α2-Adrenoceptors and I2 sites in the mammalian central nervous system

French, N

doi:10.1016/0163-7258(95)02005-5

Cited by 51 publications

(23 citation statements)

References 236 publications

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“…In addition to idazoxan, for many years the prototypical ligand for I 2 -imidazoline receptors (Miralles et al, 1993;French, 1995), other more selective and/or potent I 2 -imidazoline receptor ligands such as LSL 60101 (Alemany et al, 1995); 2-BFI (Hudson et al, 1995;Alemany et al, 1997) and LSL 61122 (Ozaita et al, 1997), also protected or attenuated morphine tolerance. It is unlikely that the eects of these imidazol(ine) drugs involve a direct interaction with opioid receptors; ®rst, because idazoxan is not active on these receptors (Doxey et al, 1983) and the m-agonist methadone displays low anity against [ 3 H]-idazoxan binding to I 2 -imidazoline receptors in the rat cerebral cortex (K i =12 mM; unpublished results from this laboratory), and second, because no potentiation or attenuation of morphine antinociception was observed when these I 2 -ligands and agmatine were administered before morphine (3 mg kg 71 , i.p.)…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have demonstrated that imidazol(ine)/ guanidine compounds elicit central and peripheral eects through the interaction with various non-adrenoceptor sites including the so-called imidazoline receptors (for a review see Bousquet, 1995;French, 1995;Regunathan & Reis, 1996;Molderings, 1997) and various cation channels, including NMDA receptors (Olmos et al, 1996). According to dierences in their pharmacological pro®les, tissue and subcellular distributions, imidazoline receptors have been classi®ed into two main types: I 1 -and I 2 -imidazoline receptors (Michel & Insel, 1989;Ernsberger, 1992).…”

Section: Introductionmentioning

confidence: 99%

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Attenuation of tolerance to opioid‐induced antinociception and protection against morphine‐induced decrease of neurofilament proteins by idazoxan and other I₂‐imidazoline ligands

Boronat

Olmos

Garcı́a-Sevilla

1998

British J Pharmacology

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1 Agmatine, the proposed endogenous ligand for imidazoline receptors, has been shown to attenuate tolerance to morphine-induced antinociception (Kolesnikov et al., 1996). The main aim of this study was to assess if idazoxan, an a 2 -adrenoceptor antagonist that also interacts with imidazoline receptors, could also modulate opioid tolerance in rats and to establish which type of imidazoline receptors (or other receptors) are involved. 2 Antinociceptive responses to opioid drugs were determined by the tail-¯ick test. The acute administration of morphine (10 mg kg 71 , i.p., 30 min) or pentazocine (10 mg kg 71 , i.p., 30 min) resulted in marked increases in tail-¯ick latencies (TFLs). As expected, the initial antinociceptive response to the opiates was lost after chronic (13 days) treatment (tolerance). When idazoxan (10 mg kg 71 , i.p.) was given chronically 30 min before the opiates it completely prevented morphine tolerance and markedly attenuated tolerance to pentazocine (TFLs increased by 71 ± 143% at day 13). Idazoxan alone did not modify TFLs. 3 The concurrent chronic administration (10 mg kg 71 , i.p., 13 days) of 2-BFI, LSL 60101, and LSL 61122 (valldemossine), selective and potent I 2 -imidazoline receptor ligands, and morphine (10 mg kg 71 , i.p.), also prevented or attenuated morphine tolerance (TFLs increased by 64 ± 172% at day 13). This attenuation of morphine tolerance was still apparent six days after discontinuation of the chronic treatment with LSL 60101-morphine. The acute treatment with these drugs did not potentiate morphineinduced antinociception. These drugs alone did not modify TFLs. Together, these results indicated the speci®c involvement of I 2 -imidazoline receptors in the modulation of opioid tolerance. The potencies of the imidazolines idazoxan, RX821002 and moxonidine were similar, indicating a lack of relationship between potency on NMDA receptors and ability to attenuate opioid tolerance. These results suggested that modulation of opioid tolerance by idazoxan is not related to NMDA receptors blockade. 6 Chronic treatment (13 days) with morphine (10 mg kg 71 , i.p.) was associated with a marked decrease (49%) in immunolabelled neuro®lament proteins (NF-L) in the frontal cortex of morphine-tolerant rats, suggesting the induction of neuronal damage. Chronic treatment (13 days) with idazoxan (10 mg kg 71 ) and LSL 60101 (10 mg kg 71 ) did not modify the levels of NF-L proteins in brain. Interestingly, the concurrent chronic treatment (13 days) of idazoxan or LSL 60101 and morphine, completely reversed the morphine-induced decrease in NF-L immunoreactivity, suggesting a neuroprotective role for these drugs. 7 Together, the results indicate that chronic treatment with I 2 -imidazoline ligands attenuates the development of tolerance to opiate drugs and may induce neuroprotective eects on chronic opiate treatment. Moreover, these ®ndings oer the I 2 -imidazoline ligands as promising therapeutic coadjuvants in the management of chronic pain with opiate drugs.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Attenuation of tolerance to opioid‐induced antinociception and protection against morphine‐induced decrease of neurofilament proteins by idazoxan and other I₂‐imidazoline ligands

