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At least 19 recordsLinked to original sources

PubMed2005

Duloxetine for management of stress urinary incontinence.

OBJECTIVE: The aim of this article was to review data regarding the efficacy and tolerability of duloxetine, a selective serotonin (5-HT)-norepinephrine (NE) reuptake inhibitor that has received US Food and Drug Administration marketing approval for the treatment of major depressive disorder and painful diabetic neuropathy, and that has been investigated as a treatment for stress urinary incontinence. METHODS: A MEDLINE/PubMed search was conducted to identify English-language study reports. In addition, proceedings of meetings of the International Continence Society, European Association of Urology, American Urological Association, and American College of Obstetrics and Gynecology were reviewed for relevant abstracts (search terms included duloxetine, thiophenes, serotonin uptake inhibitors, adrenergic uptake inhibitors, and stress urinary incontinence). Additional references were obtained from the bibliographies of these sources. Data for the period from 1986 through January 2005 were reviewed. RESULTS: All in vitro and in vivo studies of duloxetine were included. Because both 5-HT and NE are involved in the maintenance of urinary continence, duloxetine may have a role in the treatment of urinary incontinence. Duloxetine is primarily eliminated via metabolism, with < 1% of the parent compound excreted via urine. Duloxetine QD or BID has been found to be significantly superior to placebo in reducing incontinence episode frequency (P < 0.001 to P < 0.05), increasing the interval between micturitions (P < 0.001 to P = 0.004), and improving the condition as measured by patient self-report (P < 0.001 to P = 0.028) and incontinence quality-of-life scores (P = 0.002 to P = 0.03). The most problematic adverse events are nausea, dry mouth, constipation, dizziness, and insomnia. CONCLUSIONS: Although statistically superior to placebo in efficacy trials, the clinical effects of duloxetine therapy on incontinence are small, suggesting that any benefits to the patient would be modest and must be weighed against the drug's adverse event profile. No comparative efficacy/tolerability data with alpha-receptor agonists (eg, pseudoephedrine) are available. On the basis of available data, duloxetine is a modest, but welcome, advance in the pharmacotherapeutic management of stress urinary incontinence.

Adrenergic Uptake Inhibitors↗

PubMed1997

Alpha2-adrenergic receptor blockade markedly potentiates duloxetine- and fluoxetine-induced increases in noradrenaline, dopamine, and serotonin levels in the frontal cortex of freely moving rats.

Evidence exists that a reinforcement in monoaminergic transmission in the frontal cortex (FCX) is associated with antidepressant (AD) properties. Herein, we examined whether blockade of alpha2-adrenergic receptors modified the influence of monoamine reuptake inhibitors on FCX levels of serotonin (5-HT), noradrenaline (NAD), and dopamine (DA). The selective alpha2-adrenergic receptor agonist S 18616 (0.16 mg/kg, s.c.) suppressed extracellular levels of NAD, DA, and 5-HT (by 100, 51, and 63%, respectively) in single dialysates of FCX of freely moving rats. In contrast, the selective alpha2-adrenergic receptor antagonists atipamezole (0.16 mg/kg, s.c.) and 1-(2-pyrimidinyl)piperazine (1-PP; 2.5 mg/kg, s.c.) increased levels of NAD (by 180 and 185%, respectively) and DA (by 130 and 90%, respectively), without affecting 5-HT levels. Duloxetine (5.0 mg/kg, s.c.), a mixed inhibitor of 5-HT and NAD reuptake, and fluoxetine (10.0 mg/kg, s.c.), a selective 5-HT reuptake inhibitor, both increased levels of 5-HT (by 150 and 120%, respectively), NAD (by 400 and 100%, respectively), and DA (by 115 and 55%, respectively). Atipamezole (0.16 mg/kg, s.c.) markedly potentiated the influence of duloxetine and fluoxetine on levels of 5-HT (by 250 and 330%, respectively), NAD (by 1,030 and 215%, respectively), and DA (by 370 and 170%, respectively). 1-PP similarly potentiated the influence of duloxetine on 5-HT, NAD, and DA levels (by 290, 1,320, and 600%, respectively). These data demonstrate that alpha2-adrenergic receptors tonically inhibit NAD and DA and phasically inhibit 5-HT release in the FCX and that blockade of alpha2-adrenergic receptors strikingly potentiates the increase in FCX levels of 5-HT, NAD, and DA elicited by reuptake inhibitors. Concomitant alpha2-adrenergic receptor antagonism and inhibition of monoamine uptake may thus provide a mechanism allowing for a marked increase in the efficacy of AD agents.

