Orofacial pain disorders are frequent in the general population and their pharmacological treatment is difficult and controversial. Therefore, the search for novel, safe and efficient analgesics is an important but still elusive goal for contemporary medicine. In the recent years, the antinociceptive potential of endocannabinoids and opioids has been emphasized. However, concerns for the safety of their use limit their clinical applications. the possibility of modulating the activity of endocannabinoids by regulation of their synthesis and/or degradation offers an innovative approach to the treatment of pain. A rat model of trigeminal pain, utilizing tongue jerks evoked by electrical tooth pulp stimulation during perfusion of the cerebral ventricles with various neurotransmitter solutions can be used in the pharmacological studies of nociception in the orofacial area. The aim of this review is to present the effects of pharmacological activity of opioids and endocannabinoids affecting the transmission of the sensory information from the orofacial area on the example of trigemino-hypoglossal reflex in rats.
In vitro binding of specific opioid ligands to their respective sites in membrane fractions and the contribution of individual receptor classes (mu, delta, kappa) was studied in rats after longlasting (up to 22 months) section of spinal dorsal roots at the cervical (C5.8) or thoracic (Th^) level. This procedure leads to autotomy or scratching of the skin on the operated side. The total number of receptors in the cervical and thoracic spinal cord was more than doubled in both operated and contralalteral part of the cord in comparison with intact controls of the same age. In the cervical region, this increase mainly represented a rise in the number of free receptors, whilst in the thoracic region both free and saturated receptors were increased. On the deafferented side, receptor selectivity, especially in the delta and kappa types was decreased.
b1_Large number of extracellular signals is received by plasma membrane receptors which, upon activation, transduce information into the target cell interior via trimeric G-proteins (GPCRs) and induce activation or inhibition of adenylyl cyclase enzyme activity (AC). Receptors for opioid drugs such as morphine ( μ-OR, δ-OR and κ-OR) belong to rhodopsin family of GPCRs. Our recent results indicated a specific up-regulation of AC I (8-fold) and AC II (2.5-fold) in plasma membranes (PM) isolated from rat brain cortex exposed to increasing doses of morphine (10-50 mg/kg) for 10 days. Increase of ACI and ACII represented the specific effect as the amount of ACIII-ACIX, prototypical PM marker Na, K-ATPase and trimeric G-protein α and β subunits was unchanged. The up-regulation of ACI and ACII faded away after 20 days since the last dose of morphine. Proteomic analysis of these PM indicated that the brain cortex of morphine-treated animals cannot be regarded as being adapted to this drug because significant up-regulation of proteins functionally related to oxidativ e stress and alteration of brain energy metabolism occurred. The number of δ-OR was increased 2-fold and their sensitivity to monovalent cations was altered. Characterization of δ-OR-G-protein coupling in model HEK293 cell line indicated high ability of lithium to support affinity of δ-OR response to agonist stimulation. Our studies of PM structure and function in context with desensitization of GPCRs action were extended by data indicating part icipation of cholesterol-enriched membrane domains in agonist-specific internalization of δ-OR. In HEK293 cells stably expressing δ-OR-G i 1 α fusion protein, depletion of PM cholesterol was associated with the decrease in affinity of G-protein response to agonist stimulation, whereas maximum response was unchanged., b2_drophobic interior of isolated PM became more “fluid”, chaotically organized and accessible to water molecules. Validity of this conclusion was supported by the analysis of an immediate PM environment of cholesterol molecules in living δ -OR-G i 1 α-HEK293 cells by fluorescent probes 22- and 25-NBD-cholesterol. The alteration of plasma membrane structure by cholesterol depletion made the membrane more hydrated. Unders tanding of the positive and negative feedback regulatory loops among different OR-initiated signaling cascades (μ-, δ -, and κ-OR) is crucial for understanding of the long-term mechanisms of drug addiction as the decrease in functional activity of μ-OR may be compensated by increase of δ-OR and/or κ-OR signaling., H. Ujčíková ... [et al.]., and Obsahuje bibliografii a bibliografické odkazy
Osteoporóza je onemocnění s masovým výskytem, postihující převážně starší populaci. Osteoporózou je ohrožena každá 3. žena a každý 6. muž kavkazské rasy ve věku nad 50 let. V České republice osteoporóza postihuje 15 % mužů a 33 % žen ve věku nad 50 let a 39 % mužů a 47 % žen ve věku nad 70 let, celkově tedy více než 5 % obyvatel. Přesto zůstávala mužská osteoporóza řadu desetiletí bez povšimnutí. U mužů je nutná přítomnost androgenů k dosažení optimální hodnoty vrcholné kostní hmoty (BMD), maximální velikosti kosti a udržení rovnovážného stavu remodelace kosti. Deficience testosteronu vede k akceleraci kostní ztráty. Četné účinky cirkulujícího testosteronu jsou zprostředkovány estrogeny. Estrogen je dominantním pohlavním steroidem regulujícím kostní resorpci, zatímco estrogen a testosteron společně, jsou důležité pro kostní novotvorbu u mužů. Ztráta trámčité kosti probíhá u mužů převážně ztenčováním, u žen zejména v prvních letech po menopauze ztrátou konektivity trámců. Celotělový obsah minerálů je u mužů o 25 - 30 % větší než u žen. Muži mají kosti větší než ženy a velikost kosti je nezávislou determinantou pevnosti kosti. Hodnota plošné BMD v oblasti obratlů je vyšší u mužů než u žen, avšak