RÉSUMÉ
Opioids are the most effective painkillers, but their benefit-risk balance often hinder their therapeutic use. WLB-73502 is a dual, bispecific compound that binds sigma-1 (S1R) and mu-opioid (MOR) receptors. WLB-73502 is an antagonist at the S1R. It behaved as a partial MOR agonist at the G-protein pathway and produced no/unsignificant ß-arrestin-2 recruitment, thus demonstrating low intrinsic efficacy on MOR at both signalling pathways. Despite its partial MOR agonism, WLB-73502 exerted full antinociceptive efficacy, with potency superior to morphine and similar to oxycodone against nociceptive, inflammatory and osteoarthritis pain, and superior to both morphine and oxycodone against neuropathic pain. WLB-73502 crosses the blood-brain barrier and binds brain S1R and MOR to an extent consistent with its antinociceptive effect. Contrary to morphine and oxycodone, tolerance to its antinociceptive effect did not develop after repeated 4-week administration. Also, contrary to opioid comparators, WLB-73502 did not inhibit gastrointestinal transit or respiratory function in rats at doses inducing full efficacy, and it was devoid of proemetic effect (retching and vomiting) in ferrets at potentially effective doses. WLB-73502 benefits from its bivalent S1R antagonist and partial MOR agonist nature to provide an improved antinociceptive and safety profile respect to strong opioid therapy.
RÉSUMÉ
BACKGROUND AND PURPOSE: Osteoarthritic pain is a chronic disabling condition lacking effective treatment. Continuous use of opioid drugs during osteoarthritic pain induces tolerance and may result in dose escalation and abuse. Sigma-1 (σ1) receptors, a chaperone expressed in key areas for pain control, modulates µ-opioid receptor activity and represents a promising target to tackle these problems. The present study investigates the efficacy of the σ1 receptor antagonist E-52862 to inhibit pain sensitization, morphine tolerance, and associated electrophysiological and molecular changes in a murine model of osteoarthritic pain. EXPERIMENTAL APPROACH: Mice received an intra-knee injection of monoiodoacetate followed by 14-day treatment with E-52862, morphine, or vehicle, and mechanical sensitivity was assessed before and after the daily doses. KEY RESULTS: Monoiodoacetate-injected mice developed persistent mechanical hypersensitivity, which was dose-dependently inhibited by E-52862. Mechanical thresholds assessed before the daily E-52862 dose showed gradual recovery, reaching complete restoration by the end of the treatment. When repeated treatment started 15 days after knee injury, E-52862 produced enhanced short-term analgesia, but recovery to baseline threshold was slower. Both a σ1 receptor agonist and a µ receptor antagonist blocked the analgesic effects of E-52862. An acute, sub-effective dose of E-52862 restored morphine analgesia in opioid-tolerant mice. Moreover, E-52862 abolished spinal sensitization in osteoarthritic mice and inhibited pain-related molecular changes. CONCLUSION AND IMPLICATIONS: These findings show dual effects of σ1 receptor antagonism alleviating both short- and long-lasting antinociception during chronic osteoarthritis pain. They identify E-52862 as a promising pharmacological agent to treat chronic pain and avoid opioid tolerance.
