Adrenergic Mechanisms Research Articles

α2A-Adrenoceptors Strengthen Working Memory Networks by Inhibiting cAMP-HCN Channel Signaling in Prefrontal Cortex

Spatial working memory (WM; i.e., "scratchpad" memory) is constantly updated to guide behavior based on representational knowledge of spatial position. It is maintained by spatially tuned, recurrent excitation within networks of prefrontal cortical (PFC) neurons, evident during delay periods in WM tasks. Stimulation of postsynaptic alpha2A adrenoceptors (alpha2A-ARs) is critical for WM. We report that alpha2A-AR stimulation strengthens WM through inhibition of cAMP, closing Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels and strengthening the functional connectivity of PFC networks. Ultrastructurally, HCN channels and alpha2A-ARs were colocalized in dendritic spines in PFC. In electrophysiological studies, either alpha2A-AR stimulation, cAMP inhibition or HCN channel blockade enhanced spatially tuned delay-related firing of PFC neurons. Conversely, delay-related network firing collapsed under conditions of excessive cAMP. In behavioral studies, either blockade or knockdown of HCN1 channels in PFC improved WM performance. These data reveal a powerful mechanism for rapidly altering the strength of WM networks in PFC.

Pressor effects of noradrenaline injected into the lateral septal area of unanesthetized rats

The lateral septal area (LSA) is involved in central cardiovascular control. In the present study, we report on the cardiovascular effects of noradrenaline (NA) injection into the LSA of unanesthetized rats, as well as on local receptors and peripheral mechanisms involved in their mediation. Microinjections of NA (9, 15, 21, 27 or 45 nmol) caused long-lasting, dose-related pressor and bradycardic responses in unanesthetized rats. No responses were observed when the dose of 21 nmol of NA was microinjected into medial septal area or lateral ventricle suggesting a main action at the LSA. No changes were observed in arterial pressure and heart rate when NA was injected in the LSA of anesthetized rats. The effects of 21 nmol of NA were abolished by local pretreatment with 10 nmol of the specific α 1-receptor antagonist WB 4101, but were not affected by pretreatment with 10 nmol of the specific α 2-receptor antagonist RX 821002. The magnitude of pressor response to NA in the LSA was increased by i.v. pretreatment with the ganglion blocker pentolinium (10 mg/kg) and significantly reduced by i.v. pretreatment with the V 1-vasopressin receptor antagonist dTyr (CH2)5(Me) AVP (50 μg/kg). No pressor response to NA was observed in hypophysectomized rats. The present observation of α 1-adrenoceptor-mediated pressor responses after local injection of NA confirms earlier evidence of a LSA involvement in central cardiovascular control. Pretreatment with the α 1-adrenoceptor antagonist WB-4101 did not affect baseline blood pressure or heart rate suggesting no tonic involvement of septal adrenergic mechanisms suggesting a modulatory LSA influence on cardiovascular control. Additionally, the blockade of the pressor response by the i.v. pretreatment with a V 1-vasopressin antagonist indicates that noradrenergic LSA mechanisms modulate vasopressin release.

Paroxetine Useful for Palmar–Plantar Hyperhidrosis

To report a case of palmar-plantar hyperhidrosis (PPH) in which paroxetine was found to be helpful. A 32-year-old man with a history of excessive sweating of the palms and soles since childhood was diagnosed with PPH and was prescribed paroxetine 10 mg/day, which was increased to 20 mg/day. After one month, he experienced a marked reduction in sweating and improvement in socio-occupational functioning, which were sustained during follow-up at 6 months without any emergent adverse effects. Paroxetine's anticholinergic action may be responsible for its beneficial effect in PPH, as it may override the adrenergic mechanism, which has a minor effect on sweating from eccrine glands. Alternatively, paroxetine's beneficial effect in PPH may be secondary to its antianxiety effect, through central mechanisms. Paroxetine may be a useful option in the treatment of PPH.

