Increased lipid peroxidation in the rat hypothalamus after short-term emotional stress]

Concentrations of TBA-reactive substances (TBARS) were measured spectrophotometrically in homogenates of small samples of the brain (hypothalamus, parieto-occipital, sensori-motor and limbic cortex), heart, liver and adrenals of male August and Wistar rats; the former strain is more susceptible to emotional stress than the latter one. Forced isolation of the rats in the restraining plastic cages for 1 h increased the TBARS concentrations in the hypothalamus and liver in August rats only. TBARS accumulation in some tissues correlated with such indices of emotional stress as the changes in relative weight of thymus and adrenals. As regards the brain regions, after 1-hour emotional stress the TBARS levels were no longer different because of an increment in hypothalamic TBARS concentration. However, in control conditions the hypothalamus had significantly lower TBARS levels than any other brain structure both in Wistar and August rats.     

The activity of the monoaminergic systems of the rat hypothalamus in acute stress after chronic stressing]

The influence of chronic stress (footshock combined with randomized light flashes) on acute stress-induced (immobilization) release of noradrenaline, dopamine and serotonin in rat lateral hypothalamus was assessed by microdialysis. The chronic stress resulted in an increase and prolongation of the acute stress-induced release of noradrenaline but not of dopamine and serotonin. The increased rate of accumulation of dioxyphenylacetic acid and unchanged accumulation of homovanillic acid (dopamine metabolites) and dopamine during and after the acute stress in chronically stressed animals reflect a rise of synthetic activity of catecholaminergic systems in response to acute stress and reuptake increase. Marked stress-induced increase in hydroxyindoleacetic acid in chronically stressed rats without any changes in the ST dynamics may be regarded in a similar way. A significant increase in potassium-stimulated release of all the studied monoamines was found while their basal level remained unchanged. The conclusions was made that the hyperergic release of neurotransmitters may be the basis of an inadequate response of animals to acute stress, i.e., one of the neurotic symptoms.     

Biting reduces acute stress-induced oxidative stress in the rat hypothalamus

We investigated the inhibitory effect of para-masticatory activity, namely biting, on restraint stress-induced oxidative stress. A blood brain barrier-permeable nitroxyl spin probe, 3-methoxycarbonyl-2,2,5,5,-tetramethylpyrrolidine-1-oxyl (MC-PROXYL), was administered to rats and L-band electron spin resonance (ESR) and ESR-computerized tomography (ESR-CT) imaging were used to show that the decay rate constant of MC-PROXYL in the hypothalamus of isolated brain after 30 min of restraint stress was more rapid than in unrestrained control rats, suggesting that restraint was associated with oxidative stress. Interestingly, biting during restraint stress caused the decay rate constant of MC-PROXYL in isolated brain to approach that of the control group. These observations suggest that biting suppresses oxidative stress induced by restraint stress, and that the anti-stress effect of masticatory motor activity movements, such as biting, are important for reducing the adverse effects associated with exposure to psychological stressors.     

Accumulation and metabolism of norepinephrine in rat hypothalamus after exhaustive stress

