Incomplete, asymmetric, and route-dependent cross-tolerance between oxycodone and morphine in the Dark Agouti rat

Our previous studies indicate that oxycodone is a putative kappa-opioid agonist, whereas morphine is a well documented mu-opioid agonist. Because there is limited information regarding the development of tolerance to oxycodone, this study was designed to 1) document the development of tolerance to the antinociceptive effects of chronically infused i.v. oxycodone relative to that for i.v. morphine and 2) quantify the degree of antinociceptive cross-tolerance between morphine and oxycodone in adult male Dark Agouti (DA) rats. Antinociceptive testing was performed using the tail-flick latency test. Complete antinociceptive tolerance was achieved in 48 to 84 h after chronic infusion of equi-antinociceptive doses of i.v. oxycodone (2.5 mg/24 h and 5 mg/24 h) and i.v. morphine (10 mg/24 h and 20 mg/24 h, respectively). Dose-response curves for bolus doses of i.v. and i.c.v. morphine and oxycodone were produced in naive, morphine-tolerant, and oxycodone-tolerant rats. Consistent with our previous findings that oxycodone and morphine produce their intrinsic antinociceptive effects through distinctly different opioid receptor populations, there was no discernible cross-tolerance when i.c.v. oxycodone was given to morphine-tolerant rats. Similarly, only a low degree of cross-tolerance (approximate to 24%) was observed after i.v. oxycodone administration to morphine-tolerant rats. By contrast, both i.v. and i.c.v. morphine showed a high degree of cross-tolerance (approximate to 71% and approximate to 54%, respectively) in rats rendered tolerant to oxycodone. Taken together, these findings suggest that, after parenteral but not supraspinal administration, oxycodone is metabolized to a mu-opioid agonist metabolite, thereby explaining asymmetric and incomplete cross-tolerance between oxycodone and morphine.

Halogenated terpenoids. XXXII - Pentabromides from limonene two 1,2,8,9,9-pentabromo-p-menthanes

The problems of structure in diastereomers where one chiral centre is remote from another are further investigated in the 1,2,8,9,9-pentabromo-p-menthane series.

The advantages of theft over toil: The design inference and arguing from ignorance

Intelligent design theorist William Dembski has proposed an explanatory filter for distinguishing between events due to chance, lawful regularity or design. We show that if Dembski's filter were adopted as a scientific heuristic, some classical developments in science would not be rational, and that Dembski's assertion that the filter reliably identifies rarefied design requires ignoring the state of background knowledge. If background information changes even slightly, the filter's conclusion will vary wildly. Dembski fails to overcome Hume's objections to arguments from design.

Ecology - Is coral bleaching really adaptive?

From an experiment in which corals are transplanted between two depths on a Panamanian coral reef, Baker1 infers that bleaching may sometimes help reef corals to survive environmental change. Although Baker's results hint at further mechanisms by which reef-building corals may acclimatize to changing light conditions, we do not consider that the evidence supports his inference.

Hair morphine concentrations of fatal heroin overdose cases and living heroin users

Aims To compare heroin and other opiate use of heroin overdose fatalities, current street heroin users and drug-free therapeutic community clients. Design Hair morphine concentrations that assess heroin use and other opiate use in the 2 months preceding interview or death were compared between heroin overdose fatalities diagnosed by forensic pathologists (fOD) (n = 42), current street heroin users (CU) (n = 100) and presumably abstinent heroin users in a drug-free therapeutic community (TC) (n = 50). Setting Sydney, Australia. Findings The mean age and gender breakdown of the three samples were 32.3 years, 83% male (FOD), 28.7 years, 58% male (CU) and 28.6 years, 60% male (TC). The median blood morphine concentration among the FOD cases was 0.35 mg/l, and 82% also had other drugs detected. There were large differences between the three groups in hair morphine concentrations, with the CU group (2.10 ng/mg) having concentration approximately four times that of the FOD group (0.53 ng/mg), which in turn had a concentration approximately six times that of the TC group (0.09 ng/mg). There were no significant differences between males and females in hair concentrations within any of the groups. Hair morphine concentrations were correlated significantly with blood morphine concentrations among FOD cases (r = 0.54), and self-reported heroin use among living participants (r = 0.57). Conclusions The results indicate that fatal cases had a lower degree of chronic opiate intake than the active street users, but they were not abstinent during this period.