Boronat

Olmos

Garcı́a-Sevilla

1998

British J Pharmacology

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“…Various of the commonly used imidazoli(di)ne a-adrenoceptor ligands such as clonidine and idazoxan elicit central and peripheral effects by the activation of non-adrenoceptor sites, the so-called imidazoline receptors (for a review see Bousquet 1995;French 1995;Reis et al 1995;Regunathan and Reis 1996). Since the demonstration of the existence of these non-adrenergic targets for imidazoli(di)ne/ guanidinium compounds, efforts have been done in order to establish the pharmacological profile of the interaction and to characterize the molecular entities implicated.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological and molecular discrimination of brain I2-imidazoline receptor subtypes

Olmos

Alemany

Garcı́a-Sevilla

1996

Naunyn-Schmiedeberg's Arch Pharmacol

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I2-imidazoline receptors labelled with [3H]-idazoxan in the rabbit and rat brains displayed high and low affinity, respectively, for the guanidide amiloride; reinforcing the previous definition of I2A-imidazoline receptors expressed in the rabbit brain and I2B-imidazoline receptors expressed in the rat brain. Other drugs tested displayed biphasic curves in competition experiments, indicating the existence of high and low affinity sites for both subtypes of I2-imidazoline receptors. Among the drugs studied, bromoxidine, moxonidine, (+)- and (-)-medetomidine and clorgyline were more potent on the high and/or low affinity sites of I2B-than on their corresponding of I2A-imidazoline receptors (KiH ratios 20 to 65). No correlation was found for the potencies of the drugs tested at the low affinity sites of both I2-imidazoline receptor subtypes. Preincubation (30 min at 25 degrees C) with 10(-6) M clorgyline reduced by 60% the Bmax of [3H]-idazoxan binding to I2B-imidazoline receptors in the rat brain, but it did not affect the binding parameters of the radioligand saturation curves to I2A-imidazoline receptors in the rabbit brain. These results indicated that I2A- and I2B-imidazoline receptor subtypes differ in the pharmacological profiles of their high and low affinity sites and in the ability to irreversibly bind clorgyline. In rat cortical membranes western blot detection of immunoreactive imidazoline receptors proteins revealed a double band of approximately 29/30 kDa and two less intense bands of approximately 45 and approximately 66 kDa. In rabbit cortical membranes the antibody used detected proteins of approximately 30, approximately 57 and approximately 66 kDa. It is suggested that different imidazoline receptor proteins (approximately 45 vs approximately 57 kDa) may account for the different pharmacological profiles of I2-imidazoline receptor subtypes.