—Exhaustive stress in rats is followed by a temporary reduction of hypothalamic norepinephrine (NE) together with a persistent increase in turnover during recovery. To test for persistent alterations of NE storage and metabolism produced by stress, rats were subjected to 3 h of forced running and were then injected intraventricularly with [³H]NE or [³H]dopamine (DA). The hypothalamus was assayed for [³H]NE and its metabolites at various intervals after injection. The effects of stress were compared with those of reserpine (7·5 mg/kg) or α-methyltyrosine (AMT, 300 mg/kg) pretreatment. It was found that the stress-induced reduction of endogenous NE was not accompanied by a change in the accumulation of exogenous [³H]NE either 10 or 30 min after injection, whereas the NE depletions produced by reserpine or AMT were associated with decreased or increased accumulation, respectively. However, stress did produce an increased accumulation of [³H]NE endogenously synthesized from [³H]DA. These results indicate that exhaustive stress does not adversely affect the storage of NE. They also suggest that stores of NE depleted by stress are replenished chiefly with newly synthesized NE and not through an increased uptake and binding or decreased metabolism of extraneuronal NE. The latter factors may play a role in the maintenance of brain NE stores when biosynthesis is low, i.e. after AMT. The major metabolites of exogenous [³H]NE, at 30 min after injection, were identified as conjugates of 3,4-dihydroxyphenylglycol (DOPEG) and 3-methoxy-4-hydroxyphenylglycol (MOPEG) in approximately equal amounts. The finding of high levels of conjugated DOPEG confirms a recent report (Slgden and Eccleston , 1971) that this compound is a major metabolite of brain NE. Reserpine produced marked elevations of both conjugates; AMT slightly reduced each. Prior stress increased only conjugated MOPEG, an observation suggesting that CNS levels of this metabolite may reflect NE released by nervous activity.     

Hyperthermic stress modulates the functions of rat liver glucocorticoid receptor

A mild whole body hyperthermic stress causes a rapid and reversible reduction of rat liver glucocorticoid receptor (GR) binding capacity and affects the stability of the GR-DNA complexes formed after thermal transformation of the receptor. These changes appear to be physiologically relevant, since they are accompanied by a decrease in dexamethasone induction of hepatic tyrosine aminotransferase (TAT). In spite of the decreased rate of the GR degradation in liver cytosol of hyperthermic as compared to control rats, the total amount of the GR and its proteolytic products recognized by BuGR2 monoclonal antibody was found to be lower in the former cytosol, but higher in the respective nuclei.     

Effect of cocaine on the tyrosine hydroxylase of rat hypothalamus]

The influence of cocaine on tyrosine hydroxilase of rat brain hypothalamus was investigated in vivo (0.5 mg/kg) and in vitro (10(--6)--10(--5)M). Cocaine was used as a substance with a known adrenergic type of action. It was shown that under standard conditions cocaine in vitro increased the enzyme activity and decreased the Km for DMPH4 cofactor without changing Vmax of the reaction analyzed by the membrane enzyme. Cocaine in vitro decreased the tyrosine hydroxylase activity, especially that of the membrane enzyme. In this case there occurred a decrease of Km for DMPH4 and a decrease of Vmax of the reaction. The decrease of Vmax is considered to be the result of the secondary effect of cocaine.     

Effect of neuroleptics on tyrosine hydroxylase from rat hypothalamus synaptosomes]

A study was made of the effect of a number of neuroleptics of various chemical structure of tyrosine-hydroxilase isolated from the synaptosomes of rat hypothalamus. A direct spectrophotometric method of determination of the activity of the enzyme was used; it was based on measurement of the absorbence at 335 nm (at the isobestic point for oxidized forms of a synthetic cofactor 6,7-dimethyl-5,6,7,8-tetrahydropterine). At the tyrosine concentration of 0.15 muM haloperidol, haloanizon, and fluorophenazin were found to increase, and triperidol, droperidol and carbidin -- to decrease the initial rate of thyrosinehydroxilase reaction. All the neuroleptics under study proved to be capable of eliminating the substrate inhibition of the enzyme occurring with a rise of tyrosine concentration to 0.3 mM. The KM value for tyrosine failed to alter with the action of neuroleptics. The effect of neuroleptics was assumed to be of allosteric nature.     

