ABSTRACT
The mechanisms of non-drowsiness after oral administration of TMK688 (1- [[5'-(3"-methoxy-4"-ethoxycarbonyloxyphenyl)-2',4'-pentadienoyl ] aminoethyl]-4-diphenylmethoxypiperidine, CAS 110501-66-1) were investigated using mice. TMK688 inhibited the histamine-induced vascular permeability at oral doses of 3.2-10 mg/kg with an ID50 value of 5.4 mg/kg. More than 100 times higher doses were needed to prolong the hexobarbital-induced sleeping. Pyrilamine, a typical antihistamine agent, showed little difference among these doses and antiallergic drugs having antihistamine activity, i.e., terfenadine, azelastine and ketotifen, had effects between TMK688 and pyrilamine. The inhibitory activity of orally administered TMK688 against ex vivo [3H]-pyrilamine binding to mouse cerebral histamine receptors appeared at the same doses as its potentiating activity against hexobarbital-induced sleeping. When given orally, TMK688 was hydrolyzed to TMK777 (CAS 101619-11-8), then conjugated with glucuronic acid to TMK777-glucuronide. No TMK688 was detected in the blood. The main metabolite TMK777-glucuronide could hardly penetrate the blood-brain barrier because of its polarity. Although the plasma concentrations of TMK777 were far lower than those of TMK777-glucuronide, TMK777 was penetrable into the brain and the cerebral concentrations of TMK777 increased in parallel with the plasma concentrations of the drug. Since intracerebroventricularly-injected TMK777 prolonged the sleeping time, and since the threshold concentration of TMK777 in the cerebral cortex to potentiate the hexobarbital-induced sleeping was consistent despite different administration routes, the drowsiness elicited by markedly high doses of TMK688 is though to be caused by intracerebral TMK777. In other words, TMK688 does not seem to cause drowsiness at effective doses because of the poor prenetrability of its main metabolites into the brain.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Brain/metabolism , Histamine H1 Antagonists/pharmacology , Piperidines/pharmacology , Sleep Stages/drug effects , Administration, Oral , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Brain/drug effects , Capillary Permeability/drug effects , Capillary Permeability/physiology , Hexobarbital , Histamine/pharmacology , Histamine H1 Antagonists/administration & dosage , Histamine H1 Antagonists/adverse effects , Male , Mice , Mice, Inbred ICR , Piperidines/administration & dosage , Piperidines/adverse effects , Pyrilamine/pharmacokinetics , Rats , Rats, Sprague-Dawley , Receptors, Histamine H1/drug effects , Receptors, Histamine H1/metabolism , Sleep/drug effects , Sleep/physiologyABSTRACT
Development of cross reverse tolerance between D-amphetamine, cocaine and morphine to their ambulation accelerating- and swimming time prolonging-effects was investigated in mice. D-Amphetamine and cocaine pretreatment did not increase the ambulation or swimming time by morphine, and pretreatment with morphine produced an increase in the response to D-amphetamine and cocaine. Thus, the difference of the underlying mechanisms between morphine and other drugs for the development of reverse tolerance to their ambulation accelerating and swimming time prolonging effects was demonstrated.
Subject(s)
Cocaine/pharmacology , Dextroamphetamine/pharmacology , Morphine/pharmacology , Animals , Drug Tolerance , Male , Mice , Mice, Inbred Strains , Motor Activity/drug effects , SwimmingABSTRACT
Development and disappearance of reverse tolerance to the swimming time prolonging effect of d-amphetamine (AMP) was studied in mice in comparison with that to the ambulation accelerating effect. The swimming time prolonging effect was progressively enhanced by daily administration of 2 mg/kg AMP. The development of reverse tolerance to the effect was more rapid than that to the ambulation accelerating effect and reached its maximal level by 5-6 repetitions. Repetition at a daily interval was more effective than at the interval of 3-4 days, and administration at a weekly interval failed to develop the reverse tolerance. Restriction of swimming space or immobilization in a small box after administration of AMP blocked the development of reverse tolerance. Reverse tolerance to the swimming time prolonging effect disappeared faster than that to the ambulation accelerating effect, but the enhancement was well maintained after 30 days of withdrawal. Thus, many factors affect the development of reverse tolerance to the various effects of AMP; however, the swimming time prolonging effect is a simple, sensitive, and reproducible index for the study of this phenomenon.
