Noradrenergic Nerve Terminals Research Articles

High d-glucose concentrations increase GABA release but inhibit release of norepinephrine and 5-hydroxytryptamine in rat cerebral cortex

The effect of high d-glucose concentrations on the K + (15–25 mM)-evoked release of [ 3H]GABA, [ 3H]norepinephrine ([ 3H]NE), [ 3H]5-hydroxytryptamine ([ 3H]5-HT) and [ 3H]acetylcholine ([ 3H]ACh) was investigated in rat cerebral cortical slices and synaptosomes superfused with Krebs' solution which normally contains 11.1 mM glucose. In slices, the release of [ 3H]GABA was enhanced by increasing d-glucose by 32–320 mM, the release of [ 3H]NE and [ 3H]5-HT was inhibited when d-glucose was increased by 60–320 mM but the release of [ 3H]ACh was not affected. The increase of [ 3H]GABA release and the inhibition of [ 3H]NE release were mimicked by d-fructose and NaCl at similar osmolarities, whereas dimethylsulfoxide (DMSO; a freely membrane-permeable drug) at equimolar concentrations failed to affect the release of [ 3H]GABA and [ 3H]NE. The GABA B receptor antagonist p-(3-aminopropyl)-p-diethoxymethyl-phosphinic acid (CGP 35348) abolished the inhibitory effect of an increase in d-glucose by 60 and 100 mM on [ 3H]NE release but only tended to diminish the inhibition caused by an increase by 320 mM. In synaptosomes, the K +-evoked release of 3H-GABA was enhanced by increasing d-glucose by 60–320 mM. The K +-evoked release of [ 3H]NE was only inhibited when d-glucose was increased by 320 mM, whereas it was not affected by an increase by 100 mM. In conclusion, high d-glucose differentially influences neurotransmitter release in the brain cortex. Hyperosmolarity in the extracellular fluid together with an osmotic gradient extra- versus intracellular probably plays a role in the mechanism(s) underlying the changes observed. The inhibition of [ 3H]NE release induced by an increase in d-glucose by up to 100 mM is probably due to the enhancement of [ 3H]GABA release from GABAergic interneurons, thus leading to an increased activation of inhibitory GABA B receptors either on the noradrenergic axon terminals themselves or on an unknown excitatory neuron which innervates the noradrenergic nerve terminals. The effects of d-glucose on neurotransmitter release may contribute to the neurologic disorders during diabetic coma.

Adrenergic control of the secretion of anterior pituitary hormones

The hypothalamic hypophysiotrophic neurones are densely innervated by adrenergic and noradrenergic nerve terminals. Activation of alpha 1-adrenoceptors located in the brain stimulates the secretion of ACTH, prolactin and TSH. The effects of the alpha 1-adrenoceptors seem to be exerted on hypothalamic neurones that secrete vasopressin, CRH-41 and TRH. These mechanisms are important in the physiological control of the secretion of ACTH and TSH in humans. alpha 2-Adrenoceptors are not involved in the control of secretion of these hormones under basal conditions in humans. However, alpha 2-adrenoceptors exert an inhibitory effect that acts as a negative feedback mechanism, limiting excessive secretion of these hormones. There is no convincing evidence for the involvement of beta-adrenoceptors in the control of the secretion of these three hormones in humans. Studies on cultured anterior pituitary cells suggested that adrenaline and noradrenaline may influence the secretion of ACTH, prolactin and TSH directly at the level of the pituitary. However, these effects are not demonstrable in humans, and are likely to be due to alterations in the pituitary adrenoceptors during culture. In the case of growth hormone, activation of alpha 2-adrenoceptors located in the brain stimulates secretion of this hormone both by increasing the secretion of GHRH and by inhibiting the secretion of somatostatin. Activation of beta-adrenoceptors inhibits the secretion of growth hormone via an increase in the secretion of somatostatin. The effects of the central alpha 2- and beta-adrenoceptors are important in the physiological control of growth hormone secretion in humans. A considerable amount of evidence implicates brain alpha 1-adrenoceptors in the control of secretion of the gonadotrophins in experimental animals, but, despite intensive study, no convincing evidence has been found in humans of reproductive age.