Sujet(s)
Modèles animaux de maladie humaine , Hyperalgésie/métabolisme , Inflammation/métabolisme , Arthrose/métabolisme , Douleur/métabolisme , Récepteur sigma/métabolisme , Analgésiques morphiniques/pharmacologie , Animaux , Relation dose-effet des médicaments , Tolérance aux médicaments , Hyperalgésie/traitement médicamenteux , Inflammation/traitement médicamenteux , Injections articulaires , Acide iodo-acétique/administration et posologie , Mâle , Souris , Morphine/pharmacologie , Morpholines/pharmacologie , Arthrose/induit chimiquement , Arthrose/traitement médicamenteux , Douleur/induit chimiquement , Douleur/traitement médicamenteux , Pyrazoles/pharmacologie , Récepteur sigma/antagonistes et inhibiteurs ,RÉSUMÉ
Sigma-1 receptor (σ1R) antagonism increases the effects of morphine on acute nociceptive pain. S1RA (E-52862) is a selective σ1R antagonist widely used to study the role of σ1Rs. S1RA alone exerted antinociceptive effect in the formalin test in rats and increased noradrenaline levels in the spinal cord, thus accounting for its antinociceptive effect. Conversely, while systemic S1RA failed to elicit antinociceptive effect by itself in the tail-flick test in mice, it did potentiate the antinociceptive effect of opioids in this acute pain model. The present study aimed to investigate the site of action and the involvement of spinal noradrenaline on the potentiation of opioid antinociception by S1RA on acute thermal nociception using the tail-flick test in rats. Local administration was performed after intrathecal catheterization or intracerebroventricular and rostroventral medullar (RVM) cannulae implantation. Noradrenaline levels in the spinal cord were evaluated using the concentric microdialysis technique in awake, freely-moving rats. Systemic or supraspinal administration of S1RA alone, while having no effect on antinociception, enhanced the effect of morphine in rats. However, spinal S1RA administration did not potentiate the antinociceptive effect of morphine. Additionally, the peripherally restricted opioid agonist loperamide was devoid of antinociceptive effect but produced antinociception when combined with S1RA. Neurochemical studies revealed that noradrenaline levels in the dorsal horn of the spinal cord were not increased at doses exerting potentiation of the antinociceptive effect of the opioid. In conclusion, the site of action of σ1R for opioid modulation on acute thermal nociception is located at the peripheral and supraspinal levels, and the opioid-potentiating effect is independent of the spinal noradrenaline increase produced by S1RA.
RÉSUMÉ
Osteoarthritis is the most common musculoskeletal disease worldwide, often characterized by degradation of the articular cartilage, chronic joint pain and disability. Cognitive dysfunction, anxiety and depression are common comorbidities that impact the quality of life of these patients. In this study, we evaluated the involvement of sigma-1 receptor (σ1R) on the nociceptive, cognitive and emotional alterations associated with chronic osteoarthritis pain. Monosodium iodoacetate (MIA) was injected into the knee of Swiss-albino CD1 mice to induce osteoarthritis pain, which then received a repeated treatment with the σ1R antagonist E-52862 or its vehicle. Nociceptive responses and motor performance were assessed with the von Frey and the Catwalk gait tests. Cognitive alterations were evaluated using the novel object recognition task, anxiety-like behavior with the elevated plus maze and the zero-maze tests, whereas depressive-like responses were determined using the forced swimming test. We also studied the local effect of the σ1R antagonist on cartilage degradation, and its central effects on microglial reactivity in the medial prefrontal cortex. MIA induced mechanical allodynia and gait abnormalities that were prevented by the chronic treatment with the σ1R antagonist. E-52862 also reduced the memory impairment and the depressive-like behavior associated to osteoarthritis pain. Interestingly, the effect of E-52862 on depressive-like behavior was not accompanied by a modification of anxiety-like behavior. The pain-relieving effects of the σ1R antagonist were not due to a local effect on the articular cartilage, since E-52862 treatment did not modify the histological alterations of the knee joints. However, E-52862 induced central effects revealed by a reduction of the cortical microgliosis observed in mice with osteoarthritis pain. These findings show that σ1R antagonism inhibits mechanical hypersensitivity, cognitive deficits and depressive-like states associated with osteoarthritis pain in mice. These effects are associated with central modulation of glial activity but are unrelated to changes in cartilage degradation. Therefore, targeting the σ1R with E-52862 represents a promising pharmacological approach with effects on multiple aspects of chronic osteoarthritis pain that may go beyond the strict inhibition of nociception.
