Pulmonary vagal afferent stimulants in the conscious rat: Opioids and phenyldiguanide

Phenyldiguanide (PDG, 40 μg/kg), D-ala²-met⁵-enkephalinamide (D-AME, 250 μg/kg) and morphine sulfate (MS, 2 mg/kg) injected into the right atrium (RA) of conscious freely moving rats produced a profound bradycardia and hypotension 1–2 sec subsequent to administration. Concomitant with the cardiovascular effects apnea occurred and lasted approximately 5 sec. Atropine methyl nitrate (2 mg/kg, RA) significantly attenuated the bradycardia and hypotension produced by all three agents. Naloxone blocked only the opioid responses. Coordinated motor activity was impaired following the administration of PDG (40 μg/kg, RA). Fifty percent of the animals receiving PDG failed to remain on a rotor rod for a 2 min period. Only 8 percent of the saline treated group fell off during this period. It was concluded that the cardiovascular, respiratory, and motor effects caused by PDG, in the conscious freely moving rat, were the result of stimulation of pulmonary vagal afferents (J-receptors). The cardiovascular effects of opioids are also believed to arise from the stimulation of J-receptors. However, unlike PDG, these effects are mediated by pulmonary opiate receptors.     

Effects of stimulants,anorectics, and related drugs on schedule-controlled behavior

The effects of nine drugs were studied in rats responding under either fixed-ratio 30 (FR-30) or fixed-interval 2-min (FI-2) schedules of food presentation. All the drugs decreased average rates of responding under both schedules in a dose-related manner, with apomorphine and clonidine being the most potent and caffeine the least potent.d-Amphetamine was about three times more potent thanl-amphetamine in decreasing responding under the FR schedule, while the two isomers were equipotent in reducing the average response rates under the FI schedule. A 10 mg/kg dose of fenfluramine decreased responding for two to three days after administration, but this treatment did not produce long-lasting changes in control performance or in the effects of the serotonergic drugs quizapine andd-paramethoxyamphetamine. The effects of the drugs on the local rates of responding during the FI may be divided into three categories: (1) those drugs that increased low rates of responding and decreased high rates of responding (rate-dependent effects) at dosages that did not markedly decrease the average response rates (d-amphetamine, methylphenidate, and cocaine); (2) those that produced rate-dependent effects only at dosages that markedly reduced average response rates (fenfluramine, quipazine, and clonidine); and (3) those that did not produce clear rate-dependent effects at any dose tested (l-amphetamine, apomorphine, and caffeine). These behavioral results are discussed in relation to their known biochemical effects on brain catecholamine and serotonin systems.     

A comparative evaluation of the action of depressant and stimulant drugs on human derformance

Summary The effects of orally administered alcohol (10 and 20 cm³), alcohol (10 cm) together with distraction, of pentobarbital (150mg), of amphetamine (7.5 mg) and of caffeine (100 and 200 mg) on performance of motor and intellectual tasks by intelligent human subjects was studied.Pentobarbital depressed all of these tests, whereas the other drugs showed differential actions: alcohol prominently increased errors in the addition test at doses not affecting other intellectual tasks or motor performance. Amphetamine and caffeine decreased errors on mental tasks while not affecting the motor tasks. Distraction acted in these individuals as a stimulant, decreasing errors apparently by raising the level of alertness, and it also counteracted the deleterious effect s of alcohol on these tasks.     