Adrenergic Uptake Inhibitors↗

PubMed2000

Effects of intravenous cocaine administration on cerebellar Purkinje cell activity.

The goal of the present study was to investigate the effects of intravenous cocaine administration on cerebellar Purkinje cell firing. Extracellular neuron activity was recorded and cells were locally excited with spaced microiontophoretic pulses of glutamate. Glutamate-evoked and spontaneous discharges were compared before and immediately following cocaine administration. Cocaine injections (1. 0 and 0.25 mg/kg, i.v.) induced a reversible suppression of both spontaneous activity and glutamate-evoked excitation. Procaine was ineffective in producing similar actions. Cocaine only inhibited glutamate-induced excitation in animals pre-treated with reserpine (5 mg/kg, i.p.). Propranolol injections (10 mg/kg, i.p.) were ineffective in blocking cocaine-induced inhibitions. Yohimbine (5 mg/kg, i.p.) pre-treatment abolished cocaine-induced suppressions of either spontaneous or glutamate-evoked excitation. Therefore, cocaine administration decreases Purkinje cell spontaneous and glutamate-evoked discharges by a mechanism involving alpha(2)-adrenoceptor activation. It is suggested that by changing the normal function of the cerebellum cocaine can produce drug-related alterations in overt behavior and cognition.

Action Potentials↗

PubMed2004

Quantification and pharmacological characterization of dialysate levels of noradrenaline in the striatum of freely-moving rats: release from adrenergic terminals and modulation by alpha2-autoreceptors.

Information concerning striatal levels of noradrenaline (NA) remains inconsistent. Here we have addressed this issue using a sensitive method of HPLC coupled to amperometric detection. The NA reuptake-inhibitor, reboxetine, selectively elevated levels of NA versus dopamine (DA), and NA levels were also selectively elevated by the alpha2-adrenoceptor (AR) antagonist, atipamezole. The actions of atipamezole were mimicked by the preferential alpha2A-AR antagonist, BRL44408, while JO-1 and prazosin, preferential antagonists at alpha2C-ARs, caused less marked elevations in NA levels. In contrast to antagonists, the alpha2-AR agonist, S18616, decreased NA levels and likewise suppressed those of DA. Unilateral lesions of the substantia nigra with 6-hydroxydopamine depleted DA levels without affecting those of NA. Further, the D3/D2 receptor agonist, quinelorane, decreased levels of DA without modifying those of NA. However, the D3/D2 receptor antagonists, haloperidol and raclopride, and the DA reuptake-inhibitor, GBR12935, elevated levels of both DA and NA. Levels of 5-HT (but not of NA or DA) were increased only by the 5-HT reuptake-inhibitor, citalopram. They were decreased by S18616 and prazosin, reflecting the inhibitory and excitatory influence of alpha2- and alpha1-ARs, respectively, upon serotonergic pathways. In conclusion, NA in the striatum is derived from adrenergic terminals. Its release is subject to tonic, inhibitory control by alpha2-ARs, possibly involving both alpha2A- and alpha2C-AR subtypes, though their respective contribution requires clarification. A role of dopaminergic terminals in the reuptake of NA likely explains the elevation in its levels elicited by DA reuptake-inhibitors and D3/D2 receptor antagonists.

Adrenergic Uptake Inhibitors↗

PubMed2002

Binding and transport in norepinephrine transporters. Real-time, spatially resolved analysis in single cells using a fluorescent substrate.