volumometrická BMD je stejná u obou pohlaví. U mužů tedy dochází ke zlomeninám při vyšších hodnotách BMD. Důsledkem osteoporózy jsou zlomeniny, které výrazně zhoršují kvalitu života a mohou zkracovat jeho délku. Relativní riziko fraktury krčku femoru je pro 50letou ženu 9 - 18 %, pro 50letého muže 3 - 6 %. Ukazuje se, že až 30 % všech fraktur krčku a 20 % páteřních fraktur se týká mužů. Až 20 % pacientů, kteří utrpěli frakturu krčku femoru, do roka umírá, 30 - 40 % je trvale odkázáno na pomoc jiných osob. U mužů je vyšší mortalita při zlomeninách než u žen. Standardem pro stanovení diagnózy je měření denzity kostního minerálu v oblasti proximálního femoru. Základem prevence i léčby mužské osteoporózy je podávání kombinace kalcia a vitaminu D, léky první volby jsou bisfosfonáty a při prokázaném hypogonadizmu u mladších mužů testosteron, lékem druhé volby je kalcitonin. Osteoanabolickým lékem na poli mužské osteoporózy pro pacienty ve vysokém riziku zlomenin je parathormon., Osteoporosis is a disease with mass occurrence afflicting especially elderly population. Osteoporosis threatens every third white female and every sixth white male over 50 years of age. In the Czech Republic, the disease afflicts 15 % of men and 33 % of women over 50 and 39 % of men and 47 % of women over 70 years of age i.e. in total more than 5 % of the population. Osteoporosis in men used to be a neglected health issue for decades. For men, to achieve an optimum peak bone mass (PBM), maximum bone size and to maintain bone remodelation in equilibrium state presence of androgens is necessary. Testosterone deficiency results in acceleration of bone loss. Numerous effects of circulating testosterone are mediated through estrogens. Estrogen has been considered a dominant sex steroid regulating bone resorption; while both, estrogen and testosterone together are important for male bone formation. In men, trabecular bone loss occurs in a form trabecular thinning; in women, there is a loss of connectivity between the trabecular plates. Whole-body content of minerals in men is about 25 - 30 % higher than in women. Men?s bones are larger then women?s; the size of bones is an independent determinant of bone strength. Vertebral PBM is higher in men than in women; but volumetric BMD is the same for both sexes. In men, fractures thus occur with higher PBM. Osteoporosis results in fractures worsening significantly quality of life and shortening the life respectively. For a fifty-year-old woman, femoral neck fracture risk amounts to 9 - 18 %; for a fifty-year-old man, the risk amounts to 3 - 6 %. It has been proven that up to 30 % of all cases of femoral neck fractures and 20 % of spinal fractures respectively concern men. 20 - 30 % of patients, who have suffered a femoral fracture, die within a year; 30 - 40 % is permanently dependent on help of other people. In men, mortality in connection with femoral fracture is higher than in women. To establish diagnosis, a standard procedure includes bone mineral densitometry of proximal femur. Basic prevention and therapy of osteoporosis in men consists of administration of combination of calcium and vitamin D; first-choice drugs are bisfosfonates and testosterone; a second-choice drug is calcitonin. For male patients with the highest risk of osteoporotic fractures there is a promising drug ? parathormone., Olga Růžičková, and Lit.: 62
Supercooling point (SCP), survival at low temperatures, rate of water loss in dry air at 20°C and survival under desiccating conditions of eggs of Polydesmus angustus (Diplopoda) were determined. The results were compared with those obtained previously for the eight post-embryonic stadia, to obtain an overview of the changes in resistance to cold and desiccation throughout the species' development. The SCP temperatures of egg batches ranged from -14.8 to -30.6°C and were significantly lower than those of the active stadia. Eggs were not affected by prolonged exposure to low temperature above 0°C and survived much better than active stadia when cooled to -6 and -10°C. This indicates that the cold hardiness of P. angustus is highest in the egg stage and decreases during development. On the other hand, the rate of water loss was significantly higher from eggs than from active stadia. When eggs were taken out of their protective nest, they lost water at the high rate of 7% min-1 in dry air. They also survived for a shorter time than active stadia at 76% RH and 20°C. The resistance to desiccation of P. angustus is lowest at the egg stage and increases during development. The results suggest that the life cycle of P. angustus may have responded to selection pressures other than cold and drought, and do not support the hypothesis that cold hardiness and resistance to desiccation are overlapping adaptations in terrestrial arthropods.
The effects of nitric oxide on evoked acetylcholine (ACh) release were studied at two identified cholinergic neuro-neuronal synapses of the nervous system of the mollusc Aplysia californica. The NO- donor, 3-morpholinosydnonimine (SIN-1), decreased the amplitude of evoked inhibitory postsynaptic currents (buccal ganglion) and potentiated that of evoked excitatory postsynaptic currents (abdominal ganglion). SIN-1 acted by modulating the number of ACh quanta released. 8Br-cGMP mimicked the effects of NO on ACh release in both types of synapses thus pointing to the involvement of a NO- sensitive guanylate cyclase. Presynaptic voltage-dependent Ca2+ and K+ (Ia and late outward rectifier) currents were not modified by SIN-1 suggesting another final target for NO/cGMP. The labelling of a NO-synthase by immunostaining in several neurones as well as the modulation of ACh release by L-arginine indicate that an endogenous NO-synthase is involved in the modulation of synaptic efficacy in both buccal and abdominal ganglia.