A METHOD FOR MEASURING THE NARCOTIC ACTION OF CHEMICALS USING THE GRAIN WEEVIL, CALANDRA GRANARIA

A method of measuring narcotic potency is described. Grain weevils ( Calandra granaria ) are exposed to the narcotic vapour in 2l. round-bottomed flasks illuminated from the bottom, and narcotic potency measured as number of grain weevils so affected as to be unable to climb the glass walls. Some common anaesthetics have been examined as an illustration of this method. Results are fitted by the probit plane
Y= A + b ₁ log α+ b ₂ log t ,
where Y = a function of the number of insects affected (probit); α= the thermodynamic concentration of the narcotic vapour; t = time of exposure of insects to the narcotic vapour. The values of the coefficients b ₁ and b₂ are discussed in relation to the biological action of the narcotic vapours.     

Female Narcotic Addicts: A Follow-up Study of Criminal and Addiction Careers

A sample of 66 female narcotic addicts first examined in prison in 1967-8 was followed-up four years later. At the end of the period of follow-up 36% were off narcotics, 32% were still addicted, and 15% had died. Altogether 62% committed further offences. Drug offences and offences against property were almost equally frequent and accounted for over two-thirds of all convictions. There was no evidence of a link between prostitution and narcotic addiction. A significant association was found between continued delinquency and continued addiction during the period of follow-up. Addiction career and criminal career coincided in over three-quarters of the subjects, who tended either to continue manifesting both forms of deviant behaviour (46%) or to relinquish both (30%). The findings are in keeping with the view that narcotic addiction and crime are not causally related but may be parallel effects of common underlying factors leading to social deviance.     

Structural basis of heroin and cocaine metabolism by a promiscuous human drug-processing enzyme

We present the first crystal structures of a human protein bound to analogs of cocaine and heroin. Human carboxylesterase 1 (hCE1) is a broad-spectrum bioscavenger that catalyzes the hydrolysis of heroin and cocaine, and the detoxification of organophosphate chemical weapons, such as sarin, soman and tabun. Crystal structures of the hCE1 glycoprotein in complex with the cocaine analog homatropine and the heroin analog naloxone provide explicit details about narcotic metabolism in humans. The hCE1 active site contains both specific and promiscuous compartments, which enable the enzyme to act on structurally distinct chemicals. A selective surface ligand-binding site regulates the trimer-hexamer equilibrium of hCE1 and allows each hCE1 monomer to bind two narcotic molecules simultaneously. The bioscavenger properties of hCE1 can likely be used to treat both narcotic overdose and chemical weapon exposure.     

Selective interaction of drugs with a discriminable stimulus associated with narcotic actions

Rats were trained to bar press on either one of two levers depending on whether they received an injection of morphine (10 mg/kg) or saline. The rats responded on the morphine-correct lever when injected with another narcotic, fentanyl, but responded on the saline-correct lever when injected with a narcotic antagonist or another CNS active, but non-narcotic, drug (e.g., amphetamine, apomorphine). The narcotic antagonist, naloxone, prevented the occurrence of the narcotic discriminable stimulus, but the rats responded on the morphine-correct lever when injected with morphine plus any of a number of potent CNS active, but non-narcotic compounds. These results are discussed with reference to the specificity of this procedure for detecting drugs with narcotic agonist or antagonist properties.     

Narcotic antagonist activity of several metabolites of naloxone and naltrexone tested in morphine dependent mice (38558).

A rabbit liver enzyme system was used to produce the 6beta-OH reduced metabolites of naloxone and naltrexone. GC analysis indicated the presence of some 6alpha-OH metabolite in these samples. The narcotic antagonist activity of these 6beta-OH metabolite samples were compared to naloxone, naltrexone and standard 6alpha-OH naltrexone (EN-2260A) using the jumping response of morphine pellet implanted mice. For the naloxone series, the potencies were: Naloxone greater than EN 2265A greater than 6 beta-OH maloxone. For the naltrexone series: Naltrexone greater than EN 2260A greater than beta-OH naltrexone. The low potency of the reduced metabolites the rapid onset of action of the parent compounds militate against the formation of these metabolites contributing substantially to the overall narcotic antagonist action of the parent compounds.     

