Norepinephrine inhibits neurons of the intermediate subnucleus of the lateral septum via alpha2-adrenoceptors

The physiological and pharmacological actions of norepinephrine (NE) on neurons of the intermediate subnucleus of the lateral septum (LSI) were examined using intracellular recordings in rat brain-slices. Bath-applied NE inhibited 72.5%, excited 5.5% and had no effect on 22% of LSI neurons tested; this study focused on the inhibitory effects of NE. In current clamp recordings, 100 microM NE produced a hyperpolarization of 10.82+/-0.72 mV (n=84) with a decrease in input resistance. In voltage-clamp, NE produced a direct, post-synaptic outward current of 206.8+/-22 pA (n=37) with a 64. 3+/-4.9% increase in input conductance (IC50-17.7+/-4 microM). The NE-induced inhibition was mimicked by the alpha2-agonist, UK14,304, but not by the alpha1- or beta-adrenoceptor agonists. The alpha2-agonist, clonidine, had a weak effect in LSI neurons. Interestingly, the magnitude of the UK14,304-induced response varied between cells (ranging from 29.5 to 320% of the maximal NE inhibition), possibly suggesting the involvement of alpha2A-(high affinity for UK14,304) and non-alpha2A (low affinity for UK14,304) adrenoceptor subtypes. While the alpha2-antagonists, yohimbine, rauwolscine and idazoxan blocked NE-induced inhibition in all neurons tested, the prototypical alpha1-antagonist, prazosin produced a variable degree of block (9-58%), further indicating the possible involvement of alpha2A (prazosin-insensitive) and non-alpha2A (prazosin-sensitive) receptors. However a lack of more selective pharmacological tools precludes definitive classification of the alpha2-receptor-mediated responses into different subtypes. The alpha2-receptor-mediated current in LSI neurons displayed Ba2+-sensitive inward rectification, reversed polarity near EK and was sensitive to external K+. In conclusion, NE inhibits LSI neurons via alpha2-adrenoceptor subtypes.     

Effect of norepinephrinergic system on ipalbidine analgesia

Ipalbidine (Ipa) is a photoactive alkaloid isolated from the seeds of ipomoea hardwickki Hemsl. The analgesic effects of Ipa were determined by rat tail flick method. A dose-dependent analgesic effect was found after s.c. or i.c.v. administration of Ipa, but no analgesia was observed after intrathecal injection, indicating that the analgesic effect of Ipa is central in origin, and it acts mainly on supraspinal substrate. The analgesic effect induced by Ipa (60 mg.kg-1, s.c.) was markedly reduced by reserpine (2 mg.kg-1, i.p.) given 24 h before Ipa, which was reversed by combined administration with i.c.v. norepinephrine (NE). In addition, Ipa-induced analgesia was significantly attenuated by electrolytic lesion of bilateral destruction of locus coeruleus, and combined administration with diethyldithiocarbamate (200 mg.kg-1, i.p.), phentolamine (10 mg.kg-1, i.p. or i.c.v.), and prazosin (3 mg.kg-1, s.c.). But no influence was observed on the analgesia of Ipa after administration of yohimbine (5 mg.kg-1, s.c.) or propranolol (10 mg.kg-1, i.p.). These results suggest that the analgesia caused by Ipa is closely related to the function of the central norepinephrinergic system, and probably mediated by indirectly acting on alpha 1 receptors, but not alpha 2 or beta receptors.     

Differential effects of rANF and chronic guanabenz to presynaptic and postsynaptic alpha 2-adrenoceptor-mediated cardiovascular response in pithed rats

1. In normal rats, intracerebroventricular (i.c.v.) guanabenz induced a decrease in blood pressure (BP) and heart rate (HR), and this hypotension or bradycardia was not changed by rANF pretreatment (3 micrograms i.c.v.). 2. In pithed rats, intravenous (i.v.) guanabenz, an alpha 2-adrenoceptor agonist, produced an increase in mean blood pressure (MBP) in a dose-dependent manner. The pressor response by guanabenz was attenuated by infusion of rANF. This attenuation was additive when incubated in combination with yohimbine. 3. In pithed rats, the pressor response due to the increase of sympathetic outflow with electrical stimulation was partially blocked by rANF infusion or chronic guanabenz treatment. This reduction was not augmented by chronic guanabenz plus rANF treatment. 4. The inhibitory action of guanabenz in tachycardia evoked by electrical stimulation at the C7-T1 site was attenuated by rANF, but not by chronic treatment with guanabenz.     

