Acute effects of vitamin B6 and fixed combinations of vitamin B1, B6, B12 on nociceptive activity evoked in the rat thalamus: Dose-response relationship and combinations with morphine and paracetamol

Summary Nociceptive activity was elicited in neurones of the thalamus by supramaximal electrical stimulation of afferent C fibres in the sural nerve of rats under urethane anesthesia. The fixed combination of vitamin B₁, B₆, B₁₂ (Neurobion^®) as well as of vitamin B₆ administered by i.p. injection dose-dependently reduced the evoked nociceptive activity. The ED₅₀ of Neurobion^® is 4.6 ml/kg (at 100 min after injection) and that of vitamin B₆ is 189mg/kg (at 90 min after injection). The minimum effective doses of Neurobion^® and vitamin B₆ are 0.5 ml/kg and 40 mg/kg, respectively. When Neurobion^® or vitamin B₆ were given at their minimum effective doses, and the minimum effective doses of morphine (0.025 mg/kg) or paracetamol (5 mg/kg) were injected i.v. 80 min later, i.e., when the maximum effect of higher doses of Neurobion^® or vitamin B₆was about to develop, no supraadditive effect developed. It is concluded that the antinociceptive effect caused by a single injection of Neurobion^® is largely due to vitamin B₆. Vitamin B₁₂ may contribute to this effect, whereas vitamin B₁ alone exhibited only a slight effect on nociception. Moreover, it appears that Neurobion^® produces its antinociceptive effect after a single injection and after repeated administration during several days by different mechanisms so that the effect of analgesic agents is not enhanced following a single injection of Neurobion^® but may be enhanced after repeated administration of the compound.     

The role of descending inhibition in the antinociceptive effects of the pyrazolone derivatives,metamizol (dipyrone) and aminophenazone (“Pyramidon”)

Summary The study was carried out to provide further evidence that the two pyrazolone derivatives, metamizol and aminophenazone, produce central antinociceptive effects by stimulating inhibition descending from the periaqueductal grey (PAG) to the spinal cord. Experiments were carried out on rats in which the tail-flick response to radiant heat, nociceptive activity in ascending axons of the spinal cord, and activity of neurones in the PAG and the substantia nigra were studied. Microinjection of procaine (10 g) into the PAG reduced the tail-flick latency and abolished the increase in latency caused by i.p. injection of metamizol (40 mg/kg) and aminophenazone (150 mg/kg); it did not significantly reduce the antinociceptive effect of i.p. injection of morphine (2 mg/kg). Threshold doses of morphine (1 and 2 g) administered by intrathecal (i.t.) injection potentiated the effect of threshold doses of metamizol injected i.p. (10 mg/ kg) or into the PAG (10 g) in the tail-flick test. Morphine (2 g) injected i.t. potentiated the effect of i.v. injection of metamizol (80 mg/kg) on nociceptive activity in ascending axons by eliminating the stimulant effect of metamizol on about one third of the axons. Threshold doses of morphine injected i.t. failed to potentiate the antinociceptive effect of aminophenazone (50 mg/kg) injected i.p. in the tail-flick test. The results support the view that metamizol and aminophenazone activate pathways descending from the PAG and exerting an inhibitory effect on nociceptive impulse transmission at the spinal level.Supported by the Schwerpunkt Nociception and Schmerz of the Deutsche Forschungsgemeinschaft Send offprint requests to I. Jurna at the above address     

Geburtsschmerz—Entstehung,Erregungsleitung und Folgen

In the first stage of labor, pain is caused by distension of the cervix and low uterine segments in combination with isometric contraction of the uterus. Pain in the second stage of labor is dominated by tissue damage in the pelvis and perineum. Labor pain is due to an activation of nociceptors partly resulting from ischemia. The impulses thus generated are conducted into the spinal cord by afferent C fibers from the cervix and lower uterine segments, and by afferent Adelta and C fibers from the pelvis, pelvic organs and perineum. Labor pain is referred to the dermatomes T(11) and T(12) in the early stage of labor. It spreads to the neighboring dermatomes T(10) and L(1) and eventually involves the dermatomes S(2-4) during the second stage of labor and delivery. As in any other type of pain, labor pain stimulates respiration. This reduces the CO(2) concentration in the blood so that, in pain-free periods, respiratory stimulation is lacking and, in consequence, oxygen concentration in maternal and fetal blood is lowered. Pain-induced sympathetic activation will increase cardiac output in a way that may be deleterious in parturients with heart disease, eclampsia and anemia. Moreover, slowing of gastric emptying may cause nausea and vomiting, and slowing of intestinal propulsive movements may result in ileus and oliguria. An increase in plasma catecholamines and glucocorticoids influences uterine contractions. The amount of beta-endorphin released from the pituitary and placenta into the blood is relatively high but obviously not sufficient to depress pain effectively. Adequate nerve block and epidural anesthesia, as well as measures to relieve anxiety, will help markedly to reduce the risks associated with labor pain.     