Angiotensin II in dorsomedial hypothalamus modulates cardiovascular arousal caused by stress but not feeding in rabbits

The dorsomedial hypothalamus (DMH) is critically implicated in the cardiovascular response to emotional stress. This study aimed to determine whether the DMH is also important in cardiovascular arousal associated with appetitive feeding behavior and, if so, whether locally released angiotensin II and glutamate are important in this arousal. Emotional (air-jet) stress and feeding elicited similar tachycardic (+51 and +45 beats/min, respectively) and pressor (+16 and +9 mmHg, respectively) responses in conscious rabbits. Bilateral microinjection of GABA(A) agonist muscimol (500 pmol) into the DMH, but not nearby hypothalamic regions, attenuated pressor and tachycardic responses to air-jet by 56-63% and evoked anorexia. Conversely, stimulation of the DMH with the glutamate analog kainic acid (250 pmol) elicited hypertension (+25 mmHg) and tachycardia (+114 beats/min) and activated feeding behavior. Local microinjection of a glutamate receptor antagonist, kynurenic acid (10 nmol), decreased pressor responses to stress and eating by 46 and 72%, respectively, without affecting feeding behavior. Bilateral microinjection of a selective AT(1)-receptor antagonist, candesartan (500 pmol), into the DMH, but not nearby sites, attenuated pressor and tachycardic stress responses by 31 and 33%, respectively. Candesartan did not alter feeding behavior or circulatory response to feeding. These results indicate that, in addition to its role in mediating stress responses, the DMH may be important in regulating cardiovascular arousal associated with feeding. Local glutamatergic inputs appear to regulate cardiovascular response to both stress and feeding. Conversely, angiotensin II, acting via AT1 receptors, may selectively modulate, in the DMH, cardiovascular response to stress, but not feeding.     

Food deprivation differentially modulates orexin receptor expression and signaling in rat hypothalamus and adrenal cortex

Although starvation-induced biochemical and metabolic changes are perceived by the hypothalamus, the adrenal gland plays a key role in the integration of metabolic activity and energy balance, implicating feeding as a major synchronizer of rhythms in the hypothalamic-pituitary-adrenal (HPA) axis. Given that orexins are involved in regulating food intake and activating the HPA axis, we hypothesized that food deprivation, an acute challenge to the systems that regulate energy balance, should elicit changes in orexin receptor signaling at the hypothalamic and adrenal levels. Food deprivation induced orexin type 1 (OX1R) and 2 (OX2R) receptors at mRNA and protein levels in the hypothalamus, in addition to a fivefold increase in prepro-orexin mRNA. Cleaved peptides OR-A and OR-B are also elevated at the protein level. Interestingly, adrenal OX1R and OX2R levels were significantly reduced in food-deprived animals, whereas there was no expression of prepro-orexin in the adrenal gland in either state. Food deprivation exerted a differential effect on OXR-G protein coupling. In the hypothalamus of food deprived rats compared with controls, a significant increase in coupling of orexin receptors to Gq, Gs, and Go was demonstrated, whereas coupling to Gi was relatively less. However, in the adrenal cortex of the food-deprived animal, there was decreased coupling of orexin receptors to Gs, Go, and Gq and increased coupling to Gi. Subsequent second-messenger studies (cAMP/IP3) have supported these findings. Our data indicate that food deprivation has differential effects on orexin receptor expression and their signaling characteristics at the hypothalamic and adrenocortical levels. These findings suggest orexins as potential metabolic regulators within the HPA axis both centrally and peripherally.     

Spike activity of neurons of the ventromedial hypothalamus of the rat during stress

In fixed Wistar line rats, neuronal activity of the ventromedial hypothalamus was studied in conditions of acute emotional stress elicited by electric stimulation of the ventromedial hypothalamus stochastically alternating with electrocutaneous stimuli. Distinctions were revealed in neuronal activity of the animals with different stress resistance. The pattern of neuronal impulse activity proved to be the most informative one.     

Melatonin and gonadoliberin (LH-RH) cells in rat hypothalamus]

Immature female rats were induced to ovulate by an injection of pregnant mare serum: melatonin, intraperitonealy injected, induce an increase of LH-RH immunoreactive neurons in the hypothalamus. These neurons are localized in septo preoptic, infundibular and premammillary areas.     