Direct evidence for histamine H3 receptor-mediated inhibition of norepinephrine release from sympathetic terminals of guinea pig myocardium

AIM: To study the histamine H3 receptors mediated inhibition of norepinephrine (NE) release from cardiac sympathetic terminals of guinea pig isolated atria. METHODS: Release of NE induced by electric field stimulation (50 mA, 5 ms) in the bath solution was measured by HPLC-ECD. RESULTS: The release of NE caused by field stimulation was attenuated by (R)-alpha-methyl-histamine (alpha-MeHA, 0.1 nmol.L-1(-10) mumol.L-1) in a concentration-dependent manner. Thioperamide concentration-dependently antagonized the inhibition of alpha-MeHA. Blockade of H1, H2, alpha 2, beta 2-receptors failed to prevent the inhibitory effect of alpha-MeHA. Thioperamide (1 nmol.L-1(-10) mumol.L-1), when used alone, concentration-dependently facilitated the release of NE evoked by field stimulation. CONCLUSION: The presynaptic histamine H3-receptors inhibited the NE release from cardiac sympathetic terminals.     

Useful applications and limits of battery powered implants in functional electrical stimulations

Noradrenaline (NA) (1-10 microM), dibutyryl-cAMP (1-5 mM), and forskolin (10-20 microM) increased cytosolic Ca2+ concentration ([Ca2+]i) in isolated arginine-vasopressin (AVP)-containing neurons in the hypothalamic supraoptic nucleus (SON). The NA-induced increase in [Ca2+]i in AVP-containing neurons was abolished by a specific alpha1-antagonist, prazosin (1 microM) and was markedly reduced when treated with a protein kinase A (PKA) blocker, H89 (40 microM). The NA-induced [Ca2+]i was not altered by a protein kinase C (PKC) inhibitor, calphostin C (0.1 microM) and a PKC activator, TPA (100 nM). In general, NA, a known neurotransmitter in the SON, activates AVP-containing neurons via alpha1-receptor which is linked to stimulation of cAMP-PKA-regulated Ca2+ signaling pathway.     

Invasion depth diagnosis of depressed type early colorectal cancers by combined use of videoendoscopy and chromoendoscopy

The activation of rat mesocortical dopaminergic (DA) neurons evoked by the electrical stimulation of the ventral tegmental area (VTA) induces a marked inhibition of the spontaneous activity of prefrontocortical cells. In the present study, it was first shown that systemic administration of either clozapine (a mixed antagonist of D1, D2, and alpha1-adrenergic receptors) (3-5 mg/kg, i.v.), prazosin (an alpha1-adrenergic antagonist) (0.2 mg/kg, i.v.), or sulpiride (a D2 antagonist) (30 mg/kg, i.v.), but not SCH 23390 (a D1 antagonist) (0.2 mg/kg, i.v.), reversed this cortical inhibition. Second, it was found that following the systemic administration of prazosin, the VTA-induced cortical inhibition reappeared when either SCH 23390 or sulpiride was applied by iontophoresis into the prefrontal cortex. Third, it was seen that, whereas haloperidol (0.2 mg/kg, i.v.), a D2 antagonist which also blocks alpha1-adrenergic receptors, failed to reverse the VTA-induced inhibition, the systemic administration of haloperidol plus SCH 23390 (0.2 mg/kg, i.v.) blocked this inhibition. Finally, it was verified that the cortical inhibitions obtained following treatments with either "prazosin plus sulpiride" or "prazosin plus SCH 23390" were blocked by a superimposed administration of either SCH 23390 or sulpiride, respectively. These data indicate that complex interactions between cortical D2, D1, and alpha1-adrenergic receptors are involved in the regulation of the activity of prefrontocortical cells innervated by the VTA neurons. They confirm that the physiological stimulation of cortical alpha1-adrenergic receptors hampers the functional activity of cortical D1 receptors and suggest that the stimulations of cortical D1 and D2 receptors exert mutual inhibition on each other's transmission.     