A comparison of narcotic analgesics with neuroleptics on behavioral measures of dopaminergic activity.

Because of many practical difficulties which are encountered in obtaining direct evidence for the involvement of brain neurotransmitters in the action of narcotic drugs, several indirect procedures are often employed. One such method is to compare on the same measures of drug action the narcotic drugs with a non-narcotic drug having a known mechanism of action. Haloperidol is a prototype non-narcotic drug which blocks dopamine receptors and many of its actions are believed to be associated with this receptor blockade. In this paper we compare various actions of haloperidol or other neuroleptics with morphine or other narcotic analgesics using the same testing parameters. We hope that such a comparison would evaluate the role of dopamine receptors in narcotic action and narcotic dependence. This discussion is limited only to the behavioral measures as a comparison of neurochemical measures was recently reviewed in another paper (1).     

Differential reduction of morphine-withdrawal body shakes by butaclamol enantiomers

Rats withdrawn from continuous morphine infusion showed reliable occurrence of withdrawal body shakes. This sign of narcotic withdrawal was inhibited by the neuroleptic drug, (+) butaclamol. (?) Butaclamol was inactive. (+) Butaclamol activity was not antagonized by naloxone (5 mg/kg). The anti-withdrawal mechanism of (+) butaclamol is discussed in terms of effects on dopamine and narcotic receptors.The butyrophenone neuroleptic, haloperidol, has been used successfully to reduce signs of narcotic withdrawal in laboratory animals (1–4) and human addicts (5). Other neuroleptics of the butyrophenone type also show anti-withdrawal action (6, 7). The mechanism of action of these neuroleptics in blocking narcotic withdrawal is not understood. Butaclamol is a new neuroleptic drug that is available in two enantiomers and only (+) butaclamol possesses neuroleptic activity (8–10). Because of its demonstrated stereo-specificity in producing its pharmacological action, we employed this drug to establish specificity of action of neuroleptics in blocking narcotic withdrawal.     

A systems and control theory approach to dynamic neurotransmitter balance in narcotic addiction and narcotic antagonism.

We have formulated a pharmacological-physiological systems analysis and control theory based on interactive neuronal feedback loops (the effects of endogenous neurochemical diseases and exogenous CNS drugs on neurotransmitter synthesis and release, reuptake and metabolism) for normal, abnormal and catastrophic situations.We set up the systems diagrams for neurotransmitter systems and in that single framework were able to describe endogenous neurochemical disorders, the effect that their drug treatment modalities had on the dynamic neurochemical balance and the effect other CNS drugs such as narcotics and narcotic antagonists had on neurochemical balance. This led to a hypothesis that narcotic addiction is caused by negative feedback induced increase in synthesis and release of certain neurotransmitters, tolerance arises in a related manner, narcotic withdrawal symptoms are caused by out-of-phase feedback and a major mechanism of antagonist action of narcotic antagonists is not merely competitive displacement of a narcotic from its “receptor site” but rather is due to an increase in the concentration of catecholamines in the synaptic cleft.     

Enhancement of apomorphine-induced climbing in mice by reversible and irreversible narcotic antagonist drugs

Apomorphine produced a characteristic climbing syndrome in mice. Pretreatment of mice with increasing doses of the reversible narcotic antagonist naloxone resulted in a dose-related enhancement of this activity. Central microinjection of mice with the irreversible narcotic antagonist drug chlornaltrexamine also resulted in significant potentiation of apomorphine-induced climbing for up to fourteen days following pretreatment. These data indicate that narcotic antagonist drugs of both reversible and irreversible types are capable of enhancing this dopaminergic drug effect in mice.     