Evolvement of systems of serotonin uptake in rat hypothalamus during its development]

Kinetics of 3H serotonin accumulation into slices from hypothalamus have been compared in adult, puppy and foetus rat. In 15 days-old, as in adult rat, there are two components of 5 HT accumulation corresponding to the low and high affinity transport systems. For this latter, Km and Vmax values are much higher in adult than in 15 days old rat (in adult, Km=1,3 X 10(-7) and Vmax=0,33 X 10(-10); in 15 days old rat, Km=0,5 X 10(-7) and Vmax=0,125 X 10(-10)). On the opposite, in the 7 days old rat and in the 21 days old foetus, it is only possible to arbitrarely define one uptake system corresponding to the following apparent values: in the 7 days old rat, Km= 5 X 10(-7) and Vmax=2 X 10(-10), in the foetus, Km=0,2 X 10(-7) and Vmax=0,15 X 10(-10). These results showed important developmental differences in affinity of 3H serotonin to hypothalamus. The low and high affinity uptake systems existing in adult are only individualized in the 15 days old little rat.     

Modeling of nociceptor transduction in skin thermal pain sensation

All biological bodies live in a thermal environment with the human body as no exception, where skin is the interface with protecting function. When the temperature moves out of normal physiological range, skin fails to protect and pain sensation is evocated. Skin thermal pain is one of the most common problems for humans in everyday life as well as in thermal therapeutic treatments. Nocicetors (special receptor for pain) in skin play an important role in this process, converting the energy from external noxious thermal stimulus into electrical energy via nerve impulses. However, the underlying mechanisms of nociceptors are poorly understood and there have been limited efforts to model the transduction process. In this paper, a model of nociceptor transduction in skin thermal pain is developed in order to build direct relationship between stimuli and neural response, which incorporates a skin thermomechanical model for the calculation of temperature, damage and thermal stress at the location of nociceptor and a revised Hodgkin-Huxley form model for frequency modulation. The model qualitatively reproduces measured relationship between spike rate and temperature. With the addition of chemical and mechanical components, the model can reproduce the continuing perception of pain after temperature has returned to normal. The model can also predict differences in nociceptor activity as a function of nociceptor depth in skin tissue.     

神经生长因子在痛感受过程中的生物作用

神经生长因子（ＮＧＦ）地神经系统的生长发育具有十分重要的作用,为神经元增殖、分化和存活以及功能维持所必需,并能促进神经损伤后的修复和再生。新近研究表明ＮＧＦ是炎症致痛的重要中介物质参与对伤害性热刺激和机械性刺激的痛过敏,成为引人注目与富有挑战意义的痛觉研究前沿,为临床镇痛药物的开发提供了新的思路。     

Free radical oxidation of lipids in the rat hypothalamus under stress after cortisol pretreatment

Free radical oxidation of lipids in the rat hypothalamus after cortisol pretreatment weas investigated. Three-fold cortisol injection (25 mg/kg, once per day) resulted in significant decrease of average level of Schiffbases, the final products of lipid oxidation. Stress causes increase of average level of Schiff bases in the control animals (without cortisol pretreatment). Cortisol pretreatment potentiated stress-induced changes in the processes of free radical oxidation of lipids in the rats hypothalamus.     

Modification of neuropathic pain sensation through microglial ATP receptors

Neuropathic pain that typically develops when peripheral nerves are damaged through surgery, bone compression in cancer, diabetes, or infection is a major factor causing impaired quality of life in millions of people worldwide. Recently, there has been a rapidly growing body of evidence indicating that spinal glia play a critical role in the pathogenesis of neuropathic pain. Accumulating findings also indicate that nucleotides play an important role in neuron-glia communication through P2 purinoceptors. Damaged neurons release or leak nucleotides including ATP and UTP to stimulate microglia through P2 purinoceptors expressing on microglia. It was shown in an animal model of neuropathic pain that microglial P2X₄ and P2X₇ receptors are crucial in pain signaling after peripheral nerve lesion. In this review, we describe the modification of neuropathic pain sensation through microglial P2X₄ and P2X₇, with the possibility of P2Y₆ and P2Y₁₂ involvement.