Monoamine transporters, the molecular targets for drugs of abuse and antidepressants, clear norepinephrine, dopamine, or serotonin from the synaptic cleft. Neurotransmitters, amphetamines, and neurotoxins bind before being transported, whereas cocaine and antidepressants bind to block transport. Although binding is crucial to transport, few assays separate binding from transport, nor do they provide adequate temporal or spatial resolution to describe real-time kinetics or localize sites of active uptake. Here, we report a new method that distinguishes substrate binding from substrate transport using single-cell, space-resolved, real-time fluorescence microscopy. For these studies we use a fluorescent analogue of 1-methyl-4-phenylpyridinium, a neurotoxic metabolite and known substrate of monoamine transporters, to assess binding and transport with 50-ms, sub-micron resolution. We show that ASP(+) (4-(4-(dimethylamino)styrl)-N-methylpyridinium) has micromolar potency for the human norepinephrine transporter, that ASP(+) accumulation is Na(+)-, Cl(-)-, cocaine-, and desipramine-sensitive and temperature-dependent, and that ASP(+) competes with norepinephrine uptake. Using this method we demonstrate that norepinephrine transporters are efficient buffers for substrate, with binding rates exceeding transport rates by 100-fold. Furthermore, substrates bind deep within the transporter, isolated from both the bath and the lipid bilayer. Although transport per se depends on Na(+) and Cl(-), binding is independent of Na(+) and actually increases in low Cl(-). We further demonstrate that ASP(+) interacts with transporters not only in transfected cells but in cultured neurons. ASP(+) is also a substrate for dopamine and serotonin transporters and therefore represents a powerful new technique for studying the biophysical properties of monoamine transporters, an approach also amenable to high throughput assays for drug discovery.

Adrenergic Uptake Inhibitors↗

PubMed2003

Potential serotonergic and noradrenergic involvement in the discriminative stimulus effects of the selective imidazoline I2-site ligand 2-BFI.

The functional significance of imidazoline I2 binding sites is unknown but microdialysis studies have indicated that the administration of I2-site ligands leads to an increase in extracellular levels of monoamines. The specific I2-site ligand 2-(-2-benzofuranyl)-2-imidazoline (2-BFI) generates a cue in drug discrimination, thereby indicating functional consequences of I2-site ligand binding. In the present work, we explored the ability of selective noradrenergic and serotonergic ligands to substitute for 2-BFI. Hooded Lister rats were trained in two-lever operant chambers with condensed milk reward to distinguish 2-BFI (7 mg/kg) from saline vehicle, by pressing the correct lever to a predetermined success criterion. Training sessions were then interspersed with sessions in which animals were administered test substances and the proportion of lever presses on the 2-BFI-associated lever (substitution) recorded. Several agents exhibited significant partial substitution for 2-BFI: The monoamine-releasing agents D-amphetamine and fenfluramine dose-dependently substituted for 2-BFI, while norepinephrine (desipramine, reboxetine) and serotonin (clomipramine, citalopram) reuptake inhibitors substituted at one or more doses. Further investigation using specific receptor agonists and antagonists indicated a possible role for activation of alpha1-adrenoceptors but failed to support involvement of alpha2-adenoceptor, beta-adrenoceptor or 5-HT1A receptor activation. These results support the concept that the 2-BFI cue may contain both noradrenergic and serotonergic components.

Adrenergic Uptake Inhibitors↗

PubMed1999

Nitric oxide synthase inhibitors have antidepressant-like properties in mice. 2. Chronic treatment results in downregulation of cortical beta-adrenoceptors.