β-Adrenergic and Atrial Natriuretic Peptide Interactions on Human Cardiovascular and Metabolic Regulation

Atrial natriuretic peptide (ANP) has well-known cardiovascular effects and modifies lipid and carbohydrate metabolism in humans. The objective of the study was to determine the metabolic and cardiovascular interaction of beta-adrenergic receptors and ANP. This was a crossover study, conducted 2004-2005. The study was conducted at an academic clinical research center. PATIENTS included 10 healthy young male subjects (body mass index 24 +/- 1 kg/m2). We infused iv incremental ANP doses (6.25, 12.5, and 25 ng/kg.min) with and without propranolol (0.20 mg/kg in divided doses followed by 0.033 mg/kg.h infusion). Metabolism was monitored through venous blood sampling, im, and sc microdialysis and indirect calorimetry. Cardiovascular changes were monitored by continuous electrocardiogram and beat-by-beat blood pressure recordings. Venous nonesterified fatty acid, glycerol, glucose, and insulin; and microdialysate glucose, glycerol, lactate, and pyruvate were measured. ANP increased heart rate dose dependently. beta-Adrenergic receptor blockade abolished the response. ANP elicited a dose-dependent increase in serum nonesterified fatty acid and glycerol concentrations. The response was not suppressed with propranolol. Venous glucose and insulin concentrations increased with ANP, both without or with propranolol. ANP induced lipid mobilization in sc adipose tissue. In skeletal muscle, microdialysate lactate increased, whereas the lactate to pyruvate ratio decreased, both with and without propranolol. Higher ANP doses increased lipid oxidation, whereas energy expenditure remained unchanged. Propranolol tended to attenuate the increase in lipid oxidation. Selected cardiovascular ANP effects are at least partly mediated by beta-adrenergic receptor stimulation. ANP-induced changes in lipid mobilization and glycolysis are mediated by another mechanism, presumably stimulation of natriuretic peptide receptors, whereas substrate oxidation might be modulated through adrenergic mechanisms.

Acute restraint stress induces hyperalgesia via non-adrenergic mechanisms in rats

Analgesia or hyperalgesia has been reported to occur in animals under different stress conditions. This study examined the effect of acute restraint stress on nociception in rats. Acute restraint stress produced a time-dependant decrease in pain threshold; this hyperalgesia was not affected by prior administration of adrenergic blockers suggesting the non-involvement of adrenergic mechanisms. The hyperalgesia may however result from a change in the affective state of the animal and not from a change in sensory processing of noxious stimulus. Keywords : stress, hyperalgesia, tail-flick test, sympathetic nervous system African Journal of Biomedical Research Vol. 8(2) 2005: 123-125

Salivary α-Amylase Levels after Yohimbine Challenge in Healthy Men

We and others have previously shown that standardized psychosocial stress significantly increases salivary alpha-amylase (sAA), but it remains unclear whether sAA reflects autonomic nervous system activation. The aim of this study was to assess cardiovascular effects and sAA and catecholamine secretion after iv injection of yohimbine. We conducted a randomized double-blind placebo-controlled study at an academic research unit. Thirteen healthy males (aged 20-28 yr) were examined. Participants received iv injection of yohimbine (0.4 microg/kg) or placebo (0.9% NaCl). Eight saliva and blood samples were taken before and after injection for the assessment of salivary flow rate and sAA and catecholamine concentrations. In addition, blood pressure, mood, and anxiety were assessed repeatedly. Yohimbine induced increases of sAA activity and output in comparison to placebo (P = 0.034). Blood pressure (P < 0.001), salivary flow rate (P = 0.007), and catecholamines (P < 0.001) were also significantly increased. No significant correlations between alpha-amylase parameters and catecholamines were observed. The results indicate that yohimbine administration activates not only autonomic parameters but also sAA via adrenergic mechanisms, suggesting that sAA might be an indirect indicator of the central sympathetic system.