Intrathecal substance P depresses the tail-flick response — Antagonism by naloxone

Summary Substance P injected into the lumbar subarachnoid space of rats depressed the tail-flick response to radiant heat in a dose-dependent way. The effective doses ranged from 0.1 g to 100 g per rat (ED 50: 1.5 g/rat). The maximum of the effect was reached 20 min after intrathecal injection and the effect lasted for about 30 min. An antinociceptive effect was also observed after intrathecal injection of substance P 1 g to spinal rats. The depression of the tail-flick response produced by intrathecal administration of substance P was abolished by intrathecal (5 g/rat) or i.p. (0.5 mg/kg) injections of naloxone.Supported by the Sonderforschungsbereich 38 Membranforschung     

Prevalence of oral anticoagulation in atrial fibrillation

OBJECTIVES:

Atrial fibrillation is the most common sustained arrhythmia and is associated with poor outcomes, including stroke. The ability of anticoagulation therapy to reduce the risk of stroke has been well established; however, the prevalence of anticoagulation therapy use in the Public Health System is unknown. The aim of this study is to evaluate both the prevalence of anticoagulation therapy among patients with atrial fibrillation and the indications for the treatment.

METHODS:

In this cross-sectional study, we included consecutive patients who had atrial fibrillation documented by an electrocardiogram performed between September 2011 and March 2012 at a university hospital of the Public Health System. The variables analyzed included the risk of a thromboembolic event and/or bleeding, the use of antiplatelet or anticoagulation therapy, the location where the electrocardiogram report was initially reviewed and the specialty of the physician who initially reviewed it.

RESULTS:

We included 162 patients (mean age 68.9 years, 56% men). Hypertension (90.1%), heart failure (53.4%) and stroke (38.9%) were the most prevalent diseases found. Only 50.6% of the patients knew that they had atrial fibrillation. Regarding the use of therapy, only 37.6% of patients classified as high risk according to the CHADS2 scores and 35.5% according to the CHA2DS2VASc used oral anticoagulation. A presumptive diagnosis of heart failure and the fact that the electrocardiogram was evaluated by a cardiologist were the only independent predictors of the use of anticoagulants.

CONCLUSIONS:

Our study found a low prevalence of oral anticoagulation therapy among patients with atrial fibrillation and an indication for stroke prophylaxis for the use of this therapy, including among those with high CHADS2 and CHA2DS2VASc scores.     

Depression by morphine-6-glucuronide of nociceptive activity in rat thalamus neurons: comparison with morphine

To assess the contribution of the active metabolite of morphine, morphine-6-glucuronide (M6G), to the analgesic effect of systemically administered morphine, experiments were carried out on rats under urethane anesthesia in which nociceptive activity was evoked by electrical stimulation of afferent C fibers in the sural nerve and recorded from single neurons in the ventrobasal complex of the thalamus. Intravenous (i.v.) injections of morphine completely blocked the activity at doses of 500 and 1000 μg/kg, the ED,, being 44 μg/kg. M6G administered by i.v. injection reduced the evoked nociceptive activity only by about 40% at 80 and 160 μg/kg, the ED₅₀ being 6 μg/kg. After intrathecal (i.t.) injection, morphine produced maximum depression of 55% of the control activity at 20 μg the ED₅₀ is 18 μg. M6G injected i.t. produced maximum depression of 40% at doses ranging from 0.2 to 10 μg. The ED₅₀ of M6G i.t. is below 0.2 μg. The effects of morphine and M6G were reversed by naloxone (200 μg/kg i.v.). The results show that M6G is more potent than morphine, regardless of the route of administration, while morphine is more effective when injected i.v. Due to the low efficacy of M6G, it seems unlikely that this glucuronide contributes substantially to the analgesic effect of morphine when renal function is normal. The results also make evident that the maximum effect of morphine results from an action at spinal and supraspinal sites.     