Antinociceptive effects of ketamine-opioid combinations in the mouse tail flick test

In rats kept at an ambient temperature of 22 degrees C, centrally and peripherally administered sauvagine induces a dose-dependent hypothermia. To clarify the regulatory mechanisms and to ascertain which neurotransmitter systems mediate sauvagine-induced hypothermia, we administered sauvagine intracerebroventricularly and subcutaneously in rats pretreated with antagonists of muscarinic receptors (atropine), opiate receptors (naloxone), alpha-adrenoceptors (phentolamine, yohimbine and prazosin), beta-adrenoceptors (propranolol) and dopamine receptors (haloperidol and spiperone). Systemic pretreatment of rats with atropine, naloxone, prazosin and propranolol left sauvagine-induced hypothermia unaltered. Pretreatment with phentolamine (4 mg/kg, s.c.), a non-selective alpha-adrenoceptor antagonist, and yohimbine (3 mg/kg, s.c.), a selective alpha 2-adrenoceptor antagonist, enhanced the hypothermic action of sauvagine. Pretreatment with haloperidol (2 mg/kg, s.c.), a non-selective dopamine receptor antagonist, and spiperone (80 micrograms/kg, s.c.), a selective dopamine D2 receptor antagonist, significantly reduced the temperature fall induced by centrally (4 micrograms/rat) and peripherally (20 micrograms/kg) administered sauvagine. Thus, sauvagine-induced hypothermia appears not to be mediated by interactions with cholinergic, endogenous opiate or noradrenergic systems, but rather D2 dopaminergic pathways alone are involved in the inhibitory effect of sauvagine on body temperature in the rat.     

The effect of alpha2-adrenergic drugs on the activity of neurons in the rat nucleus raphe magnus in vitro

The nucleus raphe magnus (NRM) is an important descending inhibitory system for pain transmission. We tested whether clonidine, an alpha2-adrenergic agonist, and yohimbine, an alpha2-adrenergic antagonist, modulate the activity of NRM neurons using extracellular recording in a rat brainstem slice preparation. Clonidine 1-20 microM increased firing frequencies (FF) in 22 (37%) and decreased FF in 6 (10%) spontaneously active neurons. Correlation between the concentrations of clonidine and FF changes was unremarkable. Eight spontaneously active neurons (13%) showed increases followed by decreases in FF with increasing doses of clonidine. The remaining 24 neurons (40%) showed no change in FF. Yohimbine 1 microM decreased FF in 38 spontaneously active neurons (58%), whereas the remaining 27 neurons (42%) showed no change in FF. In some neurons, yohimbine antagonized the increase or decrease in FF by application of clonidine. In three silent neurons (25%), clonidine (5 or 10 microM) induced firing activity, which stopped or decreased with the increasing doses of clonidine. In the remaining nine neurons (75%), clonidine did not induce firing activity. We conclude that activation and inhibition of alpha2-adrenergic receptors of NRM neurons augments and suppresses output of the descending inhibitory pain pathway. Implications: The nucleus raphe magnus is implicated in descending control of the nociceptive processes. We found that clonidine and yohimbine increased and decreased, respectively, the firing activity of a substantial number of nucleus raphe magnus neurons. Clonidine and may facilitate and yohimbine may reduce the outflow of the descending inhibitory pathway.     

Biphasic modulation of spinal nociceptive transmission from the medullary raphe nuclei in the rat

The modulatory effects of electrical and chemical (glutamate) stimulation in the rostral ventromedial medulla (RVM) on spinal nociceptive transmission and a spinal nociceptive reflex were studied in rats. Electrical stimulation at a total 86 sites in the RVM in the medial raphe nuclei (n = 54) and adjacent gigantocellular areas (n = 32) produced biphasic (facilitatory and inhibitory, n = 43) or only inhibitory (n = 43) modulation of the tail-flick (TF) reflex. At these 43 biphasic sites in the RVM, facilitation of the TF reflex was produced at low intensities of stimulation (5-25 microA) and inhibition was produced at greater intensities of stimulation (50-200 microA). At 43 sites in the RVM, electrical stimulation only produced intensity-dependent inhibition of the TF reflex. Activation of cell bodies in the RVM by glutamate microinjection reproduced the biphasic modulatory effects of electrical stimulation. At biphasic sites previously characterized by electrical stimulation, glutamate at a low concentration (5 nmol) produced facilitation of the TF reflex; a greater concentration (50 nmol) only inhibited the TF reflex. In electrophysiological experiments, electrical stimulation at 62 sites in the RVM produced biphasic (n = 26), only inhibitory (n = 26), or only facilitatory (n = 10) modulation of responses of lumbar spinal dorsal horn neurons to noxious cutaneous thermal (50 degrees C) or mechanical (75.9 g) stimulation. Facilitatory effects were produced at lesser intensities of stimulation and inhibitory effects were produced at greater intensities of stimulation. The apparent latencies to stimulation-produced facilitation and inhibition, determined with the use of a cumulative sum method and bin-by-bin analysis of spinal neuron responses to noxious thermal stimulation of the skin, were 231 and 90 ms, respectively. The spinal pathways conveying descending facilitatory and inhibitory influences were found to be different. Descending facilitatory influences on the TF reflex were conveyed in ventral/ventrolateral funiculi, whereas inhibitory influences were conveyed in dorsolateral funiculi. The results indicate that descending inhibitory and facilitatory influences can be simultaneously engaged throughout the RVM, including nucleus raphe magnus, and that such influences are conveyed in different spinal funiculi.     