Quantitative mRNA analysis of adrenergic receptor subtypes in the intestines of healthy dairy cows and dairy cows with cecal dilatation-dislocation

To investigate the distribution of mRNA coding for 9 adrenoceptor subtypes in the intestines of healthy dairy cows and cows with cecal dilatationdislocation (CDD). Full-thickness specimens of the intestinal wall were obtained from the ileum, cecum, proximal loop of the ascending colon (PLAC), and external loop of the spiral colon (ELSC) of 15 cows with CDD (group 1) and 15 healthy (control) cows (group 2, specimens collected during laparotomy; group 3, specimens collected after slaughter). Concentrations of mRNA for 9 adrenoceptor subtypes (alpha(1A), alpha(1B), alpha(1D), alpha(2AD), alpha(2B), alpha(2C), beta(1), beta(2), and beta(3)) were measured by quantitative real-time reverse transcriptase-PCR assay. Results were expressed relative to mRNA expression of a housekeeping gene. Expression of mRNA for alpha(1B)-, alpha(2AD)-, alpha(2B)-, beta(1)-, and beta(2)-adrenoceptors was significantly lower in cows with CDD than in control cows. In the ileum, these receptors all had lower mRNA expression in cows with CDD than in control cows. The same effect was detected in the ELSC for mRNA for alpha(2AD)-, alpha(2B)-, beta(1)-, and beta(2)-adrenoceptors, and in the cecum and PLAC for alpha(2B)- and beta(2)-adrenoceptors. Groups did not differ significantly for alpha(1A)-adrenoceptors. The mRNA expression for alpha(1D)-, alpha(2C)-, and beta(3)-adrenoceptors was extremely low in all groups. Differences in expression of mRNA coding for adrenoceptors, most pronounced in the ileum and spiral colon, between cows with CDD and control cows support the hypothesis of an implication of adrenergic mechanisms in the pathogenesis of CDD in dairy cows.

Cardiac resynchronization therapy and adrenergic mechanisms

cardiac resynchronization therapy (CRT) is a major advance in the treatment of heart failure (HF), and thus far the most important HF therapeutic modality identified in the 21st century. When applied to patients with left ventricular dyssynchrony, CRT immediately improves chamber contractile

The Cardiac hERG/IKr Potassium Channel as Pharmacological Target: Structure, Function, Regulation, and Clinical Applications

Human ether-a-go-go-related gene (hERG) potassium channels conduct the rapid component of the delayed rectifier potassium current, IKr, which is crucial for repolarization of cardiac action potentials. Moderate hERG blockade may produce a beneficial class III antiarrhythmic effect. In contrast, a reduction in hERG currents due to either genetic defects or adverse drug effects can lead to hereditary or acquired long QT syndromes characterized by action potential prolongation, lengthening of the QT interval on the surface ECG, and an increased risk for "torsade de pointes" arrhythmias and sudden death. This undesirable side effect of non-antiarrhythmic compounds has prompted the withdrawal of several blockbuster drugs from the market. Studies on mechanisms of hERG channel inhibition provide significant insights into the molecular factors that determine state-, voltage-, and use-dependency of hERG current block. In addition, crucial properties of the high-affinity drug binding site in hERG and its interaction with drug molecules have been identified, providing the basis for more refined approaches in drug design, safety pharmacology and in silico modeling. Recently, mutations in hERG have been shown to cause current increase and hereditary short QT syndrome with a high risk for life-threatening arrhythmias. Finally, the discovery of adrenergic mechanisms of hERG channel regulation as well as the development of strategies to enhance hERG currents and to modify intracellular hERG protein processing may provide novel antiarrhythmic options in repolarization disorders. In conclusion, the increasing understanding of hERG channel function and molecular mechanisms of hERG current regulation could improve prevention and treatment of hERG-associated cardiac repolarization disorders.