A 50-year history of new drugs in Japan: the developments of antileprosy drugs and their epidemiological aspects

The developments of antileprosy drugs and their influences on the epidemiological aspects of Hansen's disease (leprosy) in Japan are investigated. 1. Hydnocarpus oil (Daifushi-Yu) products were the only useful drugs for the treatment of Hansen's disease (leprosy) in Japan from the early 1900's to just after the World War II. In those days leprosy was considered to be incurable malady. 2. The chemotherapy of leprosy, progressing from 1943 in the United States, was introduced to Japan in 1948. Promin(R) (sulfoxone sodium) for injection in 1948 and Diasone(R), and Promizole(R) for oral use in 1949 were available for the treatment of leprosy patients in the National Hansen's Disease Sanatorium in Japan. Because DDS (dapsone, diaphenylsulfone) was proved to be the main ingredient of sulfone drugs, since 1958 it has been the drug of choice for all forms of leprosy. Monotherapy with DDS has continued for more than 30 years, and sulfone-resistant bacillus has appeared occasionally. 3. Clofazimine (a new type of chemotherapeutic drug) and rifampicin (an antibiotic for tuberculosis) was added to therapy treatment for leprosy in 1996. In 1983, WHO recommended multidrug therapy (MDT) to prevent resistance to sulfones. The Japanese Leprosy Association published "Guidlines" for the Treatment of Hansen's Disease in Japan" in 2000, which proposes a multidrug therapy with rifampicin, DDS, and clofazimine for a 6-month or 2-year treatment. 4. The number of leprosy patients has slowly decreased since the application of chemotherapy with sulfone drugs, and newly infected patients in Japan have decreased to less than 10 per million persons (Figs. 1 & 2). Therefore the "Leprosy Prevention Law" (1953), which compels the controlled isolation of patients, was abolished in 1996. Effective chemotherapy with sulfone and other drugs has changed incurable leprosy to a curable infective disease.     

A comparative study of two respiratory stimulants ethamivan and taloximine

Summary A new peripherally acting respiratory stimulant taloximine is shown in a limited double-blind controlled study to be an effective analeptic agent, though probably no more so than ethamivan, in chronic bronchitic patients in moderate cardio-respiratory failure as a result of acute infective exacerbations.     

Kappa Opioids,Salvinorin A and Major Depressive Disorder

Opioids are traditionally associated with pain, analgesia and drug abuse. It is now clear,however, that the opioids are central players in mood. The implications for mood disorders, particularlyclinical depression, suggest a paradigm shift from the monoamine neurotransmitters to the opioids eitheralone or in interaction with monoamine neurons. We have a special interest in dynorphin, the last ofthe major endogenous opioids to be isolated and identified. Dynorphin is derived from the Greek wordfor power, dynamis, which hints at the expectation that the neuropeptide held for its discoverers. Yet,dynorphin and its opioid receptor subtype, kappa, has always taken a backseat to the endogenous b-endorphin and theexogenous morphine that both bind the mu opioid receptor subtype. That may be changing as the dynorphin/ kappa systemhas been shown to have different, often opposite, neurophysiological and behavioral influences. This includes majordepressive disorder (MDD). Here, we have undertaken a review of dynorphin/ kappa neurobiology as related to behaviors,especially MDD. Highlights include the unique features of dynorphin and kappa receptors and the special relation of aplant-based agonist of the kappa receptor salvinorin A. In addition to acting as a kappa opioid agonist, we conclude thatsalvinorin A has a complex pharmacologic profile, with potential additional mechanisms of action. Its unique neurophysiologicaleffects make Salvinorina A an ideal candidate for MDD treatment research.     

Prevalence and concentrations of new designer stimulants,synthetic opioids,benzodiazepines, and hallucinogens in postmortem hair samples: A 13-year retrospective study

Hair samples are frequently analyzed in order to characterize consumption patterns of drugs. However, the interpretation of new psychoactive substance (NPS) findings in hair remains difficult because of lacking data for comparison. In this study, selected postmortem hair samples (n = 1203) from 2008 to 2020 were reanalyzed for synthetic cathinones, piperazines, phenethylamines, hallucinogens, benzodiazepines and opioids to evaluate prevalence data and concentration ranges. Hair samples were extracted using a two-step extraction procedure and analyzed using a validated liquid chromatography–tandem mass spectrometry (LC–MS/MS) method. Overall NPSs were detected in 381 cases (31.6%). Many cases were tested positive for more than one NPS in the same time span. A variety of NPS with a large range of concentrations was observed. For better comparability and interpretation of positive cases in routine work, quantitation data for 13 NPS were calculated as percentiles. The most frequently detected NPS in this study were N-ethylamphetamine, α-pyrrolidinovalerophenone, mephedrone, benzedrone, metamfepramone, and 4-fluoroamphetamine. In conclusion, a high prevalence of these drugs was observed from postmortem hair samples. The results show a growing use of many different NPSs by mainly young drug-using adults. Consequently, NPS screening procedures should be included in forensic toxicology. Our quantitative data may support other toxicologists in their assessment of NPS hair concentrations.     