Women victims of assault: Age differences in victim-aggressor relationship and location

This article presents the findings from a secondary analysis of the 1991 Queensland Crime Victim Survey. Although now more than 10 years old, this survey still has validity as it remains the largest of its kind conducted in Queensland, and it is a rich source of information about the experiences of victims of violence. The study investigated how the experiences of younger female assault victims differ from older female victims in terms of their relationship with their aggressor and the assault location. The following factors were examined: whether or not the assault occurred (a) at the hands of a partner or former partner, (b) in a private dwelling, (c) in a public place, and (d) in a leisure venue away from home. Results pointed to important differences between younger and older women in terms of their experiences of violence. Teenage women reported significantly more assaults in public places compared with older women, and were less likely to be assaulted in their own dwelling. Also, trends in the data suggested that compared to older women, teenage women were more likely to be assaulted in leisure venues away from home, and were less likely to be assaulted by partners or former partners. Considering that young women are at a much higher risk than older women of being assaulted, consideration of these age differences may be helpful in the design of violence prevention strategies. In particular, more attention should be paid to the public place prevention of violence against young women.

The rational reconstruction of the research program on classic rationalism: Locke and the empiricist approach

This article intends to rationally reconstruct Locke`s theory of knowledge as incorporated in a research program concerning the nature and structure of the theories and models of rationality. In previous articles we argued that the rationalist program can be subdivided into the classical rationalistic subprogram, which includes the knowledge theories of Descartes, Locke, Hume and Kant, the neoclassical subprogram, which includes the approaches of Duhem, Poincare and Mach, and the critical subprogram of Popper. The subdivision results from the different views of rationality proposed by each one of these subprograms, as well as from the tools made available by each one of them, containing theoretical instruments used to arrange, organize and develop the discussion on rationality, the main one of which is the structure of solution of problems. In this essay we intend to reconstruct the assumptions of Locke`s theory of knowledge, which in our view belongs to the classical rationalistic subprogram because it shares with it the thesis of the identity of (scientific) knowledge and certain knowledge.

Maturation temperature and rainfall influence seed dormancy characteristics of annual ryegrass (Lolium rigidum)

The role of temperature and rainfall during seed development in modulating subsequent seed dormancy status was studied for Lolium rigidum Gaud. (annual ryegrass). Climatic parameters relating to geographic origin were compared with annual ryegrass seed dormancy characteristics for seeds collected from 12 sites across the southern Western Australian cropping region. Seed germination was tested soon after collection and periodically during subsequent after-ripening. Temperature in the year of seed development and long-term rainfall patterns showed correlations with aspects of seed dormancy, particularly the proportion of seeds remaining dormant following 5 months of after-ripening. Consequently, for one population the temperature (warm/cool) and water supply (adequate/reduced) during seed development were manipulated to investigate the role of maternal environment in the quantity and dormancy characteristics of seeds produced. Seeds from plants grown at warm temperatures were fewer in number, weighed less, and were less dormant than those from plants grown at cool temperature. Seeds that developed under both cool temperature and reduced moisture conditions lost dormancy faster than seeds from well-watered plants. Seed maturation environment, particularly temperature, can have a significant effect on annual ryegrass seed numbers and seed dormancy characteristics.

The unconditioned fear produced by morphine withdrawal is regulated by mu- and kappa-opioid receptors in the midbrain tectum

We have recently shown that morphine withdrawal sensitizes the neural substrates of fear in the midbrain tectum structures-the dorsal periaqueductal gray (dPAG) and inferior colliculus (IC). In the present study, we investigated the role of mu- and kappa-opioid receptors in the mediation of these effects. Periadolescent rats chronically treated with morphine (10 mg/kg; s.c.) twice daily for 10 days were implanted with an electrode glued to a guide-cannula into the dPAG or the IC. Forty-eight hours after the interruption of this treatment, the effects of intra-dPAG or intra-IC microinjections of [D-Ala(2) N-Me-Phe(4) Gly(5)-ol]-enkephalin (DAMGO; 0.6 and 1 nmol/0.2 mu l) - a selective mu-receptor agonist - or nor-binaltorphimine (BNI; 2.5 and 5 mu g/0.2 mu l) - a selective K-receptor antagonist with tardive action - on the freezing and escape thresholds determined by electrical stimulation of the dPAG and the IC were examined. For both structures, morphine withdrawal produced pro-aversive effects. DAMGO and BNI had antiaversive effects when injected into the dPAG and IC of non-dependent rats. In morphine-withdrawn rats, only BNI continued to promote antiaversive effects in both structures. Whereas DAMGO lost its antiaversive efficacy when injected into the dPAG, only its highest dose promoted antiaversive effects in the IC of morphine-withdrawn rats, suggesting the development of an apparent tolerance. Thus, the enhanced reactivity of the midbrain tectum in morphine-withdrawn periadolescent rats may be due, at least partially, to an impairment of the inhibitory influence of mechanisms mediated by mu-receptors on the neural substrates of fear in this region. (C) 2009 Elsevier B.V. All rights reserved.