RÉSUMÉ
Selective serotonin reuptake inhibitors (SSRIs) regulate brain noradrenergic neurotransmission both at somatodendritic and nerve terminal areas. Previous studies have demonstrated that noradrenaline (NA) reuptake inhibitors are able to desensitize α2-adrenoceptor-mediated responses. The present study was undertaken to elucidate the effects of repeated treatment with the SSRI citalopram on the α2-adrenoceptor sensitivity in locus coeruleus (LC) and prefrontal cortex (PFC), by using in vivo microdialysis and electrophysiological techniques, and in vitro stimulation of [35S]GTPγS binding autoradiography. Repeated, but not acute, treatment with citalopram (5 mg/kg, i.p., 14 days) increased extracellular NA concentration selectively in PFC. The α2-adrenoceptor agonist clonidine (0.3 mg/kg, i.p.), administered to saline-treated animals (1 ml/kg i.p., 14 days) induced NA decrease in LC (Emax = -44 ± 4%; p < 0.001) and in PFC (Emax = -61 ± 5%, p < 0.001). In citalopram chronically-treated rats, clonidine administration exerted a lower decrease of NA (Emax = -25 ± 7%; p < 0.001) in PFC whereas the effect in LC was not different to controls (Emax = -36 ± 4%). Clonidine administration (0.625-20 µg/kg, i.v.) evoked a dose-dependent decrease of the firing activity of LC noradrenergic neurons in both citalopram- (ED50 = 3.2 ± 0.4 µg/kg) and saline-treated groups (ED50 = 2.6 ± 0.5 µg/kg). No significant differences between groups were found in ED50 values. The α2-adrenoceptor agonist UK14304 stimulated specific [35S]GTPγS binding in brain sections containing LC (144 ± 14%) and PFC (194 ± 32%) of saline-treated animals. In citalopram-treated animals, this increase did not differ from controls in LC (146 ± 22%) but was lower in PFC (141 ± 8%; p < 0.05). Taken together, long-term citalopram treatment induces a desensitization of α2-adrenoceptors acting as axon terminal autoreceptors in PFC without changes in somatodendritic α2-adrenoceptor sensitivity.
Sujet(s)
Citalopram/administration et posologie , Locus ceruleus/effets des médicaments et des substances chimiques , Neurones/effets des médicaments et des substances chimiques , Cortex préfrontal/effets des médicaments et des substances chimiques , Récepteurs alpha-2 adrénergiques/physiologie , Inbiteurs sélectifs de la recapture de la sérotonine/administration et posologie , Neurones adrénergiques/effets des médicaments et des substances chimiques , Neurones adrénergiques/physiologie , Agonistes des récepteurs alpha-2 adrénergiques/administration et posologie , Animaux , Encéphale/effets des médicaments et des substances chimiques , Encéphale/métabolisme , Tartrate de brimonidine/administration et posologie , Citalopram/pharmacocinétique , Locus ceruleus/métabolisme , Locus ceruleus/physiologie , Mâle , Neurones/physiologie , Norépinéphrine/métabolisme , Cortex préfrontal/métabolisme , Cortex préfrontal/physiologie , Rats , Rat Sprague-Dawley , Inbiteurs sélectifs de la recapture de la sérotonine/pharmacocinétiqueRÉSUMÉ
We have previously shown that the selective sigma-1 receptor (σ1 R) antagonist S1RA (E-52862) inhibits neuropathic pain and activity-induced spinal sensitization in various pre-clinical pain models. In this study we characterized both the behavioral and the spinal neurochemical effects of S1RA in the rat formalin test. Systemic administration of S1RA produced a dose-related attenuation of flinching and lifting/licking behaviors in the formalin test. Neurochemical studies using concentric microdialysis in the ipsilateral dorsal horn of awake, freely moving rats revealed that the systemic S1RA-induced antinociceptive effect occurs concomitantly with an enhancement of noradrenaline levels and an attenuation of formalin-evoked glutamate release in the spinal dorsal horn. Intrathecal pre-treatment with idazoxan prevented the systemic S1RA antinociceptive effect, suggesting that the S1RA antinociception depends on the activation of spinal α2 -adrenoceptors which, in turn, could induce an inhibition of formalin-evoked glutamate release. When administered locally, intrathecal S1RA inhibited only the flinching behavior, whereas intracerebroventricularly or intraplantarly injected also attenuated the lifting/licking behavior. These results suggest that S1RA supraspinally activates the descending noradrenergic pain inhibitory system, which may explain part of its antinociceptive properties in the formalin test; however, effects at other central and peripheral sites also account for the overall effect. Formalin-induced nociceptive effect occurs concomitantly with an enhancement of glutamate (Glu) level in the dorsal horn spinal cord. The selective σ1 receptor antagonist S1RA results in inhibition of formalin-evoked Glu release, no modification of GABA levels, and enhancement of noradrenaline (NA) levels. This increased spinal NA activates spinal α2-adrenoceptors producing the attenuation of the formalin-induced pain behaviour.