Presynaptic alterations associated with enhancement of evoked release and synthesis of norepinephrine in hippocampus of chronically cold-stressed rats

We have previously demonstrated that prior exposure to chronic cold stress does not alter basal levels of norepinephrine (NE) release or synthesis in hippocampus of rat. However, in response to a subsequent novel stressor, an enhancement of both of these noradrenergic parameters is observed in the chronically stressed animals relative to naive controls. In the present experiments, we have examined whether the biochemical sensitization of NE release and synthesis produced by chronic stress can be demonstrated by local depolarization of the noradrenergic nerve terminals with elevated K +. The local application of elevated K + in dorsal hippocampus resulted in a greater increase in extracellular NE and 3,4-dihydroxyphenylacetic acid (DOPAC) in chronically stressed rats than in naive controls. It is proposed that in dorsal hippocampus, extracellular NE and DOPAC provide measures of NE release and biosynthesis, respectively. Therefore, these data suggest that local depolarization, similar to novel stress, elicits both enhanced NE release and synthesis in chronically stressed rats. One factor that is known to modulate both of these processes is the presynaptic α-2 adrenergic receptor. Therefore, we examined whether a change in the sensitivity of these receptors might contribute to the altered noradrenergic responsivity observed in chronically stressed rats. Local administration of clonidine, an α-2 receptor agonist, produced a decrease in extracellular NE and DOPAC in both naive and chronically stressed rats. The dose-response curve for the effect of clonidine on NE was shifted to the left in the latter group. In addition, local administration of idazoxan, an α-2 receptor antagonist, produced a greater increase in extracellular NE and DOPAC in the chronically stressed rats than in naive controls. These data suggest that an increase in the α-2 receptor modulation of NE release and synthesis is operative in the chronically stressed animals. Although this apparent supersensitivity of the α-2 receptors cannot readily explain the enhancement of evoked noradrenergic responses observed in chronically stressed rats, it may underlie the unaltered basal levels of NE release and synthesis observed in these animals.

ATP release from dorsal spinal cord synaptosomes: characterization and neuronal origin

The present study determined the Ca 2+-dependence of the release of adenosine 5′-triphosphate (ATP) from dorsal spinal cord synaptosomes evoked by depolarization with K + and capsaicin, and the effect of intrathecal capsaicin pretreatment, dorsal rhizotomy and intrathecal pretreatment with 6-hydroxydopamine on such release. Release of ATP evoked by K + was Ca 2+-dependent, while that evoked by capsaicin was Ca 2+-independent. Capsaicin pretreatment (60μg, 7 days), which lesions small diameter afferents, did not alter release of ATP evoked by either K + or capsaicin. Dorsal rhizotomy, which lesions all afferents, produced a significant reduction in the amount of ATP released from the rhizotomized side compared to the intact side. Pretreatment with 6-hydroxydopamine (100 μg, 7 days) to destroy adrenergic nerve terminals markedly reduced spinal cord noradrenaline levels, but did not alter the K +-evoked release of ATP. These results suggest that some K +-evoked release of ATP could originate from large but not small diameter afferent nerve terminals in the spinal cord. ATP does not appear to originate from small diameter afferents as, although ATP is released by in vitro exposure to capsaicin, such release occurs only at high concentrations, release is Ca 2+-independent and it is unaltered by pretreatment with capsaicin. The bulk of the ATP released from the spinal cord does not originate from descending noradrenergic nerve terminals.