Down-regulation of cortical beta-adrenoceptors is observed in rodents following chronic treatment with many clinically effective antidepressant therapies. [3H]dihydroalprenolol binding to cortical beta-adrenoceptors was examined in mice treated with the nitric oxide (NO) synthase antagonist N(G)-nitro-L-arginine (L-NNA). Administration of L-NNA (0.1, 0.3 mg/kg) for 21 days produced a significant reduction (28%, 31%, respectively, P<0.05) in [3H]dihydroalprenolol binding to cortical membranes without affecting Kd. Dose 1 mg/kg of L-NNA given chronically also produced a 20% decrease in beta-adrenoceptor density, but this effect was not statistically significant. While chronic treatment with imipramine (15 and 30 mg/kg) produced respectively a 30% and 25% (P<0.05) reduction in the density of [3H]dihydroalpenolol, single injection of either imipramine (15 and 30 mg/kg) or L-NNA (0.1, 0.3, and 1 mg/kg) had no effect on [3H]dihydroalprenolol binding. These findings are consistent with the hypothesis that drugs which can affect the Ca2+ -calmodulin/nitric oxide synthase/guanylyl cyclase signaling pathway may represent a novel approach to the treatment of depression and are congruent with our previous observation, which has demonstrated the antidepressant-like properties of NO synthase inhibitors in the forced swim test.

Adrenergic Uptake Inhibitors↗

PubMed2002

[Antihypertensive drugs and malignant neoplasia].

Analysis of epidemiological, cohort and randomized studies of antihypertensive drugs containing reports of development of malignant neoplasms shows that long term use of some antihypertensive drugs while preventing cardiovascular complications has been associated with increased risk of malignancies. Most convincing evidence exists for association between the use of diuretics and renal cancer. Association between the use of reserpine and breast cancer in women, between atenolol and some types of cancer in elderly men also can not be ruled out. There is no proof of existence of either negative or positive correlation between malignant neoplasia and long-term use of calcium antagonists, angiotensin converting enzyme inhibitors or angiotensin receptor blockers.

Adrenergic Uptake Inhibitors↗

PubMed2005

Antidepressants and seizures: emphasis on newer agents and clinical implications.

Seizures are a known, relatively rare, consequence of antidepressant treatment. Risk estimates vary depending on the study, source of data and patient population, predisposed vs. nonpredisposed. For newer antidepressants (e.g. selective serotonin reuptake inhibitors, bupropion, mirtazepine, etc.), the risk is generally considered to be low (0.0%-0.4%) and not very different from the incidence of first seizure in the general population (0.07%-0.09%). Risk with tricyclic antidepressants at effective therapeutic doses is relatively high (0.4% to 1-2%). Seizure following overdose is a significant and relatively frequent event for some antidepressants. Patients being considered for antidepressant treatment should be screened for predisposition to seizures. Predisposed patients should receive antidepressants cautiously. The seizure potential of antidepressants in patients without a predisposition is low, especially for newer antidepressants. Seizure risk, along with other drug-related considerations, e.g. weight gain, sexual dysfunction and sedation, should be considered when prescribing an antidepressant.

Adrenergic Uptake Inhibitors↗

PubMed2005

Critical involvement of dopaminergic neurotransmission in impulsive decision making.

BACKGROUND: Impulsive decision making, apparent as intolerance for reinforcement delay, is prominent in attention-deficit/hyperactivity disorder. Commonly prescribed for this condition, amphetamine (Adderall), reduces impulsive decision making; however, the neuropharmacologic mechanism of this effect of amphetamine is unclear. METHODS: We investigated the involvement of dopaminergic and noradrenergic neurotransmission in impulsive decision making in rats, using a delayed reward task. RESULTS: Amphetamine and methylphenidate decreased impulsive decision making, which was mimicked by the selective dopamine reuptake inhibitor GBR 12909 but not by the noradrenaline reuptake inhibitor desipramine. Impulsive choice was increased by the dopamine D1 receptor antagonist SCH-23390 but not the dopamine D2 receptor antagonist eticlopride. The effect of amphetamine on impulsive choice was attenuated by pretreatment with eticlopride, whereas amphetamine retained its effect on impulsivity in the presence of SCH-23390. The alpha2 adrenoceptor agonist clonidine increased impulsivity, but the alpha1 adrenoceptor agonist phenylephrine did not affect impulsive decision making. CONCLUSIONS: These data demonstrate an important role for dopaminergic neurotransmission in impulsive decision making, whereby tolerance to delay of reinforcement depends on dopamine D1 receptor activation. Activation of dopamine D2 receptors appears to mediate the beneficial effects of amphetamine on impulsive behavior. Noradrenergic neurotransmission may play a minor role in impulsive choice.

