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Sex-related differences in the effects of morphine and stress on visceral pain

The effect of morphine (in the absence of stress and after a type of naloxone-sensitive swim-stress) on the painful contractions induced by intraperitoneal injection of hypertonic saline was studied in four groups of rats: normally cycling females in oestrus, males, ovariectomized females and females subjected to constant light, to induce a hyperoestrogenemic state. In the absence of swim-stress, the sensitivity to morphine was maximum for males (i.e. analgesia was produced with the smallest doses). After swim-stress, both males and ovariectomized rats showed less sensitivity to the analgesic effect of morphine than normal females in oestrus, while females subjected to constant light were less sensitive. In females in natural oestrus, but not in the other groups, small doses (0.05 mg/kg) of morphine, paradoxically reduced the analgesic effect of swim-stress considerably. These results show the importance of sex-related factors in the sensitivity of visceral pain to morphine and stress. A selective role for endogenous androgens and oestrogens is likely.

Involvement of spinal κ opioid receptors in a type of footshock induced analgesia in mice

We have studied the effects of several opioid antagonists on a type of footshock stress-induced analgesia (FSIA) measured by the tail-flick test in male mice. Naloxone injected either subcutaneously (0.1-10 mg/kg) or intrathecally (1-20 micrograms) antagonized FSIA at higher doses than those that blocked a similar degree of analgesia induced by morphine. Intracerebroventricular (i.c.v.) naloxone (1-20 micrograms) did not modify the FSIA while antagonizing the i.c.v. morphine-induced analgesia. As a consequence, the antagonism of the FSIA by naloxone probably occurs at the level of the spinal cord and through receptors different than mu. The delta selective antagonist naltrindole (0.1-3 mg/kg s.c.) did not antagonize the analgesic effects of the stress. Nor-binaltorphimine, a kappa selective antagonist, blocked the FSIA when administered systemically (1-4 mg/kg i.p.) or locally (0.1-1 microgram i.t.). These results strongly suggest that spinal kappa opioid receptors are responsible for this type of endogenous analgesia.

Gender and test dependence of a type of kappa mediated stress induced analgesia in mice.

1. In male mice, 80 inescapable footshocks (S-80) induce analgesic responses measured by the tail flick test that are blocked by naloxone and the kappa opioid antagonist, nor-binaltorphimine. We now study the nociceptive responses, induced after this particular stress, measured by the writhing test, the tail immersion test and a high intensity tail immersion test both in male and female mice. 2. In stressed males, analgesic responses are seen in all the nociceptive tests. Naloxone (10 mg/kg) does not prevent them. 3. In stressed females, in contrast with males, no analgesia is produced in the tail flick test. The writhing test and the tail immersion test registered analgesic responses that were not prevented by naloxone (10 mg/kg). 4. We conclude that only the antinociceptive kappa opioid mediated component of the stress we study is strongly dependent on gender, in contrast to other types of analgesia triggered by the same stress.

Opioid footshock-induced analgesia in mice acutely falls by stress prolongation

The application of 80 footshocks (S-80) to mice induces a decrease in nociceptive responses as measured by the tail-flick test, which is opioid mediated as well as prevented by naloxone (10 mg/kg, SC). When the stress is prolonged up to 240 shocks (S-240) (i.e., from 6 min 40 s to 20 min), no analgesia can be seen immediately after the stress. We have examined the two most obvious possibilities, but they do not seem to be responsible for this fact. When morphine (1-5 mg/kg IP) is injected in the S-240 situation, a potentiation of its analgesic effects is seen, so that a desensitization of mu opioid receptors is unlikely. On the other hand, although cortisol (3-30 mg/kg IP) inhibits the analgesic response to S-80, metyrapone (40 and 80 mg/kg IP) and cortexolone (3-18 mg/kg IP) do not cause S-240 to be analgesic. Thus, an increase of endogenous glucocorticoids released during the long-duration stress does not seem responsible for the lack of analgesia after S-240.

Common definition for categories of clinical research: a prerequisite for a survey on regulatory requirements by the European Clinical Research Infrastructures Network (ECRIN)

BackgroundThorough knowledge of the regulatory requirements is a challenging prerequisite for conducting multinational clinical studies in Europe given their complexity and heterogeneity in regulation and perception across the EU member states.MethodsIn order to summarise the current situation in relation to the wide spectrum of clinical research, the European Clinical Research Infrastructures Network (ECRIN) developed a multinational survey in ten European countries. However a lack of common classification framework for major categories of clinical research was identified, and therefore reaching an agreement on a common classification was the initial step in the development of the survey.ResultsThe ECRIN transnational working group on regulation, composed of experts in the field of clinical research from ten European countries, defined seven major categories of clinical research that seem relevant from both the regulatory and the scientific points of view, and correspond to congruent definitions in all countries: clinical trials on medicinal products; clinical trials on medical devices; other therapeutic trials (including surgery trials, transplantation trials, transfusion trials, trials with cell therapy, etc.); diagnostic studies; clinical research on nutrition; other interventional clinical research (including trials in complementary and alternative medicine, trials with collection of blood or tissue samples, physiology studies, etc.); and epidemiology studies. Our classification was essential to develop a survey focused on protocol submission to ethics committees and competent authorities, procedures for amendments, requirements for sponsor and insurance, and adverse event reporting following five main phases: drafting, consensus, data collection, validation, and finalising.ConclusionThe list of clinical research categories as used for the survey could serve as a contribution to the, much needed, task of harmonisation and simplification of the regulatory requirements for clinical research in Europe.