Sujet(s)
Morpholines/pharmacologie , Névralgie/métabolisme , Agents neuromédiateurs/métabolisme , Pyrazoles/pharmacologie , Récepteur sigma/antagonistes et inhibiteurs , Moelle spinale/métabolisme , Animaux , Comportement animal/effets des médicaments et des substances chimiques , Mâle , Microdialyse , Névralgie/induit chimiquement , Mesure de la douleur , Rats , Rat Wistar , Moelle spinale/effets des médicaments et des substances chimiques ,RÉSUMÉ
We evaluated the effects of σ1-receptor inhibition on µ-opioid-induced mechanical antinociception and constipation. σ1-Knockout mice exhibited marked mechanical antinociception in response to several µ-opioid analgesics (fentanyl, oxycodone, morphine, buprenorphine, and tramadol) at systemic (subcutaneous) doses that were inactive in wild-type mice and even unmasked the antinociceptive effects of the peripheral µ-opioid agonist loperamide. Likewise, systemic (subcutaneous) or local (intraplantar) treatment of wild-type mice with the selective σ1 antagonists BD-1063 [1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine dihydrochloride] or S1RA [4-[2-[[5-methyl-1-(2-naphthalenyl)1H-pyrazol-3-yl]oxy]ethyl] morpholine hydrochloride] potentiated µ-opioid antinociception; these effects were fully reversed by the σ1 agonist PRE-084 [2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate) hydrochloride], showing the selectivity of the pharmacological approach. The µ-opioid antinociception potentiated by σ1 inhibition (by σ1-receptor knockout or σ1-pharmacological antagonism) was more sensitive to the peripherally restricted opioid antagonist naloxone methiodide than opioid antinociception under normal conditions, indicating a key role for peripheral opioid receptors in the enhanced antinociception. Direct interaction between the opioid drugs and σ1 receptor cannot account for our results, since the former lacked affinity for σ1 receptors (labeled with [(3)H](+)-pentazocine). A peripheral role for σ1 receptors was also supported by their higher density (Western blot results) in peripheral nervous tissue (dorsal root ganglia) than in several central areas involved in opioid antinociception (dorsal spinal cord, basolateral amygdala, periaqueductal gray, and rostroventral medulla). In contrast to its effects on nociception, σ1-receptor inhibition did not alter fentanyl- or loperamide-induced constipation, a peripherally mediated nonanalgesic opioid effect. Therefore, σ1-receptor inhibition may be used as a systemic or local adjuvant to enhance peripheral µ-opioid analgesia without affecting opioid-induced constipation.