Adrenergic Uptake Inhibitors↗

PubMedDate not supplied

Pharmacological profile of reboxetine, a representative of new class of antidepressant drugs, selective noradrenaline reuptake inhibitor (NARI), given acutely.

Pharmacological effects of acute treatment with reboxetine (REB), a clinically active antidepressant (a noradrenaline reuptake inhibitor without any affinity for neurotransmitter receptors), were studied in mice and rats. REB inhibited the reserpine- or apomorphine-induced hypothermia in mice. It reduced the immobility time in Porsolt's test in mice and rats, but it did not change the locomotor activity in mice and rats. REB changed neither the clonidine-induced aggressiveness in mice nor the behavioral syndrome induced by oxotremorine in rats. The obtained results indicate that REB, given acutely, shows a pharmacological profile similar to that of tricyclic or tetracyclic noradrenaline reuptake inhibitors. In contrast to the antidepressants mentioned above, REB does not exhibit an alpha1-adrenolytic or cholinolytic activity (in vivo tests).

Adrenergic Uptake Inhibitors↗

PubMed2006

Role of noradrenergic pathways in sneeze-induced urethral continence reflex in rats.

To clarify the role of noradrenergic pathways in preventing stress urinary incontinence (SUI) during sneezing, we investigated the effect of the norepinephrine reuptake inhibitor nisoxetine and alpha-adrenoceptor antagonists phentolamine (nonspecific blocker) and prazosin (alpha(1)-receptor-selective blocker) on the neurally evoked urethral continence reflex induced by sneezing in rats. The amplitude of urethral pressure responses during sneezing (A-URS), urethral baseline pressure (UBP) at the midurethra, and sneeze-induced leak point pressure (S-LPP) were measured in normal female adult rats and rats with SUI induced by vaginal distention (VD). In normal rats, intrathecal (it) phentolamine (0.02 nmol) and prazosin (0.02 nmol) decreased A-URS by 11.9 and 15.7%, respectively, without affecting UBP. In both normal and VD rats, intravenous (iv) application of nisoxetine (1 mg/kg) increased A-URS by 17.2 and 18.3% and UBP by 23.7 and 32.7%, respectively. Phentolamine or prazosin (both it) eliminated nisoxetine-induced increases in A-URS, but not the increases in UBP, which were, however, suppressed by iv phentolamine (5 mg/kg) or prazosin (1 mg/kg). Sneezing induced fluid leakage from the urethral orifice in VD rats, but not in normal rats. In VD rats, S-LPP was increased by 30.2% by iv nisoxetine. Application of phentolamine and prazosin (both it) decreased S-LPP by 15.7 and 20.6%, respectively, and nisoxetine induced increases in S-LPP to 13.2 and 12.3%, respectively. These results indicate that activation of the noradrenergic system by a norepinephrine reuptake inhibitor can prevent SUI via alpha(1-)adrenoceptors by enhancing the sneeze-induced active urethral closure mechanism at the spinal level and augmenting UBP at the periphery.

Adrenergic Uptake Inhibitors↗

PubMed2006

Nonparkinsonism movement disorders in the elderly.