Prevention by morphine of N-methyl-D-aspartic acid-induced penile erection and yawning: involvement of nitric oxide

A role for catecholamines in the regulation of the blood neutrophilia induced by intravenous (i.v.) injection of lipopolysaccharide (LPS; 250 micrograms/kg) was examined in Wistar rats by means of surgical adrenalectomy or pretreatment with adrenergic and dopaminergic antagonists into naive animals. Treatment of animals with a single dose (250 micrograms/kg) of LPS caused a dramatic increase in the number of circulating neutrophils concomitant with a decrease in the number of these cells in the bone marrow. These effects were partially reversed when catecholamine stores were depleted with reserpine. It was found that neither adrenalectomy nor pretreatment with the dopaminergic antagonists, chlorpromazine and pimozide, affected the changes in neutrophil counts induced by LPS. The injection of the alpha 1/alpha 2-adrenoceptor antagonist, phentolamine, and the selective alpha 1-adrenoceptor antagonist, prazosin, significantly decreased blood neutrophilia induced by LPS. However, neither the selective alpha 2-adrenoceptor antagonist, yohimbine, nor the beta-adrenoceptor antagonist, propranolol, had any effect on LPS response. Taken together, these findings support the hypothesis that the catecholamine norepinephrine plays a role in the regulation of the LPS-induced neutrophilia through activation of alpha 1-adrenoceptors.     

The influence of DNA glycosylases on spontaneous mutation

In the present study we examined the effects of phasic activation of the nucleus locus coeruleus (LC) on transmission of somatosensory information to the rat cerebral cortex. The rationale for this investigation was based on earlier findings that local microiontophoretic application of the putative LC transmitter, norepinephrine (NE), had facilitating actions on cortical neuronal responses to excitatory and inhibitory synaptic stimuli and more recent microdialysis experiments that have demonstrated increases in cortical levels of NE following phasic or tonic activation of LC. Glass micropipets were used to record the extracellular activity of single neurons in the somatosensory cortex of halothane-anesthetized rats. Somatosensory afferent pathways were activated by threshold level mechanical stimulation of the glabrous skin on the contralateral forepaw. Poststimulus time histograms were used to quantitate cortical neuronal responses before and at various time intervals after preconditioning burst activation of the ipsilateral LC. Excitatory and postexcitatory inhibitory responses to forepaw stimulation were enhanced when preceded by phasic activation of LC at conditioning intervals of 200-500 ms. These effects were anatomically specific in that they were only observed upon stimulation of brainstem sites close to (>150 micron) or within LC and were pharmacologically specific in that they were not consistently observed in animals where the LC-NE system had been disrupted by 6-OHDA pretreatment. Overall, these data suggest that following phasic activation of the LC efferent system, the efficacy of signal transmission through sensory networks in mammalian brain is enhanced.     

Epithelial removal with the excimer laser (laser-scrape) in photorefractive keratectomy retreatment