Exercise Induced Redistribution of Lymphocytes - Influence of Exercise Intensity and Adrenergic Mechanisms

Exercise induces considerable changes of blood lymphocyte counts. Recently, we observed that at least two different mechanisms are involved. First, after exercise lymphocyte apoptosis is enhanced depending on exercise intensity. Second, exercise is followed by a redistribution of lymphocytes between lymphoid and non-lymphoid organs. These lymphocyte movements are known to be controlled by several hormones, cytokines and receptors including adrenergic mechanisms. PURPOSE: Therefore, the aim of the study was to determine the influence of different exercise intensities on lymphocyte redistribution. In a second approach we tried to find out the importance of adrenergic mechanisms on lymphocyte redistribution during exercise. METHODS: Isolated lymphocytes were labelled with a fluorescent dye (Cell-Tracker Green) and injected intravenously in male Swiss mice. Groups performed acute treadmill exercises either at 60% or 80% VO2max or swimming exercise until exhaustion. Another group exercised after a treatment with either phentolamine (PHE) or nadolol (NAD). A third group received single applications of epinephrine (E) or norepinephrine (NE). After the tests, thymus, bone-marrow, spleen, lung, liver, Peyer's patches and lymph nodes were excised. Lymphocyte distribution was investigated both qualitatively and quantitatively using either fluorescence-microscopy or flow cytometry, respectively. RESULTS: We found a decrease of splenic lymphocyte counts after exercise which was related to exercise intensity. The decrease was blocked by prior applications of both PHE and NAD and could be mimicked by an application of E. The increase in lymphocyte counts in the bone marrow and the lung seemed to be intensity dependent, too. However, both movements relied on adrenergic mechanisms only partially. CONCLUSIONS: Lymphocytes are intensity -dependent mobilised from the spleen via adrenergic mechanisms. Redistribution into the target organs is influenced by exercise intensity and is only partially dependent on adrenergic mechanisms. Instead it seems likely that other mechanisms such as the expression of various homing receptors are involved.

Noradrenergic and serotonergic modulation to treat vasomotor symptoms

Hot flushes are a major clinical problem for many menopausal women. Their aetiology is unknown. Centrally acting neurotransmitters are involved, but this involvement is yet to be fully characterized. In clinical trials with optimal patient selection and compliance, estrogen can reduce the frequency of hot flushes by 70-80%, and placebo by 20-40%. For some women, however, there are contraindications to the use of estrogen, and others are unwilling to use it. Furthermore, hot flushes may persist in spite of adequate estrogen replacement, and to improve symptoms physicians then have either to add another drug to the regimen or find an alternative to estrogen. The most commonly used non-hormonal alternatives for climacteric symptoms are neurotransmitter modulators such as the selective serotonin reuptake inhibitors. These reduce the frequency of hot flushes by 60%. The mechanism of this effect appears to differ from that underlying their effect on mood. They are generally well tolerated and rates of adverse events are far lower than those reported in studies of the use of these agents for depression. The limited efficacy of clonidine suggests that adrenergic mechanisms may be involved and data are awaited for more specific selective noradrenaline reuptake inhibitors. Thus, non-hormonal treatments are not as effective as estrogens in relieving hot flushes but may have a place as an alternative.

Neuropeptides and nitric oxide synthase in the gill and the air‐breathing organs of fishes