OBJECTIVE: The primary objective of this article is to review the clinical presentation and pharmacologic management of essential tremor and tardive dyskinesia. DATA SOURCES: The MEDLINE (1966-August 2005), Cochrane Database of Systematic Reviews, and International Pharmaceutical Abstracts (1970-August 2005) databases were searched for original research and review articles published in English. The search terms were essential tremor and tardive dyskinesia. Reference lists from articles were also consulted. DATA SYNTHESIS: Essential tremor is most commonly manifested as a postural or action tremor of the upper extremities. Midline regions such as the head and voice are also commonly affected. Based on review of the literature, propranolol and primidone are the current pharmacologic mainstays for treating essential tremor of the upper extremities. The choice of agent depends on patient-specific factors such as underlying medical conditions. Other agents with demonstrated efficacy include gabapentin and topiramate. Benzodiazepines are effective adjunctive agents, but should be utilized judiciously in the elderly. Botulinum toxin is effective for essential tremor of the voice and head. Surgery is very effective, but may not be appropriate in the frail elderly and should be avoided in the presence of cognitive impairment. Tardive dyskinesia is characterized by involuntary choreoathetoid movements of the orofacial region. For the management of tardive dyskinesia, emphasis is placed on primary prevention and early recognition of signs and symptoms. In some cases, discontinuation of the offending agent can result in reversal of symptoms. If a conventional neuroleptic is the causative agent, switching to an atypical antipsychotic may be helpful. Overall, few treatments have proven to be consistently useful. Other agents that may be helpful include acetylcholinesterase inhibitors, amantadine, baclofen, benzodiazepines, branched chain amino acids, gabapentin, levetiracetam, pyridoxine, verapamil, and vitamin E. CONCLUSION: Current pharmacologic agents for essential tremor can be expected to provide partial benefit. However, agents for the symptomatic management of tardive dyskinesia are limited, and additional research is warranted in this area.

Adrenergic Uptake Inhibitors↗

PubMedDate not supplied

Effect of repeated treatment with reboxetine on the central alpha1-adrenergic system.

The obtained results indicate that repeated administration of reboxetine (selective noradrenaline reuptake inhibitor, without any affinity for neurotransmitter receptors) increased the responsiveness of alpha1-adrenergic system (potentiating the methoxamine-induced exploratory hyperactivity in rats and clonidine-induced aggressiveness in mice), as tricyclic antidepressants did. However, the question whether the increased functional responsiveness found in the present study is important for the clinical antidepressant efficacy, remains open.

Adrenergic Uptake Inhibitors↗

PubMed2002

Differential pre- and postsynaptic effects of desipramine on cardiac sympathetic nerve terminals in RHF.

Right heart failure (RHF) is characterized by chamber-specific reductions of myocardial norepinephrine (NE) reuptake, beta-receptor density, and profiles of cardiac sympathetic nerve ending neurotransmitters. To study the functional linkage between NE uptake and the pre- and postsynaptic changes, we administered desipramine (225 mg/day), a NE uptake inhibitor, to dogs with RHF produced by tricuspid avulsion and progressive pulmonary constriction or sham-operated dogs for 6 wk. Animals receiving no desipramine were studied as controls. We measured myocardial NE uptake activity using [(3)H]NE, beta-receptor density by [(125)I]iodocyanopindolol, inotropic responses to dobutamine, and noradrenergic terminal neurotransmitter profiles by glyoxylic acid-induced histofluorescence for catecholamines, and immunocytochemical staining for tyrosine hydroxylase and neuropeptide Y. Desipramine decreased myocardial NE uptake activity and had no effect on the resting hemodynamics in both RHF and sham animals but decreased myocardial beta-adrenoceptor density and beta-adrenergic inotropic responses in both ventricles of the RHF animals. However, desipramine treatment prevented the reduction of sympathetic neurotransmitter profiles in the failing heart. Our results indicate that NE uptake inhibition facilitates the reduction of myocardial beta-adrenoceptor density and beta-adrenergic subsensitivity in RHF, probably by increasing interstitial NE concentrations, but protects the cardiac noradrenergic nerve endings from damage, probably via blockade of NE-derived neurotoxic metabolites into the nerve endings.

Adrenergic Uptake Inhibitors↗

PubMed2005

Noradrenergic modulation of emotion-induced forgetting and remembering.