Spinal cord localization of the motoneurons innervating the sacrococcygeus dorsi lateralis muscle and their noradrenergic nerve terminals in rats

We examined in the present study the spinal cord localization of motoneurons innervating the caudal portion of the sacrococcygeus dorsi lateralis (SCDL) muscle and their noradrenergic nerve terminals in Sprague-Dawley rats, using horseradish peroxidase (HRP) and dopamine-β-hydroxylase (DBH) double-labeling techniques. Retrogradely HRP-labeled motoneurons innervating the caudal part of the SCDL muscle were located ipsilaterally in the ventromedial aspect of the ventral horn (lamina IX) in spinal segments of S 2–S 4. These cells were polygonal in shape, with an average soma diameter of 37.0 ± 1.1 μm (mean ± S.E.M., n = 95) and amounted to 33.6 ± 5.7 ( n = 7) in the horizontal plane. Of note was the presence of abundant DBH-positive nerve terminals arborizing on the soma and dendrites of HRP-labeled motoneurons. These results provided anatomical evidence to further support our previous findings that the coerulospinal noradrenergic neurotransmission is involved in the mediation of fentanyl-induced muscular rigidity.

?2 and ?-adrenergic stimulation of corticosterone secretion in rats

Bilateral injection of 6-hydroxydopamine into the medial forebrain bundle (MFB) significantly decreased monoamine concentrations in the hypothalamus. The noradrenaline and serotonin content of the paraventricular nucleus (PVN) was also significantly reduced. These drastic decreases in neurotransmitter concentration did not alter basal secretion of corticosterone. Isoproterenol, a beta-adrenoceptor agonist (1 mg/kg, i.p.), significantly stimulated corticosterone release in saline and MFB lesioned rats. This stimulation did not differ significantly between the two groups. Clonidine, an alpha 2-adrenoceptor agonist, injected either intraperitoneally or intracerebrally just dorsal to the PVN, caused a dose-dependent increase in corticosterone secretion. The stimulation of corticosterone release by clonidine (250 micrograms/kg, i.p.) was antagonised by the selective alpha 2-adrenoceptor antagonist, yohimbine (1 mg/kg, i.p.) and significantly reduced by the MFB lesion. These results suggest that corticosterone secretion is stimulated by activation of alpha 2-adrenoceptors which occur on noradrenergic nerve terminals in the PVN.

Synaptic inputs of neuropeptide Y-immunoreactive noradrenergic nerve terminals to neurons in the nucleus preopticus medianus which project to the paraventricular nucleus of the hypothalamus of the rat: a combined immunohistochemical and retrograde tracing method

The nucleus preopticus medianus (POMe) is known to serve as a relay site in the neural pathway, from the subfornical organ to the paraventricular nucleus of the hypothalamus (PVN), and to play an important role in the regulation of fluid balance and caridovascular control. A neural connection of noradrenergic nerve terminals in the POMe was examined using electron microscopic immunohistochemistry with the retrograde tract tracing method. Double immunofluorescent labelling revealed nerve terminals immunoreactive to both tyrosine hydroxylase (TH) and neuropeptide Y (NPY) and those immunoreactive to both TH and noradrenaline in the POMe. This indicates that there is an NPY-immunoreactive noradrenergic innervation in the POMe. At the electron microscopic level, nerve terminals immunoreactive to TH or NPY in the POMe formed synapses with dendrites or cell bodies of neurons which were retrogradely labeled after injection of the retrograde tracer, WGA-HRP-colloidal gold, in the PVN. These observations suggest that neurons in the POMe with projections to the PVN may be directly affected by NPY-immunoreactive noradrenergic afferent fibers which presumably originate in the brainstem.

Presynaptic inhibitory effect of TNF-α on the release of noradrenaline in isolated median eminence

The effect of tumor necrosis factor-α (TNF-α) on the stimulation-evoked release of noradrenaline (NA) from isolated rat median eminence (ME) was investigated, using a low-volume perfusion system. Median eminence, loaded with [ 3H]noradrenaline, was superfused with Krebs solution and stimulated electrically (2 Hz, 120 shocks). The effect of TNF-α was studied on the S 2 S 1 ration. It was found that stimulation-evoked relesed of NA from noradrenergic axon terminals in the isolated rat ME was inhibited by TNF-α and this effect was concentration-dependent. In contrast, TNF-α had no effect on the release of [ 3H]NA from the spleen. Since NA released in the ME might be involved in the modulation of corticotropin-releasing factor (CRF) production, it is suggested that TNF-α, through presynaptic modulation of NA release from noradrenergic nerve terminals in the ME, might regulate CRF and other neurohormone release in this hypothalamic structure.