Anatomical and histochemical studies have demonstrated that the bulk of autonomic neurotransmission in fish gill is attributed to cholinergic and adrenergic mechanisms (Nilsson. 1984. In: Hoar WS, Randall DJ, editors. Fish physiology, Vol. XA. Orlando: Academic Press. p 185-227; Donald. 1998. In: Evans DH, editor. The physiology of fishes, 2nd edition. Boca Raton: CRC Press. p 407-439). In many tissues, blockade of adrenergic and cholinergic transmission results in residual responses to nerve stimulation, which are termed NonAdrenergic, NonCholinergic (NANC). The discovery of nitric oxide (NO) has provided a basis for explaining many examples of NANC transmissions with accumulated physiological and pharmacological data indicating its function as a primary NANC transmitter. Little is known about the NANC neurotransmission, and studies on neuropeptides and NOS (Nitric Oxide Synthase) are very fragmentary in the gill and the air-breathing organs of fishes. Knowledge of the distribution of nerves and effects of perfusing agonists may help to understand the mechanisms of perfusion regulation in the gill (Olson. 2002. J Exp Zool 293:214-231). Air breathing as a mechanism for acquiring oxygen has evolved independently in several groups of fishes, necessitating modifications of the organs responsible for the exchange of gases. Aquatic hypoxia in freshwaters has been probably the more important selective force in the evolution of air breathing in vertebrates. Fishes respire with gills that are complex structures with many different effectors and potential control systems. Autonomic innervation of the gill has received considerable attention. An excellent review on branchial innervation includes Sundin and Nilsson's (2002. J Exp Zool 293:232-248) with an emphasis on the anatomy and basic functioning of afferent and efferent fibers of the branchial nerves. The chapters by Evans (2002. J Exp Zool 293:336-347) and Olson (2002) provide new challenges about a variety of neurocrine, endocrine, paracrine and autocrine signals that modulate gill perfusion and ionic transport. The development of the immunohistochemical techniques has led to a new phase of experimentation and to information mainly related to gills rather than air-breathing organs of fishes. During the last few years, identification of new molecules as autonomic neurotransmitters, monoamines and NO, and of their multiple roles as cotransmitters, has reshaped our knowledge of the mechanisms of autonomic regulation of various functions in the organs of teleosts (Donald, '98).NO acts as neurotransmitter and is widely distributed in the nerves and the neuroepithelial cells of the gill, the nerves of visceral muscles of the lung of polypterids, the vascular endothelial cells in the air sac of Heteropneustes fossilis and the respiratory epithelium in the swimbladder of the catfish Pangasius hypophthalmus. In addition, 5-HT, enkephalins and some neuropeptides, such as VIP and PACAP, seem to be NANC transmitter candidates in the fish gill and polypterid lung. The origin and function of NANC nerves in the lung of air-breathing fishes await investigation. Several mechanisms have developed in the Vertebrates to control the flow of blood to respiratory organs. These mechanisms include a local production of vasoactive substances, a release of endocrine hormones into the circulation and neuronal mechanisms. Air breathers may be expected to have different control mechanisms compared with fully aquatic fishes. Therefore, we need to know the distribution and function of autonomic nerves in the air-breathing organs of the fishes.

α2 Adrenoceptors are involved in the regulation of the gripping-induced immobility episodes intaiep rats

In 1989 Holmgren et al. (Holmgren et al. 1989 Lab Anim Sci 39:226-228) described a new mutant rat that developed a progressive motor disturbance during its lifespan. The syndrome is characterized by a tremor in the hind limbs followed by ataxia, episodes of tonic immobility, epilepsy, and paralysis. The acronym of these symptoms (taiep) became the name of this autosomic, recessive mutant rat. The taiep rats are neurological mutant animals with a hypomyelination, followed by a progressive demyelination process. At 7-8 months of age, taiep rats develop immobility episodes (IEs) characterized by a cortical desynchronization, associated with the theta rhythm in the hippocampus and changes of the nucal electromyogram (EMG), whose pattern is like rapid-eye-movement (REM) sleep. These rats also show an altered sleep pattern with an equal REM sleep distribution. This study analyzed therole of alpha(2) adrenoceptors in the expression of gripping-induced IEs in 8-month-old male taiep rats. The alpha(2) adrenoceptor agonists clonidine and xylacine increased the frequency of gripping-induced IEs whereas the alpha(2) antagonists yohimbine and idazoxandecreased or prevented such episodes. These findings correlate with the pharmacological observations in narcoleptic dogs and humans in which alpha(2) adrenergic mechanisms are involved in the modulation of cataplexy. Unexpectedly, the repetitive administration of clonidine resulted in jumping behavior, indicative of phasic activation of extensor musculature. Taken together, our results show that alpha(2) adrenoceptors are involved in the modulation in gripping-induced IEs and after the administration of several doses of clonidine produced phasic motor activation.