We used a free-recall paradigm to establish a behavioral index of the retrograde and anterograde interference of emotion with episodic memory encoding. In two experiments involving 78 subjects, we show that negatively valenced items elicit retrograde amnesia, whereas positively valenced items elicit retrograde hypermnesia. These data indicate item valence is critical in determining retrograde amnesia and retrograde hypermnesia. In contrast, we show that item arousal induces an anterograde amnesic effect, consistent with the idea that a valence-evoked arousal mechanism compromises anterograde episodic encoding. Randomized double-blind administration of the beta-adrenoceptor antagonist propranolol compared with the selective norepinephrine (NE) reuptake-inhibitor reboxetine, and placebo, demonstrated that the magnitude of this emotional amnesia and hypermnesia can be upregulated and downregulated as a function of emotional arousal and central NE signaling. We conclude that a differential processing of emotional arousal and valence influences how the brain remembers and forgets.

Adrenergic Uptake Inhibitors↗

PubMed2002

In vivo monitoring of evoked noradrenaline release in the rat anteroventral thalamic nucleus by continuous amperometry.

Continuous amperometry coupled with untreated carbon-fibre electrodes was used in anaesthetized rats to measure the noradrenaline release evoked in the anteroventral thalamic nucleus by electrical stimulation of the dorsal noradrenergic bundle. As expected, the variations in the oxidation current detected in the anteroventral thalamic nucleus exhibited the characteristics of the in vivo noradrenaline release. They were closely correlated with stimulation and consistent with the anatomy of the noradrenergic system involved. They were abolished by the ejection of tetrodotoxin in the vicinity of the carbon-fibre electrode, diminished by clonidine, an alpha-2 agonist, and restored by yohimbine, an alpha-2 antagonist. Furthermore, the time course of these variations was dramatically increased by desipramine, a specific noradrenaline reuptake blocker. In contrast, neither dopamine nor serotonin reuptake blockers, nor the monoamine oxidase inhibitor pargyline were able to alter them. The main advantage of the present approach is its excellent time resolution. We show here for the first time that after single pulse stimulation, noradrenaline is released and eliminated in 118 milliseconds, this time lapse corresponding to the maximal period beyond which subsequent noradrenaline releases could not add up. These observations are in good agreement with the physiological relationship previously observed between impulse flow and noradrenaline overflow.

Adrenergic Uptake Inhibitors↗

PubMed1996

Intrathecal Tyr-W-MIF-1 produces potent, naloxone-reversible analgesia modulated by alpha 2-adrenoceptors.

Spinal administration of morphine or [D-Ala2,MePhe4,Gly(ol)5)]enkephalin (DAMGO) produces potent, naloxone-reversible analgesia that is modulated by alpha 2-adrenoceptors. Tyr-W-MIF-1 (Tyr-Pro-Trp-Gly-NH2) is a naturally occurring, amidated tetrapeptide that is structurally related to the melanocyte-stimulating hormone release inhibiting factor-1 (MIF-1) family of endogenous peptides. Tyr-W-MIF-1 displays high selectivity for the mu-opioid receptor. We investigated the effect of spinal administration of Tyr-W-MIF-1 on analgesia using the mouse tail-flick assay. Intrathecal (i.t.) administration of Tyr-W-MIF-1 produced a dose-dependent analgesic response, with an ED50 of 0.41 microgram, that was reversed by naloxone. Pretreatment with the mu-opioid receptor-selective antagonist beta-funaltrexamine blocked the effect of i.t. Tyr-W-MIF-1. However, pretreatment with the mu1-opioid receptor-selective antagonist naloxonazine did not antagonize the analgesia, indicating the effect was mediated through spinal mu2-opioid receptors. Pretreatment with desipramine, an inhibitor of norepinephrine reuptake, potentiated the analgesic effect of i.t. Tyr-W-MIF-1, producing a 3.1-fold leftward shift in the dose-response curve. Spinal administration of yohimbine, an alpha 2-adrenoceptor-selective antagonist, significantly attenuated the analgesic effect of Tyr-W-MIF-1. Thus, the potent analgesic effect of i.t. Tyr-W-MIF-1 is mediated through spinal mu2-receptors, and is modulated by norepinephrine and alpha 2-adrenoceptors.

Adrenergic Uptake Inhibitors↗