Desmethylimipramine pretreatment prevents 6-hydroxydopamine induced somatostatin receptor reduction in the rat hippocampus

Several studies have shown anatomical and functional interconnections between catecholaminergic and somatostatinergic systems. To assess whether somatostatin (SS) may act presynaptically on catecholamine neurons, SS receptors were measured using radioligand test-tube binding assays on synaptosomes from hippocampus and frontoparietal cortex — areas that are innervated by catecholaminergic neurons with different densities and that have a high number of SS receptors — from control and 6-hydroxydopamine (6-OHDA)-treated rats. Intracerebroventricular (i.c.v.) injection of the catecholamine neurotoxin 6-OHDA (0.78 mg free base/kg of body weight in saline with 0.1% ascorbic acid) lowered hippocampal and frontoparietal cortical noradrenaline (NA) and dopamine (DA) levels at 1 week following the injection. Pretreatment of rats with desmethylimipramine (DMI) (40 mg/kg, intraperitoneal) prevented the drop in NA levels, but was not effective in attenuating DA depletion in the two brain areas studied. Treatment with 6-OHDA lowered the number of 125I-Tyr 11-SS receptors in the hippocampus ( 130 ± 19 vs. 266 ± 16 fmol/mg protein , P < 0.001), whereas in the frontoparietal cortex a non significant 20% reduction in receptor number was found. The dissociation constants of 125I-Tyr 11-SS binding to synaptosomes from frontoparietal cortex ( 0.65 ± 0.06 vs. 0.60 ± 0.04, P not significant) and hippocampus ( 0.44 ± 0.04 vs. 0.63 ± 0.14, P not significant) were similar in control and treated groups. Pretreatment with DMI reversed up to 80% of the effect of 6-OHDA on hippocampus SS receptors. DMI alone had no observable effect on the number and affinity of SS receptors. The 6-OHDA and the DMI treatment did not affect SLI levels in the brain areas studied. These results suggest that a portion of the hippocampal SS receptors may be localized presynaptically on the noradrenergic and dopaminergic nerve terminals.

Decreased density of presynaptic alpha 2-adrenoceptors in postmortem brains of patients with Alzheimer's disease.

The full agonist [3H]bromoxidine (UK 14304) was used to quantitate alpha 2-adrenoceptors in postmortem brains of patients with Alzheimer's disease. The effects of aging and human serum Cohn fraction IV on [3H]bromoxidine binding were also assessed. In patients with Alzheimer's disease, the binding capacity (Bmax) of [3H]bromoxidine was lower in the frontal cortex (37%), hypothalamus (33%), and cerebellum (52%) than in matched controls. In the hippocampus, amygdala, and head of caudate, the binding capacities (Bmax) were unchanged. Quantitative autoradiographic analyses with [3H]bromoxidine confirmed the existence of a marked reduction (55-60%) in alpha 2A-adrenoceptor density in the frontal cortex (layers I and III). In patients with dementia who did not meet neuropathological criteria for Alzheimer's disease, the density of alpha 2-adrenoceptors was unchanged. In control subjects, the density of alpha 2A-adrenoceptors in the frontal cortex showed a significant negative correlation with age at death. The inhibitory effect of human serum Cohn fraction IV on [3H]bromoxidine was very similar in control subjects and patients with Alzheimer's disease. The observed decrease in the density of brain alpha 2-adrenoceptors in Alzheimer's disease may represent direct biochemical evidence of a presynaptic location of this receptor on noradrenergic nerve terminals in the human CNS.

Sympathetic denervation and chronic serotonin uptake blockade by fluoxetine do not affect pineal gland 5-hydroxyindole acetic acid: evidence that oxidative deamination of pineal serotonin is a property of the pinealocyte.

