[Central effect of xylazine and yohimbin on pain sensitivity of rat during estrous cycle in formalin test]

Sex hormone is supposed to modify pain sensitivity. The aim of the present study was to investigate, the role of 2 adrenergic receptors in nociception using formalin test. Formalin test was performed by subcutaneous injection of 50 ml formalin [%2.5] solution into hind paw. Animals were divided into 4 groups as control group [intact animal], sham group [received 2 micro l of artificial CSF by ICV route], agonist group [received 2 micro l of xylazine 5 and 10 mg/ rat by ICV route] and antagonist group [received 2 micro l of yohimbin 5 and 10 mg/ rat by ICV route]. Data were analyzed by two way ANOVA and post- hoc test of tukey's test. Data showed that xylazine significantly decreased [p<0.05] pain sensitivity during all stages of estrous cycle; analgesic effect of xylazine was high in estrus stage of estrous cycle and low in metestrous stage of estrous cycle. Yohimbin in all stages of estrous cycle significantly increased [p<0.05] pain sensitivity. Hyperalgesic effect of yohimbin was high during metestrous stage of estrous cycle and it was low in proestrous stage of estrous cycle. Results of present study indicated that interaction of alpha2 adrenergic system with endogenous sex steroid is important in the modulation of pain sensitivity

Role of peripheral alpha2 adrenergic receptors in tonic pain during different stages of estrous cycle in rats

Estrogen and progesterone are supposed to modify pain sensitivity. However, the actual role of each of these steroid hormones in this respect is not well known. Plasma concentrations of these hormones show variation during estrous cycle. The role of alpha2 receptors in tonic pain has been pointed out. The aim of the present study was to investigate the agonist and antagonist effect of alpha2 adrenergic receptors on tonic pain sensitivity during all stages of estrous cycle in female rats. Xylasine as alpha 2 agonist and yohimbin as alpha 2 antagonist were used via intraperitoneal route [IP]. Adult rats weighing 180-200 grams were used. Animals were maintained on 12h reverse light/dark cycle for 7 days prior to the experiment. Water and food was available ad libitum. Formalin test was performed by subcutaneous injection of 50 micro l formalin [2.5%] solution into the hind paw. Formalin test was performed in all stages of estrous cycle for 60 minutes. Animals were divided into four groups; 1- control group [intact animal], 2- Sham group [animals received 0.2 ml normal saline by IP route], 3- Agonist groups [animals received 0.2 ml xylasine 1, 3 mg/kg body weight by IP route] and 4- Antagonist group [animals received 0.2 ml yohimbine 1, 3 mg/kg body weight by IP route]. Data were statistically analyzed using 2 way ANOVA test followed by Tukey's test as posthoc test. P < 0.05 was considered significant. Results showed that xylasine significantly [p < 0.05] decreases pain sensitivity in all stages of estrous cycle. Analgesic effect of xylasine was maximum in estrus stage of estrous cycle and minimum in metestrus stage of estrous cycle. Yohimbine significantly [p < 0.05] increases pain sensitivity in all stages of estrous cycle. Hyperalgesic effect of yohimbine was maximum in metestrus stage of estrous cycle and minimum in estrus stage of estrous cycle. These results indicate that alpha2 adrenergic system and endogenous steroids have an important role in pain sensitivity

Adrenergic involvement in the locus ceruleus and adjoining regions in the facilitation of predatory attack behavior as induced by hypothalamic stimulation in cats.

