The responses of human cutaneous, pulmonary, intestinal, and cardiac tissue masi cells to the histamine-releasing agent morphine sulfate (MS) were investigated in vitro. Human cutaneous mast cells released significant amounts of histamine in the presence of 1 to 100 μmol/L concentrations of MS. Histamine release was detectable within 5 minutes after challenge and was complete, by 15 minutes. A maximal histamine release of 21.6% (±1.4 SEM) was observed after stimulation with 100 μmol/L of MS. This MS effect was inhibited by the opiate receptor antagonist naloxone with a 59% inhibition detected at equimolar, concentrations and an 88% inhibition occurring in the presence of a tenfold molar excess of naloxone. Naloxone did not alter the cutaneous mast cell response to the calcium ionophore A23187. Human mast cells derived from pulmonary, intestinal, and cardiac tissues, as well as blood basophils, did not release histamine after stimulation with 1 to 200 μmol/L of MS, whereas each of these cell preparations responded to an IgE-mediated stimulus. The results of this study demonstrate that cutaneous mast cells release inflammatory mediators after stimulation by MS, whereas mast cells residing in lung, heart, and gastrointestinal tissues do not. These observations indicate that human mast cells in different anatomic sites can vary in their functional responses.

https://www.jacionline.org/article/S0091-6749(87)80162-8/pdf

Functional heterogeneity of human mast cells from different anatomic sites: in vitro responses to morphine sulfate.

A study was performed about the effects of increasing concentrations of muscle relaxants (suxamethonium, d-tubocurarine, vecuronium, and atracurium), hypnotics (propofol, ketamine, and thiopental), opioids (morphine, buprenorphine, and fentanyl), and benzodiazepines (diazepam, flunitrazepam, and midazolam) on the release of preformed (histamine and tryptase) and de novo synthesized (prostaglandin D2: PGD2 and peptide-leukotriene C4: LTC4) chemical mediators from human basophils and mast cells isolated from skin (HSMC), lung parenchyma (HLMC) and heart tissue (HHMC). None of the drugs tested induced the release of histamine or LTC4 from basophils of normal donors. Suxamethonium did not induce mediator release from any type of human mast cell tested. Only the highest concentration of d-tubocurarine used caused histamine release from HSMC and HLMC. Atracurium, more than vecuronium, induced concentration-dependent histamine release from HSMC and HLMC. Propofol induced a concentration-dependent histamine release from HLMC, but not from HHMC. Only the highest concentrations of ketamine and thiopental used caused a significant release of histamine from HLMC. The muscle relaxants and hypnotics examined did not induce any de novo synthesis of PGD2 or LTC4 in mast cells. Morphine only induced histamine and tryptase release from HSMC, but not the de novo synthesis of PGD2. In contrast, buprenorphine caused histamine and tryptase release from HLMC, and not from HSMC, whilst it also induced de novo synthesis of PGD2 and LTC4 in HLMC. Fentanyl did not give any histamine and tryptase release from mast cells. Diazepam and flunitrazepam only induced a small release of histamine from mast cells, whereas midazolam caused the release of histamine from HLMC. The biochemical pathways underlying the release of mediators from human mast cells induced by drugs used during general anaesthesia are different from those underlying the immune release of histamine. From the results obtained with the in vitro model described here, it is clear that new drugs promising for the anesthesiologic arena should be tested in vitro before their potential histamine-releasing activity is experienced in vivo.

Mechanisms of activation of human mast cells and basophils by general anaesthetic drugs

A 15-year-old patient with cystic fibrosis developed urticarial reactions to tobramycin, gentamicin, and cephoperazone, and an anaphylactic reaction to ticarcillin during therapy for an extensive pulmonary infection with Pseudomonas aeruginosa and Staphylococcus aureus . Immediate wheal-and-flare skin tests were positive with tobramycin and with penicilloylpoly-l-lysine. Desensitization with tobramycin in gradually increasing intravenous doses was accomplished during 8 hours. The procedure was complicated by a macular rash that remitted within minutes without therapy, but no symptoms or signs of an allergic reaction to tobramycin were detected during full dose therapy. Skin test responses to tobramycin became negative by the end of the desensitization procedure, whereas the responses to penicilloylpoly-l-lysine and histamine remained positive. A worsening course led to an unsuccessful attempt to desensitize the patient to β-lactam determinants. Wheezing appeared during the administration of oral doses. This case demonstrates the feasibility of acute, antigen-specific desensitization of an aminoglycoside-allergic patient and the failure to achieve a second, simultaneous desensitization. This patient experienced the first serious reaction to oral penicillin desensitization.

