Morphine, codeine, and pethidine induced histamine release from isolated rat mast cells in the same concentration range. The histamine release induced by morphine and by codeine occurred rapidly, in contrast to the release induced by pethidine. The effect of morphine was reduced by the presence of calcium, enhanced by magnesium, and unaffected by phosphatidyl serine. Pretreatment of the cells with the ionophore A23187 inhibited the response to morphine, indicating a requirement for intracellular calcium. The release induced by morphine and by codeine was inhibited by antimycin A, but the release induced by pethidine was unaffected. The effect of morphine was inhibited by both naloxone and codeine, and naloxone also reduced the release induced by codeine. The effect of pethidine was inhibited by codeine, whereas the influence of naloxone was less pronounced. Preincubation of cells with lower concentrations of morphine reduced the response to a subsequent exposure to morphine. The release induced by compound 48/80 was similarly inhibited after preincubation with morphine as well as after preincubation with codeine and with pethidine. In contrast, preincubation with pethidine enhanced the effect of subsequent incubation with pethidine. Preincubation with low concentrations of compound 48/80 reduced the response to compound 48/80 in the absence of calcium, but was without effect in the presence of calcium. It is suggested that morphine, codeine, pethidine, and naloxone act on common or closely relates sites on the mast cell and that these sites may account for the action of compound 48/80 as well. The results indicate similar mechanisms for the histamine release induced by morphine and by codeine, whereas pethidine clearly has a different mode of action.

Histamine release induced by the antigen from mast cells obtained from actively sensitized rats was enhanced by the same concentration of calcium in the medium, irrespective of whether the mast cells were isolated from contaminating cells or not. The time course of the release from isolated mast cells in the presence or absence of calcium was similar at 21 and 37 °C, respectively. The enhancing effect of calcium on the release was gradually lost when the cells were exposed to antigen prior to the addition of calcium. At equivalent concentrations, no other divalent cation tested could substitute for calcium. Similar concentrations of antimycin A prevented histamine release induced by antigen or compound 48/80. In the presence of the inhibitor, energy derived from glycolysis completely restored the release when induced by compound 48/80, whereas only partial restoration could be obtained in anaphylaxis. The latter effect was inhibited with iodoacetate in concentrations which were without effect in the absence of antimycin A. The results agree well with the view that antigen causes a passing state of increased permeability of the plasma membrane of the mast cells whereby calcium and eventually sodium might enter. Provided metabolic ATP is available, intracellular reactions are hereby initiated which lead to the release of histamine from its binding sites within the granular matrix.

The time courses for histamine release and uptake of 45Ca were compared on isolated rat mast cells after stimulation under different experimental conditions with antigen, compound 48/80, ATP, or the ionophore A23187. Except for ATP the results did not show a time-dependent correlation between histamine release and 45Ca uptake.The uptake of 45Ca under conditions where membrane-bound calcium is utilized for optimal anaphylaetie histamine release did not differ from that of controls, whereas the presence of 45Ca in the incubation medium led to a substantial uptake without influence on the histamine release.The uptake of 45Ca induced by antigen or compound 48/80 was completely inhibited by antimyein A as confirmed by the use of two different methods. In addition, an energydependent restitution of the permeability properties of the plasma membrane seemed to follow histamine release. Antimycin A partly reduced the uptake of 45Ca after stimulation with ATP, and did not affect binding following exposure of the cells to the ionophores A23187 or X53 7A.The ionophore A23187 was able to reduce the 45Ca content of mast cells previously loaded with the isotope. Mast cells pretreated with A23187 in the absence of extracellular calcium did, after washing, accumulate substantial amounts of 45Ca without release ofhistamlne.The results suggest that only small amounts of calcium are required to trigger histamine release and that studies with 4sea do not distinguish between specifie uptake of calcium and nonspeeifie equilibration secondary to morphological secretory changes.

No abstract

Plasma concentrations of morphine were studied in 16 patients with chronic pain due to advanced cancer, treated with regular doses of morphine chloride by the oral route. Doses ranged from 20 to 125 mg every 4 h and a significant, positive, linear correlation was found between dose (range 0.22-3.01 mg/kg) and mean plasma concentration (range 22-364 ng/ml). The profile of the 4 h concentration curve is described and found to be subject to considerable, individual variation. The present investigation supports the experience that good pain relief can be obtained, if individual requirements as to dose and dose interval are taken into consideration.