The present study was carried out in five cats which did not attack the rats spontaneously. Predatory attack on an anaesthetized rat was elicited by electrical stimulation of extreme lateral regions of hypothalamus. These sites were stimulated at a current strength from 300-700 microa to evoke a predatory attack on an anaesthetized rat. The attack was accompanied by minimal affective display such as alertness, pupillary dilatation, and culminated in beck biting at higher current strength. A scoring system allowed the construction of stimulus response curves, which remained fairly constant when repeated over a period of 3-4 weeks. Microinfusions of norepineprine and clonidine in 4.0 and 5.0 microg dose respectively in locus ceruleus and adjoining tegmental fields facilitated the predatory attack and there was a significant reduction in the threshold current strength for the elicitation of affective and somatomotor components. Microinfusions of yohimbine, an alpha-2 blocker, in 5 microg dose completely blocked the predatory attach response as indicated by an increase in the threshold current strength for the affective components. The somatomotor components were completely inhibited and could not be elicited even when the current strength was increased to 1000 microA. The predatory attack behavior remained completely inhibited for almost two hours following microinfusion of yohimbine. During this period, the animal was extremely drowsy and reacted very slowly even to a painful stimulus such as pinching of tail. Microinfusions of propranalol (beta-blocker), practalol (beta-1 blocker), prazosin (alpha-1 antagonist), propylene glycol as well as saline in similar volumes (0.5 microl) as control failed to produce any blocking effect, thus indicating the involvement of alpha-2 adrenoceptive mechanisms in the modulation of predatory attack in this region of midbrain. The facilitatory effects of norepinephrine and clonidine were significant at P<0.01 and P<0.05 respectively with Wilcoxon's signed rank test. The inhibitory effects of yohimbine were significant at P<0.05. The present study indicates the involvement of alpha-2 adrenoceptive mechanisms in the facilitation of hypothalamically elicited predatory attack.

Darkened Xenopus tadpoles appeared with neurochemical agents.

Skin darkened tadpoles sometimes appear spontaneously. Darkened was artificially induced in Xenopus larvae by yohimbine or chlorpromazine. These phenomena look like that are seen at pinealectomized or hypothalamus separated Xenopus larva. In this experiment, such a morphological color changed Xenopus larva is suggested by cause of inhibition of alpha2-adrenargic receptor or dopamine receptor from gastrula stages.

Alpha-adrenergic pathways in the lateral hypothalamus are important for the dipsogenic effect of carbachol injected into the medial septal area

We studied the effect of the Ó1-and Ó2-adrenergic receptors of the lateral hypothalamus (LH) on the control of water intake induced by injection of carbachol into the medial septal area (MSA) of adult male Holtzman rats (250-300g) implanted with chronic stainless steel cannulae into the LH and MSA. The volume of injection was always 1 µl and was injected over a period of 30-60 s. For control, 0.15MNaCl was used. Clonidine (20 nmol) but not phenylephrine (160 nmol) injected into the LH inhibited water intake induced by injection of carbachol (2 nmol) into the MSA, from 5.4 ñ 1.2ml/h to 0.3 ñ 0.1 and 3.0 ñ 0.9 ml/h, respectively (N=26). When we injected yohimbine (80nmol) + clonidine (20nmol) and prazosin (40nmol) + clonidine (20nmol) into the LH, water intake induced by injection of carbachol into the MSA was inhibited from 5.4 ñ 1.2 ml/h to 0.8 ñ 0.5 and 0.3 ñ 0.2 ml/h, respectively (N=19). Water intake induced by carbachol (2nmol) injected into the MSA was decreased by previous injection of yohimbine (80 nmol) + phenylephrine (160 nmol) and prazosin (40 nmol) + phenylephrine (160 nmol) from 5.4 ñ 1.2ml/h to 1.0 ñ 0.7 and 1.8 ml/h, respectively (N = 16). The cannula reached both the medial septal area in its medial portion and the lateral hypothalamus. It has been suggested that the different pathways for induction of drinking converge on a final common pathway. Thus, adrenergic stimulation of Ó2-adrenoceptors of LH can influence this final common pathway

On the characterization of dopamine-induced contractile response of rat anococcygeus muscle preparation.

Presence of specific dopamine (DA) receptors and their characterization was attempted in rat anococcygeus muscle preparation. Dopamine (10(-6) M) and B-HT 920 (10(-6) M) produced concentration dependent contractions of the rat anococcygeus muscle preparation. The response of DA was shifted towards right in presence of haloperidol (10(-6) M; pA2 = 6.8) and sulpiride (10(-4) M) in a competitive manner. Alpha 2 antagonists yohimbine (10(-5) M) and idazoxan (10(-5) M) blocked the response to DA in a competitive manner, while alpha 1 antagonist prazosin (10(-5) M) completely blocked the response to DA. SCH 23390 (10(-5) M), a D1 DA antagonist potentiated the response to DA. Reserpinization (5 mg/kg, 24 hr prior) brought about a shift towards the right, and this response was similarly blocked by haloperidol, sulpiride and yohimbine without affecting the maximum response. Desipramine (10(-5) M) blocked the response of DA in a non-competitive manner. Pretreatment of animals with desipramine (10 mg/kg) followed by reserpine, brought about a reversal of action of reserpine. The response to B-HT 920 (10(-6) M), was blocked similarly by haloperidol and yohimbine. However, the effect of desipramine was more pronounced when compared to DA per se. SKF 38393, a D1 DA agonist, potentiated the response to B-HT 920. The findings suggest the presence of both D1 and D2 DA receptors in rat anococcygeus muscle and that DA also acts on adrenergic receptors to produce a contractile response of this muscle preparation.