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“…1 There are 3 members of the ␣ 2 -AR family: ␣ 2A/D , ␣ 2B , and ␣ 2C (on the basis of sequence homology, the ␣ 2D subtype is the rat equivalent to the human ␣ 2A -AR subtype). 2 All are known to inhibit adenylate cyclase and to be involved in both central and peripheral control of blood pressure (BP), behavior, insulin release, sedation, and the presynaptic regulation of neurotransmitter release. 3-6 ␣ 2 -AR subtypes differ in their structure, patterns of tissue expression, and pharmacological profile.…”

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confidence: 99%

Effects of Antisense Oligodeoxynucleotide Targeting of the α _2B -Adrenergic Receptor Messenger RNA in the Central Nervous System

et al. 2001

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Abstract-The results of previous studies with genetically engineered mice have suggested that an intact central ␣ 2B -adrenergic receptor (␣ 2B -AR) subtype mediates the development and maintenance of salt-induced hypertension. In the present study, we sought to further define the role of this receptor by injecting antisense oligodeoxynucleotides (AS-ODNs), targeting a selected sequence of the ␣ 2B -AR mRNA, into the lateral cerebral ventricle of rats that had undergone prior subtotal nephrectomy and dietary salt loading. Cell culture studies showed that these AS-ODNs could block ␣ 2B -AR protein generation. Before AS-ODN injection, blood pressure (BP) averaged 133Ϯ5 mm Hg during the daytime and rose to 165Ϯ4 mm Hg during the nighttime activity hours (PϽ0.001 versus baseline average of 120Ϯ2 mm Hg). The injection of AS-ODNs during the early afternoon prevented the BP rise and was associated with a significant fall in heart rate (from 385Ϯ12 to 306Ϯ15 bpm, PϽ0.05) and symptoms of sedation that lasted for several hours, with a peak at 3 to 6 hours and full recovery by 24 hours. At that time, a second injection produced identical effects in all rats (nϭ9). Control rats (nϭ10) that received scrambled ODN injections had no changes in BP or heart rate patterns, and neither group had evidence of neurotoxicity, indicating that these effects are specifically due to translational inhibition of central ␣ 2B -AR. We conclude that a fully functional central ␣ 2B -AR is necessary for the induction of salt-dependent hypertension.

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α2-Adrenoceptors and I2 sites in the mammalian central nervous system

Cited by 51 publications

References 236 publications

Attenuation of tolerance to opioid‐induced antinociception and protection against morphine‐induced decrease of neurofilament proteins by idazoxan and other I₂‐imidazoline ligands

Attenuation of tolerance to opioid‐induced antinociception and protection against morphine‐induced decrease of neurofilament proteins by idazoxan and other I₂‐imidazoline ligands

Pharmacological and molecular discrimination of brain I2-imidazoline receptor subtypes

Effects of Antisense Oligodeoxynucleotide Targeting of the α _2B -Adrenergic Receptor Messenger RNA in the Central Nervous System

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α2-Adrenoceptors and I2 sites in the mammalian central nervous system

Cited by 51 publications

References 236 publications

Attenuation of tolerance to opioid‐induced antinociception and protection against morphine‐induced decrease of neurofilament proteins by idazoxan and other I2‐imidazoline ligands

Attenuation of tolerance to opioid‐induced antinociception and protection against morphine‐induced decrease of neurofilament proteins by idazoxan and other I2‐imidazoline ligands

Pharmacological and molecular discrimination of brain I2-imidazoline receptor subtypes

Effects of Antisense Oligodeoxynucleotide Targeting of the α 2B -Adrenergic Receptor Messenger RNA in the Central Nervous System

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Attenuation of tolerance to opioid‐induced antinociception and protection against morphine‐induced decrease of neurofilament proteins by idazoxan and other I₂‐imidazoline ligands

Attenuation of tolerance to opioid‐induced antinociception and protection against morphine‐induced decrease of neurofilament proteins by idazoxan and other I₂‐imidazoline ligands

Effects of Antisense Oligodeoxynucleotide Targeting of the α _2B -Adrenergic Receptor Messenger RNA in the Central Nervous System