ABSTRACT
The stability of dopamine-sensitive adenylate cyclase, guanylate cyclase, ATPase, and GTPase was measured in homogenates of rat striatal tissue frozen from 0 to 24 h postmortem. ATPase, GTPase, and Mg2+-dependent guanylate cyclase activities showed no significant change over this period. Mn2+-dependent guanylate cyclase activity was stable for 10 h postmortem. Basal and dopamine-stimulated adenylate cyclase activity decreased markedly during the first 5 h. However, when measured in washed membrane preparations, these adenylate cyclase activities remained stable for at least 10 h. Therefore, the postmortem loss of a soluble activator, such as GTP, may decrease the adenylate cyclase activity in homogenates. These results are not consistent with an earlier suggestion that there is a postmortem degradation of the enzyme itself. Other kinetic parameters of dopamine-sensitive adenylate cyclase can also be measured independently of postmortem changes. Thus, it is possible to investigate kinetic parameters of dopamine-sensitive adenylate cyclase, guanylate cyclase, ATPase, and GTPase in human brain obtained postmortem.
Subject(s)
Adenosine Triphosphatases/metabolism , Adenylyl Cyclases/metabolism , Corpus Striatum/enzymology , Dopamine/pharmacology , GTP Phosphohydrolases/metabolism , Guanylate Cyclase/metabolism , Phosphoric Monoester Hydrolases/metabolism , Postmortem Changes , Adenylyl Imidodiphosphate/pharmacology , Animals , Corpus Striatum/pathology , Guanylyl Imidodiphosphate/pharmacology , Kinetics , Magnesium/pharmacology , Male , Rats , Rats, Inbred Strains , Time FactorsSubject(s)
Brain/metabolism , Naloxone/analogs & derivatives , Naltrexone/analogs & derivatives , Receptors, Opioid/metabolism , Animals , Chromatography, Gel , Dextrorphan/pharmacology , In Vitro Techniques , Mice , Naltrexone/metabolism , Naltrexone/pharmacology , Nitrogen Mustard Compounds/metabolism , Receptors, Opioid/isolation & purificationABSTRACT
The 6-bis(2)chloroethyl)amino derivatives of oxymorphone and naltrexone, chloroxymorphamine (COA) and chlornaltrexamine (CNA), respectively, produce an irreversible inhibition of [3H]naltrexone binding to mouse brain homogenates. Intracerebroventricular (i.c.v.) injection of COA (4 nmol/mouse) elicits analgesia which lasts 4 times longer than analgesia produced by equimolar and equieffective dose of oxymorphone. The analgesia induced by COA can be reversed and blocked by naloxone. Injections of both COA and CNA i.c.v. antagonize morphine-induced analgesia for 3 days. Similarly, when [3H]naltrexone binding is measured in brains from mice pretreated i.c.v. with COA or CNA, there is a significant decrease in total specific binding for 3 days after pretreatment. These data suggest that CNA and COA alkylate the opioid receptors to produce antagonist and agonist-antagonist effects, respectively. The implications of these findings are discussed with respect to their effect on our perception of the opioid receptor-narcotic agonist interaction and the mechanisms of tolerance and dependence.
Subject(s)
Analgesics , Hydromorphone/analogs & derivatives , Naloxone/analogs & derivatives , Naltrexone/analogs & derivatives , Narcotic Antagonists/pharmacology , Narcotics/pharmacology , Nitrogen Mustard Compounds/pharmacology , Oxymorphone/analogs & derivatives , Animals , Brain/drug effects , Brain/metabolism , Male , Mice , Morphine/antagonists & inhibitors , Naltrexone/metabolism , Naltrexone/pharmacology , Oxymorphone/pharmacologyABSTRACT
Chloroxymorphamine, the 6beta-N,N-bis(2-chloroethyl) derivative of oxymorphone, is a potent nonequilibrium narcotic agonist in the longitudinal muscle preparation of guinea pig ileum. The corresponding naltrexone analog,chlornaltrexamine, is a potent nonequilibrium antagonist of morphine. These receptor sitedirected alkylating agents possess considerable potenial as pharmacologic and biochemical probes of apoid receptors.
Subject(s)
Alkylating Agents , Hydromorphone/analogs & derivatives , Nitrogen Mustard Compounds/pharmacology , Oxymorphone/analogs & derivatives , Receptors, Opioid/drug effects , Animals , Chlorambucil/pharmacology , Dose-Response Relationship, Drug , Drug Synergism , Guinea Pigs , In Vitro Techniques , Morphine/pharmacology , Naloxone/pharmacology , Naltrexone/analogs & derivatives , Naltrexone/pharmacology , Norepinephrine/pharmacology , Oxymorphone/pharmacology , Phenoxybenzamine/pharmacologyABSTRACT
Chlornaltrexamine (CNA) produces ultralong-lasting (3--6 days) narcotic antagonism in mice and persistent stereospecific binding to rat-brain homogenate. Protection studies in mice suggest that CNA mediates its narcotic antagonist effects by interacting with the same receptors that are occupied by naloxone. A single icv dose of CNA also has been found to inhibit the development of physical dependence in mice for at least 3 days. These studies suggest that CNA exerts its sustained effects by selective covalent association with opioid receptors.