This investigation tested the hypothesis that oxidative deamination of 5HT in the pineal gland occurs primarily in cellular compartments other than the pinealocyte (i.e., noradrenergic nerve terminals and glia). Following sympathetic denervation of the pineal gland by bilateral superior cervical sympathectomy, pineal levels of 5HT and its oxidative metabolite, 5HIAA, were measured by HPLC from samples collected at six time points over the 24 h photoperiod. The role of glia in 5HT deamination was further examined by chronic treatment with the 5HT uptake blocker, fluoxetine (10 mg/kg). Sympathectomy abolished the circadian rhythms of both 5HT and 5HIAA, but had no statistically significant effect on the ratio of 5HIAA/5HT compared to sham-operated and intact controls over the 24 h period. Pineal daytime levels of both 5HT and 5HIAA were unaffected by fluoxetine treatment. These findings indicate that the pinealocyte is an important cellular compartment for 5HT oxidative metabolism.

Failure by tricyclic antidepressants to affect the increase of dopamine extracellular concentrations produced by haloperidol in the caudate and accumbens nuclei of rats

The effect of different inhibitors of monoamine uptake on dopamine (DA) and dihydroxy-phenylacetic acid (DOPAC) neuronal outflow was studied in the caudate and accumbens nuclei of rats, using the in vivo brain microdialysis method coupled to HPLC electrochemical detection. Under conditions of DA receptor blockade (as produced by the i.p. administration of 0.25 mg/kg of haloperidol), cocaine, GBR-12909 and d-amphetamine increased the concentration of extracellular DA beyond the effect produced by haloperidol alone in both areas studied. GBR-12909 and cocaine also increased DOPAC concentration, while d-amphetamine decreased it. On the contrary, the tricyclic antidepressants (TCA), desipramine and chloripramine, failed to modify the effect of haloperidol on DA and DOPAC neuronal outflow. It was concluded that: (a) noradrenergic and serotonergic nerve terminals do not take up DA released from dopaminergic neurons, and (b) TCA have no effect on dopaminergic terminals.

Activation of noradrenergic and nitrergic mechanisms in the rat anococcygeus muscle by nicotine.

1. Nicotine (10 mumol/L) produced rapidly developing but transient contractions of anococcygeus muscle isolated from rats. The magnitude of the response varied considerably between preparations. Tachyphylaxis occurred, such that no response was elicited by the same or a larger concentration in the continued presence of 10 mumol/L nicotine. 2. Contractions produced by nicotine were not affected by atropine, but were abolished by Hexamethonium and the alpha-adrenoceptor antagonists prazosin and phentolamine. Contractions were absent in the anococcygeus muscles of rats pretreated with reserpine. 3. The alpha 2-adrenoceptor agonist UK14304, or guanethidine, raised the tone of the anococcygeus muscle, and converted responses to field stimulation and nicotine to relaxations. Nicotine-induced relaxations were more pronounced in the presence of UK14304 than guanethidine. 4. Relaxations produced by nicotine (1-18 mumol/L) were transient, and tachyphylaxis occurred. When precautions were taken to avoid tachyphylaxis, concentration-response curves could be constructed. The relaxations elicited by nicotine were abolished or greatly reduced by hexamethonium, tetrodotoxin or omega-conotoxin GVIA. 5. The nitric oxide synthase inhibitor L-NG-nitroarginine methyl ester (90 mumol/L) enhanced contractile responses to field stimulation and nicotine, and markedly reduced relaxations elicited by field stimulation and nicotine in the presence of UK14304. These relaxations were restored by L-arginine (270 mumol/L). 6. The results suggest that nicotine acts on nicotinic receptors of noradrenergic and nitrergic nerve terminals in the rat anococcygeus muscle, resulting in the release of noradrenaline and nitric oxide respectively.

Ultrastructural analysis of noradrenergic nerve terminals in the cat lumbosacral spinal dorsal horn: a dopamine-β-hydroxylase immunocytochemical study

Noradrenaline-containing nerve terminals within the cat spinal dorsal horn were studied by immunocytochemical localization of dopamine-β-hydroxylase. Immunoreactive terminals formed symmetrical (Gray type II) synaptic specializations with dendrites and somata throughout laminae I–IV, but no junctions were formed with other axons. These findings suggest that noradrenaline regulates sensory transmission through the dorsal horn via a postsynaptic action.