Inhibition of Gastric Acid Secretion by Unfractionated and Low Molecular Weight Heparins in the Rat

The majority of patients receiving heparin preparations are at stress, which is a risk factor for the development of gastric erosions. Our aim was to examine the effect of unfractionated heparin (UFH) and low molecular weight heparins (LMWHs) on gastric acid secretion. Gastric acid secretion was induced in urethane-anesthetized rats by distention of the stomach (2 ml saline for 2 h) in addition to histamine or bethanechol stimulation. Distension-stimulated acid secretion (2 ml for 2 h) was significantly inhibited by intraperitoneal administration of UFH (2000 IU/kg, 19% reduction), enoxaparin (180 or 360 IU/kg, 59.2 and 87.1%, reduction, respectively), nadroparin (1000 or 2000 IU/kg, 36 and 60.7% reduction, respectively), and tinzaparin (3000 IU/kg, 41.3% reduction). All tested heparins also suppressed acid secretion in response to distention and histamine or bethanechol stimulation. Pretreatment with indomethacin did not abolish the gastric inhibitory action of nadroparin. After truncal vagotomy or atropine, nadroparin failed to inhibit acid secretion stimulated by histamine. Ganglionic blockade with guanethidine abolished the gastric inhibitory action of nadroparin or UFH. It is concluded that both UFH and LMWHs administered peripherally inhibit stimulated gastric acid secretion in the rat. This effect of heparins is determined by cholinergic and partly by adrenergic mechanisms.

Neurobiology of Sexual Response in Men and Women

Sexual desire, arousal, and orgasm are mediated by complex--and as yet not fully understood--interactions of the somatic and autonomic nervous systems, operating at cerebral, spinal, and peripheral levels. Furthermore, neural activity within these systems is modulated by the presence of steroid and peptide hormones, which affect male and female response differentially. At the central level, dopaminergic and serotonergic systems appear to play a significant role in various components of sexual response, although adrenergic, cholinergic, nitergic, gamma-aminobutyric acidergic, and other neuropeptide transmitter systems may contribute as well. At the peripheral level, adrenergic, cholinergic, and nitergic activation mechanisms control vascular changes that underlie vaginal lubrication and penile erection. In addition, these systems respond to descending brain and spinal influences that generate orgasmic response. Disruption of endocrine, neural, or vascular response--caused by aging, disease, surgery, or medication--has the potential to lead to sexual inadequacy. At the same time, psychological and relationship factors play an important role in healthy sexual response and may enhance or impair sexual functioning.

P.3.e.009 Cognitive enhancement in schizophrenia: the role of dopamine and noradrenaline in the prefrontal cortex

The present experiments were designed to examine the effects of alpha-1 adrenergic stimulation and inhibition on memory encoding and to investigate whether the alpha-1 adrenergic and muscarinic cholinergic systems interact in the regulation of spatial navigation behavior in the Morris water maze test and we also studied the effects of d-cycloserine, a partial agonist at the glycine binding site on the N-methyl-d-aspartate (NMDA) receptor complex, on the performance of scopolamine-treated rats in this task. Pre-training subcutaneous administration of St-587 (a putative alpha-1 agonist) at 1000 μg kg−1 or 1500 μg kg−1 improved water maze navigation to a hidden platform. Prazosin (an alpha-1 antagonist), 300–2000 μg kg−1, did not significantly impair the spatial navigation performance. Pre-training administration of prazosin 1000 μg kg−1, but not 300 μg kg−1, slightly potentiated the deficit in water maze navigation seen after scopolamine (200 μg kg−1, pre-training intraperitoneal injection). Pre-training administration of St-587 at a dose 1500 μg kg−1, but not 500 μg kg−1, slightly ameliorated the scopolamine-induced (200 μg kg−1) impairment in performance of rats. Pre-training administration of prazosin at doses 300 or 1000 μg kg−1 or St-587 at doses 500 μg kg−1 or 1500 μg kg−1 did not have any significant influence on the scopolamine-induced (200 μg kg−1) increase of swimming speed. Furthermore, d-cycloserine at the dose of 300 μg kg−1 but not 1000 or 3000 μg kg−1 reversed the scopolamine (200 μg kg−1)-induced deficit in acquisition of the water maze task but not the increase in motor output (increased swimming speed). These results indicate that the stimulation of alpha-1 adrenoceptors may facilitate the encoding of new information. These findings suggest that alpha-1 adrenergic mechanisms do not participate or at least are not the most critical part of the noradrenergic system in the interaction between noradrenaline and muscarinic receptors in the modulation of learning and memory. In addition, these results suggest that d-cycloserine may be effective in alleviating states of central cholinergic hypofunction.

