODS A double-blind procedure was used for all experiments, and each peptide was tested in at least two independent experiments. Male Swiss Webster mice (Scientific Small Animal Farm, Inc., Melrose Park, IL) weighing 24 ± 2 g (mean E SD) were used. The mice were housed five or six per cage in temperature (23 ± 1"C) and light (light 0600-1800 hr) controlled rooms and were kept in our laboratory for a minimum of 7 days prior to the initiation of experiments. Food (Purina Laboratory Chow) and water were available ad lib.Mice were randomly divided into two groups. One group received subcutaneous injections of 0.1 ml of water (vehicle). The other group received peptide dissolved in 0.1 ml of water; in the case of the structure-activity studies, a single dose of 50 ,ug of peptide per mouse was given on day 1, and in the doseresponse studies 50, 5, 0.5, or 0.005 tig of peptide was administered to the respective groups of mice. Two hours later the mice were implanted with morphine pellets. The injections ofThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. §1734 solely to indicate this fact. 518 vehicle and respective peptides were repeated 24 and 48 hr after the first injection in their respective groups. Morphine pellets, containing 75 mg of mo...

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Section: Resultssupporting

confidence: 91%

Prolyl-leucyl-glycinamide, cyclo(leucylglycine), and derivatives block development of physical dependence on morphine in mice.

Walter¹,

Ritzmann²,

Bhargava³

et al. 1979

Proc. Natl. Acad. Sci. U.S.A.

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“…Many investigators have also utilized the subcutaneous implantation of one or two pellets, each containing 75 mg of morphine base, for a period of 3 days in rats and assumed that sufficient tolerance and dependence developed without providing a quantitative measure. Under the above conditions, it has been shown (Bhargava, Afifi & Way, 1973;Bhargava, 1977;Bhargava, 1978) that an extremely low degree of tolerance and dependence develops in the rat. Furthermore, implantation of 1 or 2 morphine pellets in the rat does not alter the brain 5-HT turnover ).…”

Section: Introductionmentioning

confidence: 90%

“…Under the above conditions, it has been shown (Bhargava, Afifi & Way, 1973;Bhargava, 1977;Bhargava, 1978) that an extremely low degree of tolerance and dependence develops in the rat. Furthermore, implantation of 1 or 2 morphine pellets in the rat does not alter the brain 5-HT turnover .…”

Section: Introductionmentioning

confidence: 99%

The Synthesis Rate and Turnover Time of 5-Hydroxytryptamine in Brains of Rats Treated Chronically With Morphine

Bhargava¹

1979

British Journal of Pharmacology

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1 Four schedules of subcutaneous pellet implantation were used to induce tolerance to and physical dependence on morphine in Sprague-Dawley rats. 2 The schedules included implantation of four morphine pellets (each containing 75 mg of morphine free base) during a 3 day period (schedule 1); six pellets during 3 days (schedule 2); six pellets during 7 days (schedule 3) and ten pellets during a 10 day period (schedule 4). 3 A high degree of tolerance and dependence on morphine, comparable to that induced in mouse by implantation of a single morphine pellet for 3 days, was produced with schedule 4. 4 Brain 5-hydroxytryptamine (5-HT) turnover rates as measured by rate of accumulation of 5-HT after monoamine oxidase inhibition by pargyline were not different in rats rendered tolerant to and dependent on morphine according to schedules 1 to 4 when compared with corresponding placebo pellet-implanted rats. 5 The turnover rates of 5-HT in brain of morphine-and placebo pellet-implanted rats (schedule 4) from which the pellets had been removed for 24 h were also similar. 6 It is concluded that tolerance to, and physical dependence upon morphine in the rat is not associated with changes in brain 5-HT dynamics.

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“…For example, (a) tolerance was reported to be completely inhibited by depletion of brain norepinephrine (Tabakoff et al 1978) and acetylcholine (Brezenoff & Mycek 1974, whereas tolerance development was only retarded by 5-HT depletion, (b) depletion of brain acetylcholine interfered with the expression of tolerance to barbiturates (Brezenoff & Mycek 1976) whereas depletion of brain norepinephrine or serotonin had no effect on the expression of tolerance (Tabakoff et al 1978, Frankel et al 1978a, (c) a brain norepinephrine system is important for hypnosedative drug tolerance, but not for morphine tolerance (Friedler et al 1972, Bhargava et al 1973, Blasig et al 1975, Elchisac & Rosecrans 1979. Such a possibility would suggest complete lack of specificity, i.e., manipulation of any neurotransmitter would result in a similar effect regardless of the drug or the paradigm employed for testing tolerance.…”

Section: Drug Tolerance and General Adaptationmentioning

confidence: 99%

Role of Serotonin (5‐ht) in Drug Tolerance and General Adaptation

Khanna¹,

Kalant²,

Le³

et al. 1980

Acta Psychiatr Scand

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To date, studies of functional tolerance have embodied one of three types of approaches. The first is essentially descriptive and attempts to characterize the conditions and outcomes of chronic drug exposure, and the role of pharmacological and behavioral factors in the genesis of such tolerance. At best, these studies provide kinetic data regarding the development of tolerance, and at worst, they simply indicate whether or not functional tolerance is apparent, following a specific set of treatments or testing paradigms.The second approach attempts to unravel the physiological events or mechanisms that subserve functional tolerance and can be subdivided into experimental strategies that are either specifically descriptive or that provide a theoretical perspective. The former examine the effects of certain extraneous manipulations on the development of tolerance, such as brain lesions, inhibition of protein synthesis or alterations in normal neurotransmitter function or content. The latter attempt to draw parallels, based on observations on functional tolerance, to specific theoretical models derived from other fields. Examples of this include theories of enzyme repression and induction (Goldstein & Goldstein 1968) or of denervation supersensitivity (Jaffe & Sharpless 1968).A considerable body of literature indicates that the stimulus required to elicit functional tolerance is not merely the presence of a drug in the CNS, but rather, the nature and intensity of the functional disturbance that is produced (Kalant et al. 197 1, Kalant 1977, LeBlanc et al. 1978). A third approach which is evoked by such a postulate, and which was adopted in our work, has attempted to synthesize the theories arising from the first two, and to investigate drug tolerance within the conceptual framework of general biological adaptation. The thrust of this approach is to emphasize the commonalities between functional tolerance and other adaptive capabilities of the central nervous system.In this paper, a specific series of interventions that affect tolerance are described and then discussed in the context of the general theory of adaptation. The outcomes of two of our recent studies, namely, (i) cross-tolerance between alcohol and morphine and (ii) reversal of tolerance to ethanol on continued exposure, further support the predictive values of the general adaptation model of functional, tolerance.

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Effect of chemical sympathectomy on morphine antinociception and tolerance development in the rat

Cited by 31 publications

References 6 publications

Prolyl-leucyl-glycinamide, cyclo(leucylglycine), and derivatives block development of physical dependence on morphine in mice.

Prolyl-leucyl-glycinamide, cyclo(leucylglycine), and derivatives block development of physical dependence on morphine in mice.

The Synthesis Rate and Turnover Time of 5-Hydroxytryptamine in Brains of Rats Treated Chronically With Morphine

Role of Serotonin (5‐ht) in Drug Tolerance and General Adaptation

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