Involvement of mesolimbic and extrapyramidal nuclei in the motor depressant action of narcotic drugs

The ability of narcotic drugs to induce motor depression from the mesolimbic nucleus accumbens (ACB) and extrapyramidal caudate-putamen (CP) was investigated using the bilateral intracerebral injection technique. Fluphenazine and procaine were used as control agents. Firstly, drugs were injected alone into the ACB or CP and catalepsy was assessed. Fentanyl (2·5–10μg), sufentanil (0·25–1 μg) and carfentanil (0·05–0·5μg) were shown to be potent cataleptogens when injected into both the ACB and CP, the responses being dose-dependent and achieving maximum intensity. Morphine (1–50 μg) also induced a marked dose-dependent catalepsy, but only after injection into the ACB. In contrast, pethidine and methadone, in doses up to 160 μg, caused only weak and inconsistent responses from the ACB and CP. Similar injections of procaine (50–200 μg) were ineffective, but fluphenazine (25–200 μg) induced a moderate dose-dependent response from both the ACB and CP, although onset of action was more rapid and the duration markedly longer for the latter injections. Secondly, drugs were injected peripherally and intracerebrally to determine their ability to antagonize the marked hyperactivity induced by intra-ACB dopamine in the presence of nialamide. Two agents shown to induce catalepsy from the ACB, fluphenazine and morphine, antagonized dopamine hyperactivity when they were administered peripherally or directly into the ACB (0·1–0·2 mg kg^?1, i.p. or 3·1–25 μg fluphenazine and 1–5 mg^?1 kg, s.c. or 1–5 μg morphine), but only a weak antagonism occurred at much larger doses after intra-CP injections (100 μg fluphenazine and 50 μg morphine). Larger doses of intra-ACB pethidine (160 μg) and procaine (100–200 μg) also antagonized the dopamine response, but methadone was inactive. Again, the most potent and effective drugs in this test were fentanyl (1–5 μg), sufentanil (0·25–0·5μg) and carfentanil (0·05–0·1 μg). It is suggested that the ACB, and not the CP, is the site at which morphine acts to cause motor depression, whilst other narcotic drugs are able to act in both areas (although there is some indication of a further unspecified site of action for methadone). In contrast, the neuroleptic fluphenazine appears to differentially affect motor function via the ACB and CP, antagonizing a dopamine hyperactivity in the former and primarily inducing catalepsy from the latter nucleus.     

Modification of learning and memory in goldfish through the use of stimulant and depressant drugs

The effects of stimulants and depressants on learning and memory in goldfish were investigated in a series of four experiments. Avoidance performance in a two-way, light-cued shuttle task was significantly facilitated by intracranial injection of picrotoxin (1.50 mg/kg) but significantly impaired by injection of sodium pentobarbital (30 mg/kg) 5 min before 20 training trials were given. These drugs in the dosages used in the present study did not affect general activity of the fish. When identical doses of the drugs (along with saline controls) were given immediately after the first two of three 10-trial training sessions given 48 h apart, avoidance performance during the second and third sessions was facilitated and impaired by the posttrial injections of the stimulant and depressant drugs respectively. Moreover, it was found in an extended experiment that picrotoxin improved performance if injected 25 sec or 1 h after each of two 10-trial training sessions, but not if injected after a 4 h delay. Pentobarbital impaired performance if injected 25 sec after training, but not if injected after a 1/2 h or a 1 h delay.These stimulant and depressant effects demonstrated in goldfish were interpreted in terms of their effects on memory consolidation processes.This report is based upon dissertation research by the first author under the supervision of the second author in partial fulfillment of the requirements for the Ph. D. degree in the Department of Psychology at the University of Houston, 1972.     