Acute desensitization of a patient with cystic fibrosis allergic to both beta-lactam and aminoglycoside antibiotics

https://epub.uni-regensburg.de/21766/1/lorenz32.pdf

Perioperative uses of histamine antagonists.

Background: The metabolic activation of morphine, cocaine and methadone into free radicals could have pathophysiological relevance in the organic injuries of drug addiction.¶Methods: Isolated purified rat serosal mast cells were incubated with morphine, cocaine and methadone (10−7 M–10−4 M) with oxidative enzymes (prostaglandin-H-synthetase, 25 mU; rat liver homogenate fraction S 10-mix, 400 μl), and with the drugs of abuse in the presence of oxidative enzymes. Histamine and lactate dehydrogenase (LDH) were analysed with a fluorimetric and spectrophotometric assay, respectively; the generation of malonyldialdehyde (MDA) was measured by a spectrophotometric assay.¶Results: The release of mast cell histamine and the generation of MDA are present only when mast cells were incubated with the drugs of abuse in the presence of oxidative enzymes. This release was dependent on the concentration of the drug in question and showed a maximum value at 10−4 M. Moreover, in parallel experiments we demonstrated that, under the same experimental conditions, the release of LDH was always less than 20% of the total, suggesting that this effect is due to a selective exocytotic process. Histamine release and MDA generation were abated by the free radical scavengers: reduced glutathione, 10−4 M GSH and α-tocopherol, 10−4 M and by the spin trapper 5,5-dimethyl-l-pyrroline-N-oxide, 10−4 M DMPO. The light and electron microscopic features are consistent with exocytotic secretion in the cases of morphine and methadone and with cell lysis in the case of cocaine.¶Conclusion: These results suggest that morphine, cocaine and methadone are activated into free radicals which produce membrane lipid perturbation and histamine release, suggesting that a massive release of mast cell histamine could be an additional risk factor in heroin and cocaine overdoses.

/pdf/histamine-release-from-rat-mast-cells-induced-by-the-1wwjk9tmdx.pdf

Histamine release from rat mast cells induced by the metabolic activation of drugs of abuse into free radicals

High dose narcotic anesthesia with fentanyl or morphine is not associated with significant direct myocardial depression. Morphine is reported to produce arteriolar dilatation and a decrease in SVR (probably due to histamine release) while fentanyl is not. Studies were undertaken to determine if morphine or fentanyl caused histamine release; if such a release correlated with hemodynamic changes, and if H1 and H2 antagonists could provide protection. In a randomized double blind study of 40 patients in 4 groups, patients who received morphine (1 mg/kg) demonstrated significant increases in plasma histamine (880±163 to 7,437±2,684 pg/ml−p<0.01) accompanied by an increase in CI (2.4±0.2 to 3.0±0.2 l/min/m2−p<0.01) and decreases in\(\overline {BP} \) (88±4 to 61±4 torr−p<0.01) and SVR (15.5±1 to 9.0±1 torr-l-min−1p<0.01). The prior administration of H1 (dyphenhydramine 1 mg/kg) and H2 (cimetidine 4 mg/kg) antagonists provided significant protection (SVR 17.4±1 to 14.6±1 torr-l-min−1−p<0.05) although histamine increased comparably (1,059±22 to 7,653±4,242 pg/ml−p<0.05). In a separate study, seven patients receiving fentanyl 50 µg/kg showed no histamine changes (935±51 to 685±51 pg/ml) and no significant hemodynamic response. Eight patients receiving morphine 1 mg/kg again showed significant increases in plasma histamine (880±163 to 7,480±2,230 pg/ml−p<0.05) which collelated with the decrease in SVR (r=0.81). These data demonstrate that morphine releases histamine in amounts which correlate with the hemodynamic changes seen. Prior administration of H1 and H2 histamine antagonists provide significant protection — more so than either alone. Fentanyl produced no histamine release which may account for much of the cardiovascular stability reported with this drug.

James L. Rosenberger

Papers

Histamine release with intravenous narcotics: protective effects of H1 and H2-receptor antagonists.