Sujet(s)
Analgésiques morphiniques/pharmacologie , Mesure de la douleur/méthodes , Récepteur mu/physiologie , Récepteur sigma/physiologie , Analgésiques morphiniques/antagonistes et inhibiteurs , Animaux , Constipation/induit chimiquement , Constipation/génétique , Constipation/métabolisme , Femelle , Ganglions sensitifs des nerfs spinaux/effets des médicaments et des substances chimiques , Ganglions sensitifs des nerfs spinaux/métabolisme , Ganglions sensitifs des nerfs spinaux/physiologie , Souris , Souris knockout , Récepteur mu/métabolisme , Récepteur sigma/déficit , Récepteur sigma/génétique ,RÉSUMÉ
RATIONALE: Selective serotonin reuptake inhibitors (SSRIs), in addition to being able to enhance serotonergic neurotransmission, are able to modulate other brain systems involved in depression. OBJECTIVES: This study evaluates the neurochemical effect of the SSRI citalopram on brain noradrenergic activity and the serotonin receptor involved in this effect. METHODS: Dual-probe microdialysis in the locus coeruleus (LC) and prefrontal cortex (PFC) was performed in freely awake rats. RESULTS: Systemic citalopram (10 mg/kg, i.p.) increased noradrenaline (NA) in the LC (E max = 141 ± 13%) and simultaneously decreased NA in the PFC (Emax = -46 ± 7%). In the local presence into the LC of the α2-adrenoceptor antagonist RS79948 (1 µM), systemic citalopram increased NA in the LC (Emax = 157 ± 25%) and PFC (Emax = 175 ± 24%). Local citalopram (0.1-100 µM) into the LC induced NA increase in the LC (Emax = 210 ± 25%) and decrease in the PFC (Emax = -38 ± 9%). Local LC citalopram effect was abolished by LC presence of the 5-HT3 receptor antagonist MDL72222 (1 µM) but not the 5-HT1/2 receptor antagonist methiothepin (1 µM). Systemic citalopram in the LC presence of MDL72222 did not modify NA in the LC but increased NA in the PFC (Emax = 158 ± 26%). Local citalopram into the PFC enhanced NA (Emax = 376 ± 18%) in the area, which was prevented by MDL72222. CONCLUSIONS: The SSRI citalopram modulates central noradrenergic neurotransmission by activation, through endogenous serotonin, of 5-HT3 receptors expressed in the somatodendritic (LC) and terminal (PFC) areas, which subsequently promote an enhancement of local NA. Therefore, 5-HT3 receptors and somatodendritic α2-adrenoceptors in the LC play an important role in the global effect of SSRIs.
Sujet(s)
Locus ceruleus/métabolisme , Norépinéphrine/métabolisme , Cortex préfrontal/métabolisme , Récepteurs sérotoninergiques 5-HT3/métabolisme , Analyse de variance , Animaux , Aire sous la courbe , Chromatographie en phase liquide à haute performance , Relation dose-effet des médicaments , Interactions médicamenteuses , Électrochimie , Isoquinoléines/pharmacologie , Locus ceruleus/effets des médicaments et des substances chimiques , Mâle , Microdialyse , Naphtyridines/pharmacologie , Cortex préfrontal/effets des médicaments et des substances chimiques , Rats , Rat Sprague-Dawley , Agents sérotoninergiques/pharmacologie , VigilanceRÉSUMÉ
While opioids are potent analgesics widely used in the management of pain, a number of well-known adverse effects limit their use. The sigma-1 receptor is a ligand-regulated molecular chaperone involved in pain processing, including modulation of opioid antinociception. However, data supporting the potential use of sigma-1 receptor ligands as suitable opioid adjuvants are based on studies that use non selective ligands. Also, safety issues derived from combination therapy are poorly addressed. In this study we used the new selective sigma-1 receptor antagonist S1RA (E-52862) to characterize the effect of selective sigma-1 receptor blockade on opioid-induced efficacy- and safety-related outcomes in mice. S1RA (40 mg/kg) had no effect in the tail-flick test but did enhance the antinociceptive potency of several opioids by a factor between 2 and 3.3. The potentiating effect of S1RA on morphine antinociception did not occur in sigma-1 receptor knockout mice, which supports the selective involvement of the sigma-1 receptor. Interestingly, S1RA co-administration restored morphine antinociception in tolerant mice and reverted the reward effects of morphine in the conditioned place preference paradigm. In addition, enhancement of antinociception was not accompanied by potentiation of other opioid-induced effects, such as the development of morphine analgesic tolerance, physical dependence, inhibition of gastrointestinal transit, or mydriasis. The use of sigma-1 receptor antagonists as opioid adjuvants could represent a promising pharmacological strategy to enhance opioid potency and, most importantly, to increase the safety margin of opioids. S1RA is currently in phase II clinical trials for the treatment of several pain conditions.