1. A study was made relating the involvement of alpha-adrenoceptors in the cardiovascular responses to intracerebroventricular (i.c.v.) injection of B-HT 920, a clonidine-type drug, in conscious sham-operated and sinoaortic-denervated rats. 2. Wistar rats were used, 7 days after the sham operation or sinoaortic denervation. For i.c.v. injection of drugs, a guide cannula had been previously implanted in the left lateral ventricle. 3. In sham-operated rats, cardiovascular responses to B-HT 920 (10-60 microg) were increased blood pressure and bradycardia; but, in sinoaortic-denervated rats, after the pressor response, a decrease in blood pressure also was seen. The responses to this agent were greater in sinoaortic-denervated rats than in sham-operated animals. Treatment with the alpha2-adrenoceptor antagonist yohimbine (30 microg), the imidazoline receptor antagonist idazoxan (15 microg) and the alpha1A-adrenoceptor antagonist 5-methylurapidil (15 microg) blocked the responses to B-HT 920 (30 microg). The alpha1-adrenoceptor antagonist prazosin (15 microg) and the alpha1B-adrenoceptor antagonist chloroethylclonidine (100 microg) did not modify the responses to agonist. 4. Sinoaortic denervation enhances the cardiovascular responses to B-HT 920. Moreover, the effects of i.c.v. administration of B-HT 920 could be mediated by several types of brain receptors: imidazoline receptors and alpha1A- and alpha2-adrenoceptors.     

VDAC/porin is present in sarcoplasmic reticulum from skeletal muscle

Direct intraspinal injection of the catecholamines epinephrine and norepinephrine, and the alpha-adrenergic agents dexmedetomidine and clonidine, produced a dose-dependent elevation of pain thresholds in the Northern grass frog, Rana pipiens. Significant analgesic effects were noted for at least 4 h. The analgesic effect of intraspinal dexmedetomidine or epinephrine was blocked by systemic pretreatment with the alpha 2-adrenoceptor antagonists, yohimbine and atipamezole, but not with the alpha 1-adrenoceptor antagonist, prazosin. Dose-response analyses showed that dexmedetomidine, epinephrine, norepinephrine had similar analgesic potencies, but clonidine was significantly less potent. Analgesia was observed without accompanying motor or sedative effects. These results suggest that alpha 2-adrenoceptor mechanisms which mediate analgesia may have evolved early in vertebrate evolution and that descending epinephrine-containing fibers in the amphibian nervous system may be the source of endogenous catecholamines regulating nociceptive sensitivity in the amphibian spinal cord.     

Supplemental dietary arginine accelerates intestinal mucosal regeneration and enhances bacterial clearance following radiation enteritis in rats

Medetomidine was administered to sheep and horses at a dose rate of 5 microg kg(-1) (i.v.). Heart rate and blood pressure were recorded. Medetomidine induced bradycardia and a biphasic blood pressure response consisting of a transient hypertension followed by hypotension. Administration of prazosin (an alpha1 adrenoceptor antagonist; 100 microg kg(-1), i.v.) had no effect on the cardiovascular response to medetomidine (5 microg kg(-1), i.v.), but inhibited the cardiovascular response of methoxamine (an alpha1 adrenoceptor agonist; 75 microg kg(-1), i.v.). L-659,066 (an alpha2 adrenoceptor antagonist which does not cross the blood brain barrier; 264 microg kg(-1), i.v.) attenuated the medetomidine induced bradycardia, but had no effect on the cardiovascular response to methoxamine. L659,066 also reduced the medetomidine induced hypertension in sheep, but had less effect on the horse. It is concluded that both alpha1 and alpha2 adrenoceptors are important in the control of cardiovascular function in horses and sheep. Medetomidine appears to act on alpha2 adrenoceptors alone in the sheep. The cardiovascular effects of medetomidine in the horse are complex and may be influenced by central alpha2 adrenoceptor regulation or effects on other receptor subtypes as well as direct stimulation of peripheral alpha2 adrenoceptors.     

Alpha1-adrenergic and dopaminergic receptors are involved in the anoretic effect of corticotropin-releasing factor in goldfish

This study investigates the noradrenergic and/or dopaminergic receptors subtypes involved in the anoretic action of CRF in goldfish. Agonists and antagonists of alpha1- and alpha2-adrenoceptors, and D1- and D2-dopaminergic receptors were intracerebroventricularly (i.c.v.) administered alone or in combination with CRF in the case of antagonists. Food intake and hypothalamic content of catecholamines and their metabolites were measured at 2 h postinjection. On one hand, alpha1-adrenergic receptor antagonist, but not alpha2, blocked the anoretic effect of CRF. Moreover, we found a blockade of CRF-induced anoretic action by pretreatment with specific D1- and D2-dopaminergic antagonists. On the other hand, the i.c.v. administration of CRF reduced hypothalamic norepinephrine (NE) and dopamine (DA) content, without modifications in their metabolism. Thus, our results suggest that the anoretic effect of CRF appears to be mediated by alpha1-adrenergic and dopaminergic receptors in fish. Second, the reduction in hypothalamic NE and DA synthesis could be due to a direct effect of CRF treatment and/or a secondary effect of food intake reduction.     