Dopamine receptor mediated antidepressant action of B-HT 920 in mice.

Possible involvement of dopaminergic (DAergic) system in forced swimming-induced immobility (despair behaviour) was investigated in mice. B-HT 920 (0.05 and 0.1 mg/kg), a post-synaptic DAergic agonist, produced a dose dependent reduction in immobility period, which was sensitive to blockade by haloperidol (0.5 mg/kg) and sulpiride (100 mg/kg). This effect was also blocked by alpha 2 antagonist yohimbine (5 mg/kg). SKF 38393 (5 mg/kg), a D1-DA agonist potentiated the action of B-HT 920. Reserpinization (2 mg/kg, 24 hr prior) produced despair immobility in mice. When a low dose of B-HT 920 (0.05 mg/kg) was given to reserpinized animals, the duration of immobility period was further increased. But on the other hand, a higher dose (0.1 mg/kg) of it reduced reserpine-induced immobility. Desipramine (5 and 10 mg/kg), elicited a dose dependent reduction in the immobility period, which was sensitive to blockade by sulpiride (100 mg/kg). Desipramine (10 mg/kg) showed a diphasic response in combination with B-HT 920, i.e., a potentiation of the response due to a low dose of B-HT 920 (0.05 mg/kg) and an antagonism of the response due to a higher dose of B-HT 920 (0.1 mg/kg), respectively. SKF 38393 (5 mg/kg), potentiated the action of desipramine (5 mg/kg). SKF 38393 (5 mg/kg) further potentiated the action of desipramine (5 mg/kg) and B-HT 920 (0.05 mg/kg). These observations suggests that B-HT 920 reduces behavioural immobility by DAergic mechanism and desipramine also modulates D2-DA receptors in its anti-depressant action.

Mechanism of decrease in heart rate by peripheral dopaminergic D2-receptors

We performed this study in order to verify the heart rate decrease caused by the D2-receptor on cardiac sympathetic nerve endings and its relation to the concentration of norepinephrine in synaptic clefts. Sprague-Dawley rats were pithed and the heart rate was increased either by electrical stimulation of the cardiac accelerator nerve or by intravenous infusion of norepinephrine, tyramine, or isoproterenol. Increased heart rate by electrical stimulation of cardiac accelerator nerve was dose-dependently lowered by lisuride and its effect was blocked by pretreatment with sulpiride but not with yohimbine and SCH 23390. Also, the heart rate was decreased in a dose-dependent manner by clonidine and this effect was blocked by pretreatment with yohimbine, but not with sulpiride. For increased heart rate by infusion of norepinephrine, tyramine, or isoproterenol, the heart rate lowering effect of lisuride was more marked in the norepinephrine-and tyramine-infusion groups, in which the intrasynaptic concentration of norepinephrine was elevated, compared to the isoproterenol-infusion group, in which intrasynaptic concentration of norepinephrine was not elevated. In conclusion, there is a D2-receptor on the cardiac sympathetic nerve endings which decreases the heart rate and is different from the presynaptic alpha 2-receptor. Also, the heart rate lowering effect via stimulation of the D2-receptor by lisuride was more marked with increased concentration of norepinephrine in the synaptic cleft.

Influência dos adrenoceptores alfa1 e alfa2 do hipotálamo médio sobre a pressao arterial sistêmica em ratos / Role of the alfa1 and alfa2 adrenoceptores in the medial hypothalamus on the arterial pressure in rats

Foram estudados os efeitos sobre a pressäo arterial sistêmica após a administraçäo de noradrenalina e de dois antagonistas de alfa-adrenoceptores no hipotálamo médio de ratos normotensos. Tanto o prazosin quanto a ioimbina antagonizaram a açäo do agonista misto de alfa1/alfa2-adrenoceptores, a noradrenalina ; entretanto a administraçäo prévia de prazosin mostrou uma maior interaçäo da noradrenalina pelos adrenoceptores alfa1. Estes resultados sugerem que os adrenoceptores alfa1 do hipotálamo médio exerceriam uma maior influência que os adrenoceptores alfa2 no controle de pressäo arterial sistêmica

Effects of yohimbine on dopamine dependent behaviours in rats and mice.

