Opiate effects

We examined the effects of three such stereoisomer pairs of "sigma opiates" on 86Rb efflux in synaptosomes in the presence of 10 pM naloxone (to avoid classical opiate effects). Our data show (Bartschat et al. 1985) that dexoxadrol blocks Sv at one-thousandth the concentration of its stereoisomer, levoxadrol ... 

Do not try to overcome reversal of opiate effects by self-administration of large doses of narcotic... 

In the course of clinical treatment with methadone, certain situations relating to adverse effects are characteristic. Nausea is a general opiate effect, but complaints most frequently relate to the methadone mixture. This preparation does have a syrupy consistency, but the problem for clinicians is that the alternatives - sugar-free mixture or methadone tablets - are both more injectable, and therefore requests or implied requirements for these are often manipulative. So are requests for the antiemetic cyclizine tablets, which are crushed and injected by drug misusers along with injected methadone. As indicated in Chapter 4, thankfully these particular claims have become less common now that guidelines are much more discouraging of any use of methadone tablets. 

Diphenoxylate is a synthetic compound designed to have the antidiarrheal effects of the opiates, but it also retains some less desirable opiate effects. It is generally combined with atropine, as co-phenotrope, which was originally added to the formulation in the hope of preventing misuse, although it can itself cause problems, especially if the combination is intentionally or accidentally used to excess. 

Opiate effects are mediated via multiple opioid receptors such as the mu, kappa, delta, and sigma. The mu receptors mediate analgesia, euphoria, physical dependence, and depression of ventilation. 

Alcohol, Naltrexone is a p-opioid receptor antagonist first synthesized in the opioid 1960s. Naltrexone was approved by the FDA for the treatment of opioid addiction treatment in 1984 and alcohol addiction in 1994 [247]. Naltrexone blocks the euphoric effects of opioids by binding competitively to opioid receptors, but does little to curb craving for opioids. Because naltrexone is an opioid antagonist there is little risk of abuse or dependence given that it does not have intrinsic opiate effects and therefore is not reinforcing [248]. 

Morphinans. Only one of the two enantiomeric quaternary iodides, N-methyl-levorphanol exhibited specific opiate effects while the other enantiomer, N-methyl-dextrorphan was, as expected, inactive.In a series of 14-hydroxymorphinans, the epimeric isomorphinan (6) was a more potent antagonist than oxilorphan (5)(BC-2605).121 a review on the pharmacology of butorphanol (cyclobutyl analog of 5) has been published- - and clinical investigation of both the oral and parenteral forms is continuing.123-128... 

Unlike the situation with analgesia, it appeared that Mg + and Mn + did not cause antagonism of opiate effects (31,33,36). 

An alternative explanation for experiments where Ca + is used to overcome the effects of opiates, is that the ions, by promoting increased neurotransmitter release, are simply masking the opiate effect. The molecular events resulting from opiate receptor activation would thus still occur, but would be detected to a lesser degree. In this case, Ca2+ antagonism of opiates would thus not necessarily imply an... 

Opiate effects on Ca + fluxes have been shown in a number of different experimental preparations. Kakunaga (57) reported that a high concentration of morphine (10 M) inhibited K+ and EDTA stimulated Ca + influx and efflux in rat brain slices. The effect was partially nalorphine reversible, was seen in low-Ca + medium (0.1 mM), but not at a higher Ca + concentration (1.3 mM). We have re-examined these phenomena and have found naloxone-reversible morphine inhibition of K+-stimulated Ca + uptake into brain slices from cortex or midbrain, but not cerebellum (10). Unlike the earlier report this effect was observed at Ca + concentrations up to 1.4 mM. These results were not obtained below morphine concentrations... 

