Morphine antagonism

Morphine Antagonism. In order to verify that morphine competes with enkephalin for binding to PS we added morphine sulfate pentahydrate CIO mg) to a mixture of [2-[2- C]glycine]enkephalin Cl.2 mg) and PS C20 mg) in D2O at "pH" 6.3. Under this condition, the Itnewidth and intensity of the glycyl-2 resonance reverted to those of free enkephalin. Under similar conditions, but with PS C3Q mg) and morphine sulfate pentahydrate (5.4 mg), the linewidth and intensity of the glycyl-2 resonance was again essentially that of free enkephalin. 

OPIOIDS ANXIOLYTICS AND HYPNOTICS 1. t sedation with BZDs 2. Respiratoiy depressant effect of morphine antagonized by lorazepam 1. Additive effect both drugs are sedatives 2. Uncertain 1. Closely monitor vital signs during co-administration 2. Although this effect may be considered to be beneficial, risk of additive effects should be borne in mind if the combination of an opioid and BZDs is used for sedation for painful procedures... 

With the availability of a viable synthesis of 14-aminocodeinone (13) and the closely related analogues 20a, 26 and 27, Reckitt and Colman in collaboration with Professor Kirby set about the synthesis of a whole range of 14-alkylamino-, 14-arylalkylamino- and 14-acylaminocodeinones and equivalent morphinones as well as the 7,8-dihydro analogues and the /V-cyclopropylmethyl equivalents. The synthesised compounds were listed in two patents, US 4,241,066 and US 4,241,067 [8,9]. Many of them were evaluated in a primary screen for MOR activity, in vitro in the mouse vas deferens assay and in vivo in rat antinociceptive assays (Tables 1 and 2). In the in vivo assays tail pressure was the nociceptive stimulus for agonist activity, whereas for morphine antagonism warm water (55 °C) was used with tail withdrawal as the end point. 

Attention was drawn to the 4 -substituted 14-cinnamoylamino-17-cyclopropyl-methyl-7,8-dihydronorcodeinones and equivalent morphinones (40) (Fig. 3). Of particular interest to Reckitt and Colman s target of buprenorphine-like opioid activity were the dihydrocodeinones (40a-c) from which the 4 -chloro derivative, called methoclocinnamox (40a, MC-CAM), was selected for detailed study. The Reckitt and Colman group had shown the three 4 -substituted dihydrocodeinones (40a-c) to be predominantly MOR partial agonists of long duration in vivo [14], Importantly, MC-CAM showed bell-shaped dose-response curves in both tail withdrawal and tail pressure antinociceptive assays. In this respect and in the inability of naltrexone to reverse its antinociceptive effect, as well as its long-lived morphine antagonism, its similarity to buprenorphine was demonstrated. 

Preliminary metabolism studies in rats and cynomolgus monkeys showed that MC-CAM was substantially O-demethylated to C-CAM [14]. Thus the delayed long-term morphine antagonism displayed by MC-CAM could have been caused by its transformation to C-CAM. That this was probably not the case was later shown by i.c.v. administration of MC-CAM which resulted only in MOR antagonist activity [24]. 

The Lewis and Husbands group have studied in some detail structure-activity relationships relating to the 14-cinnamoylaminodihydrocodeinones and morphi-nones [37]. In light of the possibility that the delayed morphine antagonism of MC-CAM could be due to its metabolism to C-CAM, a range of alternative phenolic ethers (41) (Fig. 4) of C-CAM were prepared and evaluated [21]. The study showed that, when compared to the methyl ether (41a, MC-CAM), the cyclopropylmethyl... 

In 1915, it was shown that N-allylnorcodeine abolished both heroine- and morphine-indueed respiratory depression. Almost 25 years later (1940), it was observed that N-allylnormorphine (eom-monly known as nalorphine) possessed more marked and signifieant morphine antagonizing aetions. Thirteen years later (1953), it was demonstrated that nalorphine had the ability to arrest severe abstinence syndromes in postaddicts who were earlier treated briefly with either morphine, methadone or heroine. Examples of narcotic antagonists include nalorphine hydrochloride naloxone hydrochloride propiram fnmarate and pentazocine. 

Dynorphin may also influence nociception at the spinal level. The levels of prodynorphin mRNA and immunoreactive dynorphin increase in the chronic inflammatory arthritic model (158). Dynorphin also inhibits morphine or P-endorphin-induced analgesia in naive animals and enhances analgesia in tolerant animals, indicating that this peptide may have a regulatory role in opioid analgesia (159). This effect does not appear to be mediated by a classical opioid receptor, since des-tyrosine dynorphin, which does not bind to opioid receptors, also antagonizes morphine analgesia (160). 

The replacement of the /V-methyl group on the nitrogen atom of the piperidine ring of morphine and analogues by aHyl, isopropyl, or methyl cyclopropyl, an isopropyl isostere, results in compounds which antagonize opioid responses, especially respiratory depression. Naloxone [465-65-6] C22H2 N04 (10... 

Based upon recent controlled studies, there is considerable evidence that opioids such as morphine induce substantial effects on immune status. For example, it has been shown that morphine administration is associated with alterations in a number of immune parameters, such as natural-killer cell activity [12,13], proliferation of lymphocytes, [13, 14] antibody production [15,16], and the production of interferon [17]. Studies in our laboratory have shown that acute morphine treatment in rats suppresses splenic lymphocyte proliferative responses to both T- and B-cell mitogens, splenic natural-killer cell activity, blood lymphocyte mitogenic responsiveness to T-cell mitogens, and the in vitro production of the cytokines interleukin-2 and interferon-y [18-22], Furthermore, the immune alterations induced by morphine are dose-dependent and antagonized by the opioid-receptor antagonist, naltrexone (e.g., [22]). 

Lysle, D.T. et al., Morphine-induced alterations of immune status Dose-dependency, compartment specificity and antagonism by naltrexone, J. Pharmacol. Exp. Ther., 265, 1071, 1993. 

Ramarao P, Bhargava HN. (1990). Antagonism of the acute pharmacological actions of morphine by Panax ginseng extract. Gen Pharmacol. 21(6) 877-80. 

Pearl SM, Hough LB, Boyd DL, Glick SD. (1997). Sex differences in ibogaine antagonism of morphine-induced locomotor activity and in ibogaine brain levels and metabolism. Pharmacol Biochem Behav. 57(4) 809-15. 

Pearl SM, Maisonneuve IM, Glick SD. (1996). Prior morphine exposure enhances ibogaine antagonism of morphine-induced dopamine release in rats. Neuropharmacology. 35(12) 1779-84. 

Russell J, Bass P, Goldberg LI, Schuster CR, Merz H. (1982) Antagonism of gut, but not central effects of morphine with quaternary narcotic antagonists. Eur J Pharmacol 78 255-261. 

Foss JF, Bass AS, Goldberg LI. (1993) Dose-related antagonism of the emetic effect of morphine by methylnaltrexone in dogs. J Clin Pharmacol 33 747-751. 

The unusual combination of release and antagonism of noradrenaline has been noted above, while another property separating oxypertine from other major tranquillizers is that it does not potentiate the analgesia produced by morphine or pethidine [161]. The compound is anti-emetic and weakly antihistaminic [160-2]. 

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