Reduction in postsynaptic α2-adrenoceptor activity by endogenous angiotensin III in the nucleus reticularis gigantocellularis of the rat

We investigated in adult, male Sprague-Dawley rats anesthetized with pentobarbital sodium the synaptic location of the interaction between endogenous angiotensin III (AIII) and the α 2-adrenoceptors in the medulla oblongata that are involved in cardiovascular regulation. The circulatory suppressant efficacy of a centrally acting α 2-adrenoceptor agonist, guanabenz, was used as the experimental index. Direct bilateral microinjection of AIII (40 pmol) into the nucleus reticularis gigantocellularis (NRGC), a medullary site believed to be intimately related to the cardiovascular inhibitory actions of guanabenz, attenuated, whereas the selective AIII receptor antagonist, Ile 7-AIII (20 nmol), potentiated, the circulatory suppressant effects of guanabenz (100 μg/kg, i.v.). These two respective actions were essentially unaffected by immunocytochemically verified depletion of noradrenergic nerve terminals in the NRGC, elicited by a selective noradrenergic neurotoxin, DSP4. These data suggest that endogenous AIII may exert a tonic inhibitory action on the α 2-adrenoceptors located postsynaptically on neurons in the NRGC that are involved in central cardiovascular regulation.

μ-Opioid receptor-regulated adenylate cyclase activity in primary cultures of rat striatal neurons upon chronic morphine exposure

Rat striatal neurons cultured in serum-free, hormone-supplemented medium, were exposed to 10 μM morphine for several hours or days before intracellular cyclic AMP production was measured. Dopamine D 1 receptor- and β-adrenoceptor-stimulated cyclic AMP production were prefoundly increased upon morphine exposure (up to 150% of control). In contrast, cyclic AMP production induced by direct activation of the catalytic unit of adenylate cyclase with forskolin remained unaffected. Interestingly, the relative inhibitory effect of the μ-opioid receptor agonist [D-Ala 2,MePhe 4,Gly-ol 5]enkephalin (DAGO) on dopamine D 1 receptor-stimulated cyclic AMP production was unchanged after exposure to morphine. On the other hand, unlike μ-opioid receptors chronically exposed to morphine, β-adrenoceptors mediating activation of adenylate cyclase were rapidly desensitized upon prolonged exposure of the neurons to isoprenaline. It is suggested that tolerance to morphine may be caused by the fact that morphine is acting against up-regulated signal transduction mechanisms rather than by μ receptor desensitization. Moreover, this enhanced effector system function may be involved in opioid dependence. The adaptive changes following morphine treatment appear to be independent of possible alterations at the level of dopaminergic or noradrenergic nerve terminals which are not present in primary cultures of rat striatum.

Ventral Horn Neuropeptides Modulate the Release of Noradrenaline from Tissue Slices of Rat Brainstem and Ventral Thoracic Spinal Cord

The release of endogenous noradrenaline (NA) from slices of adult rat brainstem and ventral thoracic spinal cord was investigated using a fixed-volume incubation technique and HPLC with electrochemical detection. Incubation with potassium (15-50 mM) produced a dose-related increase in basal NA release that was calcium dependent. The potassium-evoked release of NA from spinal cord or brainstem slices was potentiated according to dose by preincubation with either (a) the selective alpha 2-adrenoceptor antagonist idazoxan (10(-6)-10(-4) M) or (b) the thyrotrophin-releasing hormone (TRH) analogue RX 77368 (pGlu-His-3,3'-dimethyl ProNH2; 10(-5) and 10(-4) M). Incubation of spinal cord slices with the NA uptake inhibitor maprotiline (1 microM) enhanced the effect of idazoxan but inhibited that of RX 77368. The effects of RX 77368 and potassium alone (15 mM) on NA release from both spinal cord and brainstem slices were reduced to basal levels with tetrodotoxin (10(-7) M). Similarly, preincubation of spinal cord, but not brainstem, slices with the insect neuropeptide proctolin (10(-4) M) significantly attenuated the potassium- or RX 77368-induced release of NA, whereas substance P (3 X 10(-5) and 1 X 10(-4) M) had no effect on either tissue. These results suggest that changes in NA release in the spinal cord and brainstem may mediate some of the actions of neuropeptides in ventral spinal cord, although the peptides may not be acting directly on the noradrenergic nerve terminals in these tissues.