Modulatory effects of regional cortical activation on the onset responses of the cat medial geniculate neurons

Corticofugal modulation on activity of the medial geniculate body (MGB) was examined by locally activating the primary auditory cortex (AI) and looking for effects on the onset responses of MGB neurons to acoustic stimuli. Of 103 MGB neurons recorded from 13 hemispheres of 11 animals, 91 neurons (88%) showed either a facilitatory or inhibitory effect or both; of these neurons, 72 showed facilitatory effects and 25 inhibitory effects. The average facilitatory effect was large, with a mean increase of 62.4%. Small inhibitory effects (mean: -16.2%) were obtained from a few neurons (6 of 103) when a pure tone stimulus was used, whereas the effect became larger and more frequent when a noise burst stimulus was used (mean: -27.3%, n = 22 of 27 neurons). Activation of an AI site having the same best frequency (BF) as the MGB neuron being recorded from produced mainly a facilitatory effect on MGB neuronal responses to pure tones. Activation of AI at a site neighboring the BF site produced inhibitory effects on the MGB response when noise burst stimuli were used. We found that the effective stimulation sites in AI that could modulate MGB activity formed patchlike maps with a diameter of 1.13 +/- 0.09 (SE) mm (range 0.6-1.9 mm, n = 15) being larger than the patches of thalamocortical terminal fields. Examining the effects of sound intensities, of 18 neurons tested 9 neurons showed a larger effect for low-sound-intensity stimuli and small or no effects for high-sound-intensity stimuli. These were named low-sound-intensity effective neurons. Five neurons showed high sound intensity effectiveness and four were non-intensity specific. Most low-sound-intensity effective neurons were monotonic rate-intensity function neurons. The AI cortical modulatory effect was frequency specific, because 15 of 27 neurons showed a larger facilitatory effect when a BF stimulus was used rather than a stimulus of any other frequency. The corticothalamic connection between the recording site in MGB and the most effective stimulation site in AI was confirmed by injecting wheat germ agglutinin-horseradish peroxidase tracer at the stimulation site and producing a small lesion in the recording site. The results suggest that 1) the large facilitation effects obtained by AI activation at the region that directly projected to the MGB could be the result mainly of the direct projection terminals to the MGB relay neurons; 2) the large size patches of the effective stimulation site in AI could be due to widely ramifying corticothalamic projections; and 3) the corticofugal projection selectively gates auditory information mainly by a facilitatory effect, although there is also an inhibitory effect that depends on the sound stimulus used.     

Norepinephrine-induced contraction of isolated rabbit bronchial artery: role of alpha 1- and alpha 2-adrenoceptor activation

The contractile effect of norepinephrine (NE) on isolated rabbit bronchial artery rings (150-300 microns in diameter) and the role of alpha 1- and alpha 2-adrenoceptors (AR) on smooth muscle and endothelium were studied. In intact arteries, NE increased tension in a dose-dependent manner, and the sensitivity for NE was further increased in the absence of endothelium. In intact but not in endothelium-denuded arteries, the response to NE was increased in the presence of both indomethacin (Indo; cyclooxygenase inhibitor) and NG-nitro-L-arginine methyl ester [L-NAME; nitric oxide (NO) synthase inhibitor], indicating that two endothelium-derived factors, NO and a prostanoid, modulate the NE-induced contraction. The alpha 1-AR antagonist prazosin shifted the NE dose-response curve to the right, and phenylephrine (alpha 1-AR agonist) induced a dose-dependent contraction that was potentiated by L-NAME or removal of the endothelium. The sensitivity to NE was increased slightly by the alpha 2-AR antagonists yohimbine and idazoxan, and this effect was abolished by Indo or removal of the endothelium. Similarly, contractions induced by UK-14304 (alpha 2-AR agonist) were potentiated by Indo or removal of the endothelium. These results suggest that NE-induced contraction is mediated through activation of alpha 1- and alpha 2-ARs on both smooth muscle and endothelium. Activation of the alpha 1- and alpha 2-ARs on the smooth muscle causes contraction, whereas activation of the endothelial alpha 1- and alpha 2-ARs induces relaxation through release of NO (alpha 1-ARs) and a prostanoid (alpha 2-ARs).     