Kaku et al. (55) reported that acute in vivo or in vitro morphine treatment inhibited Ca uptake into mouse brain synaptosomes, an effect which disappeared with tolerance development. A series of experiments have been conducted in this laboratory in order to examine opiate effects on Ca fluxes in synaptosomes. Morphine caused dose-dependent decreases in synaptosomal Ca uptake at low K+ concentrations (in the presence of ATP and Mg2+) after in vitro or acute in vivo treatment (58). This effect was naloxone reversible and stereospecific, with levorphanol also causing inhibition but not dextrorphan. Uptake was apparently inhibited in a noncompetitive fashion. In contrast, mice made tolerant by morphine pellet implantation showed progressive increases in ca uptake with increasing degrees of tolerance that had developed, p-endorphin similarly inhibited Ca uptake into synaptosomes after in vitro treatment or after i.c.v. injection (59). 

With prolonged narcotic treatment a homeostatic mechanism increasingly take over to retain Ca +, which results from increased Ca + binding and/or uptake at synaptic vesicle and SPM sites (Fig. 2). The elevated Ca + necessitates more narcotic to produce acute opiate effects, i.e. more is required to again reduce intracellular Ca + and produce analgesia. Therefore, tolerance develops as higher doses of opiate are required to produce an effect, and this in turn leads to further adaptation and an increasing cellular Ca + accumulation. 

This model would suggest that Ca + administration, by inhibiting opiate effects, should reduce tolerance development and such results have been noted previously (11-14). Furthermore, EGTA (due to its Ca + depleting effects) should enhance tolerance development, and again, such an effect has been reported by Schmidt (73). 

Studies of opiate effects on ATPase activities have been conducted both by us and others, as a direct consequence of the earlier results showing opiate-induced alterations in Ca + levels. Synaptic vesicles are known to contain... 

Synaptic membrane-bound protein kinase activity is regulated by both cAMP and Ca + (106,107). Opiates might thus alter protein kinase activity by reducing Ca + availability, either directly or indirectly via adenylate cyclase. Enzyme induced protein phosphorylation is reported to cause altered membrane ion permeability and thus changes in neuronal excitability. Direct opiate effects on the enzyme could thus produce changes in Ca + distribution such as those discussed previously. 

This is especially true since a number of Ca2+-dependent effects are known to be susceptible to opiate action. The picture is further complicated by the possibility that in some cases opiate effects may not involve Ca +, while in the instances where opiate-Ca + interactions can be demonstrated, the effects on Ca + may be either directly related to drug action or may be the indirect consequence of other opiate actions such as effects on body temperature, pH or oxygen tension. 

Alternatively, it may be argued that the opiate induced changes in Ca + flux, may be secondary to altered neuronal activity caused by other more important opiate actions which do not directly involve Ca + metabolism. Similarly, it may be that while Ca + has often been observed to antagonize opiate effects, this only indicates that the Ca + can alter levels of neuronal activity but does not prove a direct effect of opiates on Ca + Since these two differing interpretations may be placed on much of the data, it would seem that an important objective for future work in this field is to instigate research which will effectively demonstrate whether or not opiate effects are being produced as a direct consequence of drug effects on Ca +. 

Describe the reversal of opiate effects seen with the intravenous administration of an opiate antagonist. 

Only within the last 25 years have scientists begun to understand the effects of opioid analgesics at the molecular level. In 1954, Beckett and Casey at the University of London proposed that opiate effects were receptor mediated, but it was not until the early 1970s that the stereo-specific binding of opiates to specific receptors was demonstrated. The characterization and classification of three... 

In a comparative study, 5 extensive metabolisers and 6 poor metabolisers of the cjTochrome P450 isoenzyme CYP2D6 were given hydroeodone, and another 4 extensive metabolisers of CYP2D6 were given hydrocodone after pre-treatment with quinidine. The metabolism of the hydroeodone to its active metabolite hydromorphone was found to be high in the extensive metabolisers who described good opiate effeets but poor in the poor metabolisers and the extensive metabolisers pre-treated with quinidine who described poor opiate effects . For the effeet of quinidine on hydromorphone metabolism, see Opioids -i- Quinidine , p.l83. 

Correlation of CNS Areas with High Opiate Receptor Density and Opiate Effect ... 

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