Studies on the interaction between presynaptic alpha 2-adrenoceptors and adenosine A1 receptors located on noradrenergic nerve terminals.

The aim of the present study was to obtain a more detailed understanding of the interaction between presynaptic alpha 2-adrenoceptors and A1 adenosine receptors mediating inhibition of noradrenaline release in the central nervous system. Slices of rabbit hippocampus, prelabelled with [3H]noradrenaline, were superfused in the presence of the re-uptake inhibitor (+)-oxaprotiline and electrically stimulated during superfusion. During stimulation with 36 pulses at 3 Hz the alpha 2-adrenoceptor antagonist yohimbine induced a five-fold increase of noradrenaline release indicating a pronounced autoinhibition of approximately 80%. In these experiments the inhibition of release caused by R-PIA, a preferential A1 agonist, as well as its facilitation caused by DPCPX, a selective A1 antagonist, were smaller in comparison to the effects of these compounds on release virtually free of autoinhibition (i.e. by stimulating the tissue with 4 pulses at 100 Hz (POP-stimulation) or with 36 pulses at 3 Hz in presence of yohimbine). Clonidine, an alpha 2-adrenoceptor agonist, was used to impose a distinct alpha 2-adrenoceptor-mediated inhibition of release elicited by POP-stimulation. Only, however, in the presence of 30 nmol/l clonidine, causing maximum inhibition of approximately 80% of 3H-overflow, but not in the presence of 6 nmol/l clonidine, causing approximately 50% inhibition, a significant diminution of the inhibitory effect of R-PIA was seen. Similarly, the alpha 2-adrenoceptor mechanism was affected only by 10 mumols/l R-PIA causing maximum inhibition of approximately 80%, but remained unchanged in the presence of 30 nmol/l R-PIA diminishing release by 50%.(ABSTRACT TRUNCATED AT 250 WORDS)

Serotonin contributes to the spinal antinociceptive effects of morphine

This study was designed to determine if morphine administered intrathecally (IT) interacts with serotonergic or noradrenergic nerve terminals in the spinal cord to produce analgesia on the spinally mediated tail-flick test. Male Sprague-Dawley rats were fitted with IT catheters. One week later, animals were spinally pretreated with receptor antagonists selective for opioid, serotonin or α-adrenoceptors, and the ability of these agents to alter spinal morphine-induced antinociception was assessed. Morphine dose-dependently elevated tail-flick latency in a naltrexone-reversible manner. The serotonin receptor antagonists spiroxatrine (5-HT 1A), pindolol (5-HT 1B), ritanserin (5-HT 2) and ICS 205–930 (5-HT 3) attenuated the spinal analgesic effects of morphine. In contrast, the α 1 and α 2-adrenoceptor antagonists prazosin and yohimbine, respectively, did not alter morphine-induced elevations in tail-flick latency. These data substantiate earlier reports that spinal morphine-induced antinociception relies on an opioid receptor-mediated component in addition to a local serotonergic component. The finding that the α-adrenoceptor antagonists did not alter the antinociceptive effects of IT morphine suggests that spinal norepinephrine does not contribute to the analgesic effects of the opiate.

An α 2 antagonist, idazoxan, enhances EPSP-spike coupling in the rat dentate gyrus

the effect of the α 2 antagonist, idazoxan (IDA), on the excitability of neurons in the dentate gyrus of the hippocampus was studied. Population field potentials (PS) evoked by stimulation of the perforant pathway were measured before and after drug treatment. IDA enhanced the amplitude of the PS, while decreasing the slope of the EPSP. Neurotaxic destruction of noradrenergic nerve terminals completely abolished the IDA effect, arguing that its mechanism of action is through enhanced release of noradrenaline (NA). It is proposed that NA enhances the EPSP-to-spike coupling component of the PS.