Drug Taking in Adolescent Girls: Factors Associated with the Progression to Narcotic Use

A follow-up study of girls in a London remand home during the years 1966-8 showed that 20·6% of those taking non-narcotic drugs on admission, but only 1% of non-drug-taking control admissions, had used narcotics by June 1970. Narcotic use on admission and progression to narcotic use were associated with frequent drug taking, marked involvement in a drug milieu, and a high incidence of personal morbidity. Adolescents who use illicit drugs and have a history of court appearances for any reason are particularly vulnerable to subsequent narcotic usage and other forms of serious drug abuse.     

Narcotic dependence, narcotic action and dopamine receptors.

Acute systematic administration of narcotic analgesics increases the firing rate of nerve cells in the zona compacta of the substantia nigra, causes an increase in the rate of dopamine turnover in striatal and mesolimbic areas of the brain, stimulates prolactin release, inhibits brain self-stimulation and discriminated shock-avoidance, blocks cardiovascular effects of systemically injected dopamine, blocks aggression as well as compulsive jumping in mice treated with DOPA and amphetamine, antagonizes stereotypy induced by apomorphine or amphetamine, and blocks apomorphine-induced vomiting in dogs. Chronic administration of narcotic analgesics results in withdrawal signs upon the cessation of the drug administration. These signs include, tolerance to the increase in striatal dopamine turnover caused by narcotic analgesics or haloperidol, aggressive behaviors which are further stimulated by directly or indirectly acting dopamine-receptor agonists and are blocked by dopamine-receptor blockers, facilitation of recovery from the “lateral hypothalamic syndrome”, an increase in basal levels of striatal adenylate cyclase which shows greater sensitivity to dopamine, and, an enhanced sensitivity to apomorphine-induced reduction of dopamine turnover. It is therefore, concluded that acute administration of narcotic drugs results in an inhibition of dopamine-receptor activity while chronic administration of these drugs results in an increased response of these dopamine receptors to dopamine agonists. Recent experiments on the interaction of other drugs with narcotic analgesics suggest that, unlike the direct action of neuroleptics on the dopamine receptors, the narcotic action on dopamine receptors is indirect.     

Morphine interference with noradrenaline-mediated inhibition from the locus coeruleus.

The effect of morphine on inhibition of relay neurons in the spinal trigeminal nucleus (STN) produced by conditioning stimulation of the locus coeruleus (LC) was studied in cats. Alterations in orthodromic and antidromic spike generations in STN were absent. However, the narcotic did selectively reduce the inhibitory effect of LC conditioning stimulation on STN neurons without affecting that of the sensory ortex. Nalorphine partially antagonized this effect of the narcotic. A reduction in orthodromic spike number of STN neurons induced by intraventricular noradrenaline in reserpinized animals was unaltered by morphine treatment. These data demonstrate that morphine selectively interferes with LC-induced inhibition of STN neurons and in addition may block noradrenaline release from terminals of LC neurons.     

Stereospecific aversive property of narcotic antagonists in morphine-free rats

If endogenous, morphine-like substances have physiological functions, narcotic antagonists should have effects $\text{in vivo}$ even in the absence of exogenous, narcotic agonists. This hypothesis was supported by studies of taste aversions conditioned with narcotic antagonists; rats drank smaller amounts of distinctively flavoured solutions when their consumption on previous occasions preceded injections of naloxone (1–10 mg/kg), naltrexone (3.2 mg/kg), Mr 1452 (10 mg/kg) or (-)-BC-2860 (10 mg/kg). Stereoisomers (i.e. Mr 1453, (+)-BC-2860) which were inactive as narcotic antagonists did not induce significant taste aversions. It was suggested that the consistency and stereospecificity of aversion with the antagonists gave some support to interpretations in terms of antagonist actions at receptors for endogenous opioids.     