Die Wirkung von Adrenalin und Noradrenalin auf die Spannungsentwicklung vom Soleus und Tibialis anterior der Katze

Summary 1. The effect of adrenaline and noradrenaline upon the tension developed isometrically by the tonic soleus and the phasic tibialis anterior muscles of the cat was investigated at various extensions and different stimulation frequencies. Stretch was applied before and during stimulation of the muscles.2. Adrenaline and noradrenaline reduced the tension of the soleus and increased that of the tibialis anterior muscles, when various amounts of extension were applied previous to stimulation. With supramaximal stimulation strength these effects were only observed at lower frequencies, while with submaximal strength tension changes could be produced at all frequencies tested. The effect of both amines on the tension developed by the soleus muscle was diminished by stretch.3. When stretch was applied during stimulation, adrenaline and noradrenaline produced an effect upon tension only at larger extensions.4. Adrenaline reduced the duration of the plateau of the active state of the soleus muscle and prolonged that of the tibialis anterior; neither the duration of the plateau nor the effect of adrenaline upon the duration of the plateau were influenced by stretch applied to the muscles prior to stimulation.

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Mit 6 Textabbildungen

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Über einen Teil der Ergebnisse wurde bereits auf dem 1. Internationalen Pharmakologenkongreß in Stockholm im August 1961 berichtet.     

The dependence of the anti-nociceptive effect of morphine and other analgesic agents on spinal motor activity after central monoamine depletion

The interference of central monoamine depletion with the anti-nociceptive effect of morphine, pethidine and aminophenazone was studied in rats with regard to the changes in spinal motor activity induced by reserpine, tetrabenazine and α-methyl-p-tyrosine.All three analgesic agents prolonged the time of the tail-flick reaction in intact rats. This effect was abolished by reserpine, which prolonged the reaction time. Bilateral lesioning of the substantiae nigrae with microinjections of 6-hydroxydopamine prolonged the reaction time and abolished the anti-nociceptive effect of morphine. In spinal rats, the time of the tail-flick reaction was prolonged by morphine and reduced by aminophenazone. Reserpine did not abolish the effect of morphine in spinal rats.Morphine, pethidine and aminophenazone inhibited the α-reflex discharges facilitated by conditioning stimulation in intact and spinal rats. Pethidine and aminophenazone, but not morphine, depressed the facilitation of α-reflex discharges produced by central monoamine depletion in intact rats. The increase in the amplitude of monosynaptic mass reflexes produced by reserpine in intact rats was not reduced by morphine, whereas the depression of polysynaptic mass reflexes after reserpine was antagonized by morphine.The three analgesic agents differ markedly in their action on spinal motor activity altered by monoamine depletion. It is concluded that the antagonizing effect of central monoamine depletion on the anti-nociceptive effect of morphine, pethidine and aminophenazone in the rat is due to a change in the basal motor activity on which the spinal nociceptive reflex is elicited.     

Intrathecal apamin selectively facilitates activity in ascending axons of rat spinal cord evoked by stimulation of afferent C fibers in sural nerve

Intrathecally administered apamin was tested for its effect on activity in ascending axons of the spinal cord using decerebrate rats with low spinal cord transection. Afferent Aβ, Aδ or C fibers were stimulated in the sural nerve, and the response evoked in ascending axons was recorded below the transection. Apamin (5 ng) produced an increase in C fiber-evoked activity which developed about 30 min after injection and persisted for more than 60 min after injection. Apamin (5, 20 and 50 ng) did not change the activity in ascending axons which responded only to stimulation of afferent Aβ and Aδ fibers.The results indicate that apamin facilitates synaptic transmission from high-threshold afferent C fibers to secondary neurons.     

Inhibition of the effect of reserpine on motor control by drugs which influence reserpine rigidity

Summary The effect of monoaminergic (DOPA, metamphetamine, propylhexedrine) and cholinolytic agents (atropine, biperiden, caramiphen, trihexyphenidyl) on and reflex discharge from the spinal cord was studied in the rat. For comparison, the anticonvulsant phenytoin was included in the investigation. All drugs antagonized the action of a high dose of reserpine on motor control by reducing the increased and increasing the diminished reflex activity. The latency of reflex discharge shortened by reserpine was increased by the drugs. The results provide further support of the view that disturbance of motor control caused by reserpine in the rat derives from an imbalance between monoaminergic and cholinergic systems in the brain.Supported by a grant of the Deutsche Forschungsgemeinschaft.