Influence of some inhibitors of arachidonic acid metabolism on oxytocin contractions in the isolated testicular capsule of the rat.

Oxytocin (50-750 nM) contracted the isolated testicular capsule of the rat. Mepacrine, a phospholipase A2 inhibitor (3 X 10(-5) M) and the lipoxygenase inhibitor nordihydroguaiaretic acid (10(-5) M) inhibited this response whereas the cyclooxygenase inhibitor, diclofenac sodium (10(-5) M), and the thromboxane synthetase inhibitor imidazole (10(-5) M) did not. It appears that metabolites of arachidonic acid dependent on lipoxygenase are involved in the contractile response of the rat testicular capsule to oxytocin.

Interactions between oxytocin- and calcium-modifying agents in the rat testicular capsule in vitro

We have studied the effect of drugs which affect the movement of calcium on the contractions induced by 50 and 200 nM oxytocin in the isolated testicular capsule of the rat. The ED50 for oxytocin in this preparation was 188 (+/- 66 S.E.) nM and the maximal contraction induced by oxytocin was smaller than that obtained with 10 microM of the calcium ionophore, A23187. Lanthanum (10 mM), cobalt (2 mM), EGTA (3.5 and 5 nM, 30 s exposure) and a decrease in the calcium concentration of the medium reduced the oxytocin response. The response was completely abolished after prolonged incubation with EGTA (2 mM) in a calcium-free medium. The calcium blocking agents, nifedipine and flunarizine, and the agonist, Bay K 8644, did not modify the responses to oxytocin. Verapamil, at possibly non-specific doses (10 microM), reduced the contractions while diltiazem (0.1 mM), in a prazosin (10 microM)-resistant way, and nickel (0.1 mM) increased them. Both modifiers of intracellular calcium that were used namely TMB-8 (10 microM), in a calcium-free medium, and dantrolene sodium (10 and 30 microM), with and without calcium in the medium, decreased the oxytocin response. On the whole, it seems as if both intra- and extracellular calcium were involved in the contractile effect of oxytocin, although extracellular calcium does not seem to gain access to the cell through voltage-dependent calcium channels sensitive to selective calcium entry blockers.

Interaction among alfaxalone, pregnenolone sulfate, and two GABAA agonists on hippocampal slices

SummaryGABAA agonists do not respond to the same degree to allosteric modulators of the GABAA receptor complex such as benzodiazepines. We report there the effects of two steroids (alfaxalone and pregnenolone sulfate) on the inhibition induced by two GABAA agonists, 3-amino propane sulphonic acid (3-APS) and muscimol, on the extracellular evoked potentials obtained in CA1 of mice hippocampi. Alfaxalone (1µM) potentiates the effects of both agonists, although incubation times longer than 15 minutes are required to potentiate the inhibitory effect of muscimol. Lower doses of pregnenolone sulfate at shorter incubation periods are able to inhibit the effects produced by single doses of 3-APS as compared to muscimol (15µM during 5 minvs 30µM during 5 min). Our results confirm the possibility that there might be differences in the interaction between GABAA agonists and modulatory steroids.

Statins Use and Risk of Cataracts: Firm Conclusions Are Still Far Off

The authors analyzed 14 studies including both rando-mized and observational data and observed a significantdecreased risk of cataracts with statins use. Briefly, the authorsconcluded that ‘‘this meta-analysis indicates a clinically rele-vant protective effect in preventing cataracts (...), it includesall published reports on the topic and that the effect is consis-tent when analyzed from various aspects.’’ However, we wouldlike to reflect on some limitations that may impact on theresults presented by the authors.We acknowledge that systematic reviews and meta-analyses have become more widely accepted as a useful toolto critically assess the totality of evidence in a research ques-tion. When performed well and reported transparently, incor-porating explicit and detailed methods and results, theyproduce information that can have undoubtedly major impacton medical practice.

Perfil clínico-epidemiológico de pacientes que inician terapia intensiva con estatinas para la prevención secundaria de enfermedad vascular en España

Background: The new recommendations regarding the utilization of high potency statins (intensive therapy) for the treatment of cardiovascular disease have been based on the extrapolation of data coming from clinical trials. The objective is to describe the clinical-epidemiological profile of statin therapy users for the secondary prevention of cardiovascular disease in Spain and to examine the predictors for intensive therapy initiation. Methods: Cross-sectional study from a sample of 88,751 patients aged ≥45 years-old with previous cardiovascular disease which initiated statin therapy between 1st January 2007 to 31st December 2011. Dose treatments >40 mg simvastatin daily (or equivalent dose if different statin) were considered intensive therapy treatment. Multivariable logistic regression models were built for dependent summary variables to examine the association between and the intensive therapy utilization (vs low-moderate intensity therapy). Results: 16,857 adult patients receiving a first prescription of statin for the secondary prevention of cardiovascular diseases were identified. Predictors for intensive therapy initiation were year of statin prescription, male gender (adjusted OR: 1.70; 95% CI: 1.44-2.00), age >75 years-old (1.39; 1.15-1.69), previous history of coronary artery disease (1.71; 1.44-2.04), previous history of transient ischemic attack (1.24; 0,97-1.59), smoking (1.62; 1.34-1.95), hypertension (1.41; 1.20-1.65) and recent use of fibrates (2.32; 1.27-4.26). Conclusions: The onset of intensive therapy with statins in secondary was determined by the type of vascular event and age (>75 years-old in which the risk benefit balance could be controversial). No statistically significant differences were found according to the LDL-c levels.