Dopamine releases endothelium-derived relaxing factor via alpha 2-adrenoceptors in canine vessels: comparisons between femoral arteries and veins

1. We investigated the role of vascular smooth muscle alpha-adrenoceptor subtypes in the vasoconstrictor response of femoral arteries and veins to dopamine and whether the vasoconstriction is modified by endothelium-dependent relaxation mediated via the activation of alpha 2-adrenoceptors in ring preparations of femoral arteries and veins from mongrel dogs. 2. Dopamine contracted both arteries and veins in a dose-dependent manner and this contraction was inhibited by pretreatment with phentolamine or prazosin. Pretreatment with yohimbine shifted the dose-response curve for dopamine to the right in femoral veins, but not in arteries. 3. Phenylephrine contracted femoral arteries and veins in a dose-dependent manner and this contraction was inhibited by pretreatment with prazosin. 4. Clonidine produced a bell-shaped dose-response curve in femoral veins and this curve was shifted upwards by pretreatment with NG-nitro-L-arginine (L-NNA). In contrast, femoral arteries were not affected by clonidine. NG-Nitro-L-arginine potentiated contractile responses to dopamine in both veins and arteries. This potentiation was inhibited by yohimbine or by the removal of the endothelium in both arteries and veins. 5. These results suggest that dopamine contracts femoral arteries via stimulation of alpha 1-adrenoceptors and contracts femoral veins via stimulation of both alpha 1- and alpha 2-adrenoceptors and that these contractions are attenuated by the vasodilator action of dopamine via alpha 2-adrenoceptor-mediated release of endothelium-derived relaxing factor.     

Inhibitory effects of acupuncture manipulation and focal electrical stimulation of the nucleus submedius on a viscerosomatic reflex in anesthetized rats

To examine the participation of nucleus submedius (Sm) in the medial thalamus of pain inhibitory systems, we investigated the effects of acupuncture and focal electrical stimulation of the Sm and adjacent brain sites (0.3 ms, 50 Hz, 50-100 microA, 10 s) on the EMG activity of the external oblique muscle evoked by colorectal distension in urethane-anesthetized Wistar rats. The viscerosomatic reflex (VSR) activity was suppressed after the administration of morphine (1.0 mg/kg, i.v.) and the effect was reversed by naloxone (0.5 mg/kg, i.v.). Transection of the spinal cord at the Th2 level also eliminated the VSR. Acupuncture manipulation applied to the cheek (manual rotation at 1 Hz) suppressed the VSR, and this inhibition was eliminated by microinjections of lidocaine into the bilateral Sm nuclei (0.5 microliter of 1.0% solution). Electrical stimulation in the ventral part but not the dorsal part of the Sm suppressed the VSR. The inhibition of the VSR induced by electrical stimulation of the Sm was not reversed by the administration of naloxone (1.0 mg/kg, i.v.). Electrical stimulation of the adjacent medial thalamic nuclei (mediodorsal nucleus (MD) or centromedial nucleus (CM)) and ventrobasal complex (VB) of the thalamus had very little effect on the VSR. These results suggests that the Sm is not only involved in the relay of nociceptive information to the cortex, but may also be involved in a non-opioid mediated pain inhibitory system and may participate, at least in part, in the suppressive effects of intense acupuncture manipulation on VSR activity.     

Effects of vasopressin and involvement of receptor subtypes in the rat central amygdaloid nucleus in vitro

Effects of arginine-vasopressin (AVP) on neurons in the central amygdaloid nucleus (ACe) were investigated with rat brain slice preparations using extracellular recording methods. Of 160 ACe neurons tested, 70 cells (44%) were excited and 9 cells (6%) were inhibited by bath application of AVP at 3 x 10(-7) M. The excitatory effects of AVP were dose-dependent and the threshold concentration was approximately 10(-10) to 10(-9) M. The excitatory effects of AVP persisted under blockade of synaptic transmission by perfusing with Ca2+-free and high-Mg2+ medium, whereas the inhibitory effects were abolished by synaptic blockade. AVP-induced effects were mimicked by a V1-receptor agonist and completely blocked by a selective V1-antagonist. V2-agonist produced no effects on ACe neurons and V2-antagonist had no effect on AVP-induced excitation. These results showed that the excitatory effect of AVP on ACe neurons was produced by a direct action through the V1-receptors, whereas the inhibitory response of ACe neurons to AVP seemed to be produced by an indirect action. The results of this study suggest that AVP is involved in the amygdala-relevant functions as a neurotransmitter or a neuromodulator.