In the present study we have investigated the effect of yohimbine on dopamine-dependent behaviours in rats and mice. Yohimbine (1.25 to 10 mg/kg, ip) failed to block the conditioned avoidance response in rats, to inhibit the traction response in mice and to induce catalepsy in rats and mice. Pretreatment with yohimbine (1.25 to 10 mg/kg, ip) had no significant effect on apomorphine stereotypy in rats and apomorphine induced cage climbing behaviour in mice. However, pretreatment with yohimbine (1.25 to 10 mg/kg. ip) significantly increased the intensity of methamphetamine stereotypy and antagonised haloperidol catalepsy in rats. Our findings indicate that yohimbine does not possess postsynaptic striatal and mesolimbic D-2 dopamine receptor blocking activity.

La N-2 cloroetil N-etil-2-bromobencilamina (DSP4) aumenta la liberacion de eH- noradrenalina producida por despolarizacion del terminal nervioso / N-2 chloroethyl N-2-bromobenzylamine (DSP4) increases the 3H- noradrenaline release evoked by nerve despolarization

La administración intraperitoneal del DSP4 en roedores adultos, inhibe la captación de la 3H-NA exógena y reduce el contenido endógeno de NA en el sistema nervioso central y en la captación noradrenérgica desipramina, con el precursor de la NA, la 1-dopa o con inhibidores de la MAO B, previene los efectos neurotóxicos del DSP4. Con el objeto de investigar el mecanismo por el cual DSP4 reduce el contenido endógeno de NA, la liberación del neurotransmisor inducida por despolarización con K+, fue estudiada en cortes de la corteza cerebral de la rata, un tejido sensible a la acción neurotóxica del DSP4. La incubación con DSP4 (10 micromol/1) indujo un aumento de la liberación de NA espontánea y la inducida por estimulación con el K+. En medio libre de Ca++ sólo se incrementó la liberación espontánea. La potenciación de la liberación de NA inducida por el K+ parece estar relacionada con los mecanismos alfa2 adrenérgicos, dado que no se observa aditividad entre la potenciación producida por el antagonista alfa 2 yohimbina y el DSP4. Sin embargo, esta potenciación a través de mecanismos presinápticos no parece estar involucrada en la depleción desarrollada por el neurotóxico, dado que los tratamientos realziados con drogas con afinidad adrenérgicas son ineficaces para previnir la depleción noradrenérgica por el DSP4 en la corteza cerebral. Los resultados obtenidos en el conducto deferente avalan esta hipótesis, dado que en este tejido resistente al efecto deplecionante del DSP4, el compuesto t

Protective effect of ST-93 against ouabain induced arrhythmias in guinea pigs.

ST-93, a clonidine analog was studied for its antiarrhythmic activity in anaesthetised guinea pigs against ouabain induced arrhythmia. The amount of ouabain required (micrograms/kg) for the production of ventricular premature best. Ventricular fibrillation and cardiac arrest was recorded in control and drug treated group of animals. Both ST-93 and clonidine produced significant antiarrhythmic effect in guinea pigs. This protective effect was significantly blocked by yohimbine, suggesting that the antiarrhythmic effect is mediated through presynaptic alpha 2-adrenoceptors.

Central histaminoceptor-adrenoceptor interrelations in the release of adrenocorticotrophic hormone.

Intracerebroventricular administration of adrenaline, noradrenaline phenylephrine, clonidine and histamine produced a significant rise in plasma cortisol concentration whereas isoprenaline had no effect. alpha-Adrenoceptor blockers (yohimbine or piperoxon) per se did not alter the plasma cortisol level. Central pretreatment with yohimbine or piperoxin, blocked the rise in plasma cortisol level induced by icv noradrenaline, phenylephrine and clonidine. In another set of experiments, both H1 and H2 receptor antagonists (mepyramine, and metiamide) per se had not significant effect on plasma cortisol concentration. Central histamine induced rise in plasma cortisol concentration was significantly blocked by icv pretreatment with both H1 and H2 receptor blockers. Furthermore, yohimbine also significantly prevented the rise of plasma cortisol level induced by icv histamine.