Effect of depressant drugs on ECoG and on glutamate and ACh-excited cortical neurones in rats

At moderate levels of urethane anaesthesia, spontaneously active neurones in the rat cerebral cortex fired in bursts. The bursts coincided with spontaneous surface-positive waves in the electrocorticogram (ECoG) and the number of action potentials per burst was proportional to ECoG wave area. Initially, both iontophoretically applied glutamate or acetylcholine enhanced burst firing in spontaneously active neurones, or induced bursts of firing coincident with the ECoG waves in quiescent neurones. At deeper levels of urethane anaesthesia when the ECoG wave frequency was low, larger applications of both excitants induced firing between bursts.Administered systemically, a major effect of urethane. barbiturates, benzodiazepines and halothane was to reduce endogenous excitatory drives in the cortex and hence the response to iontophoretically applied excitants. Thus, they reduced the ECoG wave frequency and the associated burst firing, whether spontaneous or induced. Thiopentone and diazepam, but not urethane and halothane, also reduced the area of the ECoG wave and the number of action potentials per burst.Under appropriate conditions, central depressants also had an apparent muscarinic anticholinergic action, as manifested by reduction or abolition of acetylcholine, but not glutamate-induced, interburst firing and facilitated burst firing.     

A 50-year year history of new drugs in Japan: the developments of antituberculosis drugs and their influences on the epidemiological aspects

Drugs used in the treatment of tuberculosis (Tb) in Japan are investigated. Especially the chemotherapy for Tb and its influences on epidemiological aspects are discussed. 1. Various drugs were used for Tb patients before the World War II, but none was effective in curing this infectious disease. Creosote and guajacol groups were used frequently to relieve symptoms of pulmonary tuberculosis, but the disease could not cure itself. Because of the sacrifice of young patients, the mortality rate of Tb from 1935 to 1950 was ranked as the worst in Japan. So until the advent of chemotherapeutic drugs, Tb was known as the most formidable fatal plague. 2. Streptomycin (SM), the first effective chemotherapeutic drug, was imported into Japan and widely used from 1947. PAS in 1950 and isoniazid (INH) in 1952 were introduced to Tb therapy. The triple combination therapy of these drugs was considered the most favorable regimen for Tb from the 1950s to the early 1970s. Excellent results were obtained in this period. The mortality rate of Tb had dropped rapidly from its peak to half in 1952 and to a fourth in 1956 (Figs. 2, 3). 3. Several anti-Tb drugs, such as pyrazinamide ethionacide, ethambutol, and some antibiotics (kanamycin, cyloserine, and capreomycin) had been discovered and used in practice. These were not used singly, because of their weak clinical efficacies and severe side effects. They were mostly used to prevent the development of bacillus resistance to SM or INH. In the guidelines of the Japanese Society for Tuberculosis, in 1974. drugs used for Tb could be divided into two major categories: first-line and second-line groups. The second-line drugs included those that prevent a high resistance to the main (first-line) drugs. 4. Rifampicin (RFP), the most valuable drug for Tb, was introduced in therapy in Japan in 1971. RFP has a low incidence of severe side-effects, but because of the rapidity with which resistance may develop, it cannot be used alone. RFP in combination with INH is the most effective therapy for all forms of the disease. The guidelines, newly proposed in 1986 by the Japanese Society for Tuberculosis recommended the short 6-month course of treatment that used combination of RFP and INH. The advent of RFP had contributed to the cure of the individual patient, but it did not effect the mortality or the morbidity rate of Tb. Chemotherapy is the most effective means of suppressing tuberculosis, which was formerly nearly always fatal, but it could not completely eradicate the disease. Preventing the development of resistance to chemotherapeutic drugs might be a special problem.