title: Morphine and muscle relaxants are receptor-independent G-protein activators and cromolyn is an inhibitor of stimulated G-protein activity.
abstract: Morphine and muscle relaxants are classical mast cell activators and cromolyn is a mast cell inhibitor. However, the mechanisms underlying the effects of these drugs are obscure. We asked the question whether morphine and muscle relaxants may activate heterotrimeric guanine nucleotide-binding proteins (G-proteins), and whether cromolyn may prevent this activation. Morphine activated Gi-proteins in HL-60 membranes and purified transducin (TD) at concentrations above 1 mM, but the effects on morphine did not reach saturation up to 10 mM. d-Tubocurarine activated Gi-proteins and TD in a saturable manner, with EC50 values of 0.3 mM and 4.2 mM, respectively. Gallamine and succinylcholine were less effective activators of TD than d-tubocurarine, Morphine and d-tubocurarine were about similarly effective activators of Gi-proteins, whereas d-tubocurarine was a more effective activator of TD than morphine. Cromolyn at 10 microM and 100 microM had little effect on TD activity but reduced the stimulatory effect of morphine by 50% and 80%, respectively. Our data suggest the following: (1) Receptor-independent G-protein activation by morphine and muscle relaxants presumably accounts for their mast cell-activating properties. (2) Cromolyn may act by preventing G-protein activation. (3) The variability in responsiveness of mast cells towards morphine and muscle relaxants could be due to differential expression of G-proteins with different sensitivity to activation by these drugs.
authors.affiliation: Institut für Pharmakologie, Freie Universität Berlin, Germany.
authors.forename: J F
authors.initials: JF
authors.lastname: Klinker
authors.forename: R
authors.initials: R
authors.lastname: Seifert
mesh_terms: D000818:Animals; D002417:Cattle; D004205:Cromolyn Sodium / Q000378:metabolism / Q000494:pharmacology*; D020558:GTP Phosphohydrolases / Q000737:chemistry / Q000187:drug effects; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000187:drug effects* / Q000302:isolation & purification / Q000378:metabolism; D005703:Gallamine Triethiodide / Q000494:pharmacology; D020962:Heterotrimeric GTP-Binding Proteins; D009020:Morphine / Q000378:metabolism / Q000494:pharmacology*; D009467:Neuromuscular Depolarizing Agents / Q000378:metabolism / Q000494:pharmacology*; D003473:Neuromuscular Nondepolarizing Agents / Q000378:metabolism / Q000494:pharmacology*; D011955:Receptors, Drug / Q000502:physiology; D013390:Succinylcholine / Q000494:pharmacology; D015293:Transducin; D014403:Tubocurarine / Q000494:pharmacology
chemical_list: C034809:GNAT1 protein, human; D009467:Neuromuscular Depolarizing Agents; D003473:Neuromuscular Nondepolarizing Agents; D011955:Receptors, Drug; D009020:Morphine; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; D020962:Heterotrimeric GTP-Binding Proteins; D015293:Transducin; D013390:Succinylcholine; D004205:Cromolyn Sodium; D005703:Gallamine Triethiodide; D014403:Tubocurarine