Comprehensive screening method for the qualitative detection of narcotics and stimulants using single step derivatisation

A selective and sensitive screening method for the detection of prohibited narcotic and stimulating agents in doping control is described and validated. This method is suitable for the detection of all narcotic agents mentioned on the World Anti-Doping Agency (WADA) doping list in addition to numerous stimulants. The analytes are extracted from urine by a combined extraction procedure using CH(2)Cl(2)/MeOH (9/1, v/v) and t-butylmethyl ether as extraction solvents at pH 9.5 and 14, respectively. Prior to GC-MS analysis the obtained residues are combined and derivatised with MSTFA. The mass spectrometer is operated in the full scan mode in the range between m/z 40 and 550. The obtained limits of detection (LOD) for all components included in this extensive screening method are in the range 20-500 ng/ml, which is in compliance with the requirements set by WADA. Besides narcotic and stimulating agents, this method is also capable of detecting several agents with anti-estrogenic activity and some beta-agonists. As an example, a positive identification of hydroxyl-methoxy-tamoxyfen is shown.     

Nonspecific arousal with noloxone.

The use of naloxone, the first narcotic antagonist devoid of agonist properties, has become the standard way of treating narcotic-induced coma and respiratory depression. This report concerns a patient in whom a narcotic effect was unlikely, but who nevetheless showed arousal after naloxone administration.     

Presence of a non-peptide morphine-like compound in human cerebrospinal fluid

A non-peptide morphine-like compound (MLC) is present in human ventricular and lumbar cerebro spinal fluid (CSF). None of the patients studied had received any narcotic drugs. MLC was determined by using a radioimmunoassay produced for morphine.     

Human plasma-mediated hypoxic activation of indolequinone-based naloxone pro-drugs

Hypoxia is known to occur in tissues in response to narcotic analgesic therapy using as a result of respiratory depression. The aim of this study was to synthesize a narcotic antagonist pro-drug that can be activated by tissue hypoxia to prevent the damage associated with respiratory depression. We synthesized three different pro-drugs of the narcotic antagonist naloxone utilizing indolequinone as the hypoxia-sensitive moiety. The indolequinone structure in the pro-drugs was designed to have an open reactive point at the N-1 position offering the possibility of further conjugation with macromolecules to modify the bio-availability of these pro-drugs in vivo. A pro-drug (labeled 1) where naloxone and the indolequinone moiety were linked through a carbonate bond was rapidly hydrolyzed in phosphate buffered saline. However, two additional pro-drugs (labeled 2 and 3) having carbamate linkers were stable in phosphate buffered saline for 24 h. The reductive release of naloxone from the pro-drugs was achieved in the presence of the bio-reductive enzyme DT-Diaphorase, with about 80% release occurring from the two pro-drugs in 24 h. More than 99% of naloxone was released from pro-drug 2 in 30% human plasma, however the release only occurred under hypoxic conditions. This system provides a potential means for feedback control to counter critical respiratory depression induced by narcotic analgesics.     

A possible molecular mechanism of the narcotic action of noble gases

A molecular mechanism of the narcotic action of noble gases is suggested, which is based on the fact that noble gas atoms change the orientation of water molecules absorbed on the surface of axon membrane. The resulting change in the transmembrane potential deteriorates the propagation of nerve pulse.     

右美沙芬用于80 例胆囊切除术后镇痛的临床观察与分析

目的:观察和分析右美沙芬用于80例胆囊切除术的超前镇痛作用临床疗效。方法:将2009年8月~2011年11月我院接收并确诊的80例ASAⅠ~Ⅱ级择期行腹腔镜胆囊切除手术患者,按患者意愿随机分为两组。治疗组40例,麻醉诱导前30min肌注右美沙芬20mg;对照组40例,麻醉诱导前30min肌注等量生理盐水。术中监测患者的血氧饱和度值、心率、平均动脉压等;术后统计术中(除麻醉诱导外)镇痛药的用量,并对患者伤口疼痛进行VAS评分。结果:对照组术中镇痛药(除麻醉诱导外)用量大于治疗组,但二者无统计学差异(P>0.05),术后伤口无痛者治疗组明显多于对照组,治疗组VAS评分显著低于对照组,差异有统计学意义(P<0.01)。结论:右美沙芬对于胆囊切除术有超前镇痛的作用,麻醉诱导前30 min肌注20mg,不仅可以减少术中镇痛药的用量,而且在更大程度上减轻了术后患者伤口的疼痛。