Hot flashes: behavioral treatments, mechanisms, and relation to sleep

Hot flashes are the most common symptom of the climacteric and occur in about 75% of perimenopausal and postmenopausal women in Western societies. Although hot flashes accompany the withdrawal of estrogen at menopause, the decline in estrogen levels is not sufficient to explain their occurrence. Elevated sympathetic activation acting through central alpha(2)-adrenergic receptors contributes to the initiation of hot flashes, possibly by narrowing the thermoneutral zone in symptomatic women. Hot flashes are then triggered by small elevations in core body temperature acting within this narrowed zone. A relaxation-based method, paced respiration, has been shown in 3 controlled investigations to significantly reduce objectively measured hot flash occurrence by about 50% with no adverse effects. In 6 studies of physical exercise, however, investigators did not find positive effects on hot flashes, possibly because exercise raises core body temperature, thereby triggering hot flashes. Although many epidemiologic studies have found increased reports of sleep disturbance during the menopausal transition, recent laboratory investigations have not found this effect, nor have they found that hot flashes produce disturbed sleep. Therefore, sleep complaints in women at midlife should not routinely be attributed to hot flashes or to menopause.

Involvement of opioidergic and α 2-adrenergic mechanisms in the central analgesic effects of non-steroidal anti-inflammatory drugs in sheep

The level within the central nervous system where non-steroidal anti-inflammatory drugs (NSAIDs) produce analgesia and the mechanisms by which they mediate this effect are still uncertain. This study assessed the central analgesic effects of ketoprofen, phenylbutazone, salicylic acid and tolfenamic acid in sheep implanted with indwelling intrathecal (i.t.) catheters and submitted to mechanical noxious stimulation. The sheep received i.t. cumulative concentrations (0.375–200 μM; 100 μL) as well as a single intravenous (i.v.) dose (3, 8, 10 and 2 mg/kg, respectively) of each NSAID. The sheep were also given i.t. naloxone (5.49 mM; 100 μL) and atipamezole (4.03 mM; 100 μL) prior to i.v. ketoprofen. None of the i.t. NSAIDs increased mechanical thresholds. Intravenously, only ketoprofen and tolfenamic acid raised the pain thresholds. The hypoalgesic effect of i.v. ketoprofen was prevented by i.t. naloxone or atipamezole. Although NSAIDs had no direct effect on the spinal cord, their analgesic action appeared to be spinally mediated.

Role of Adrenergic Mechanisms of Erythropoiesis Regulation during Severe Hypoxia

We studied the role of beta-adrenergic mechanisms of regulation of erythropoiesis in the formation of the erythron system reaction during severe hypoxia. Blockade of beta-adrenoceptors after the incidence of hypoxic encephalopathy of different genesis was followed by an increase in the number of committed precursors in the bone marrow, hyperplasia of the erythroid hemopoietic stem, and rise in the count of peripheral blood erythrocytes. These changes were accompanied by decreased formation of abnormal erythrocytes.

Adrenergic Mechanisms and Blood-Brain Barrier Permeability

the Department of Biochemistry (U38/FCT), Faculty of Medicine, and Faculty of Nutritional Sciences, University of Porto, Porto, Portugal