Sujet(s)
Analgésiques morphiniques/effets indésirables , Analgésiques morphiniques/pharmacologie , Récepteur sigma/antagonistes et inhibiteurs , Animaux , Comportement animal/effets des médicaments et des substances chimiques , Traitement médicamenteux adjuvant , Conditionnement psychologique/effets des médicaments et des substances chimiques , Synergie des médicaments , Tolérance aux médicaments , Transit gastrointestinal/effets des médicaments et des substances chimiques , Techniques de knock-out de gènes , Intestins/effets des médicaments et des substances chimiques , Intestins/physiologie , Mâle , Souris , Morphine/effets indésirables , Morphine/pharmacologie , Mydriase/induit chimiquement , Naloxone/pharmacologie , Récepteur sigma/déficit , Récepteur sigma/génétique , Récompense , Comportement spatial/effets des médicaments et des substances chimiques ,RÉSUMÉ
Measurement of neurotransmitters in the spinal dorsal horn in conscious animals remains a technical challenge. Here we applied concentric microdialysis to measure formalin-induced glutamate (Glu) release in the ipsilateral dorsal horn in conscious, freely-moving rats. Hind paw formalin injection induced flinching nociceptive behaviors accompanied by increased Glu in the dorsal horn (maximum = 294%). Both flinching and Glu increase were prevented by morphine (3 mg/kg, s.c.). Accordingly, concentric microdialysis is a sensitive technique for studying neurochemical modulation induced by pain and analgesics in the spinal dorsal horn of awake rats. Measurement of Glu provides information on modulation of excitatory signals.
Sujet(s)
Formaldéhyde/toxicité , Acide glutamique/métabolisme , Douleur/induit chimiquement , Moelle spinale/effets des médicaments et des substances chimiques , Animaux , Mâle , Microdialyse , Rats , Rat Wistar , Moelle spinale/métabolismeRÉSUMÉ
The therapeutic activity of noradrenaline reuptake inhibitors (NaRIs) and serotonin reuptake inhibitors (SSRIs) as antidepressant is based on their ability to increase monoamine concentrations in the synaptic cleft. α(2)-Adrenoceptors inhibit noradrenaline (NA) release, which modulates antidepressant neurochemical activity. The present study assesses the influence of the addition of the selective α(2)-adrenoceptor antagonist RS79948 to the NaRI reboxetine and the SSRI citalopram on brain extracellular NA. Dual-probe microdialysis technique in the locus coeruleus (LC) and prefrontal cortex (PFC) was performed in freely moving rats. Acute reboxetine (3 and 5 mg/kg i.p.) promoted a dose-dependent increase of NA in LC (164 ± 15%; 243 ± 24%) and PFC (140 ± 7%; 181 ± 30%). Acute citalopram (5 mg/kg i.p.) did not change NA in LC or PFC, but at 10 mg/kg i.p. increased NA in LC (144 ± 14%) and decreased it in PFC (-42 ± 7%). An inactive dose of RS79948 (0.1mg/kg i.p.) in rats pretreated with reboxetine (3 mg/kg i.p.) or citalopram (5mg/kg i.p.) induced a significant enhancement of NA in LC (reboxetine: 462 ± 137%; citalopram: 142 ± 11%) and PFC (reboxetine: 281 ± 56%; citalopram: 130 ± 16%). The results indicate that co-administration of selective α(2)-adrenoceptor antagonist drugs might improve the effects of NaRI or SSRI antidepressants by enhancing extracellular NA concentrations in the brain.
Sujet(s)
Antagonistes des récepteurs alpha-2 adrénergiques/administration et posologie , Encéphale/métabolisme , Citalopram/administration et posologie , Espace extracellulaire/métabolisme , Morpholines/administration et posologie , Norépinéphrine/métabolisme , Animaux , Encéphale/effets des médicaments et des substances chimiques , Synergie des médicaments , Espace extracellulaire/effets des médicaments et des substances chimiques , Locus ceruleus/effets des médicaments et des substances chimiques , Locus ceruleus/métabolisme , Mâle , Cortex préfrontal/effets des médicaments et des substances chimiques , Cortex préfrontal/métabolisme , Liaison aux protéines/physiologie , Rats , Rat Sprague-Dawley , RéboxétineRÉSUMÉ
RATIONALE: The origin and regulation of noradrenaline (NA) in the locus coeruleus (LC) is unknown. OBJECTIVES: The neurochemical features of NA overflow (nerve impulse dependence, neurotransmitter synthesis, vesicle storage, reuptake, alpha2-adrenoceptor-mediated regulation) were characterized in the LC. METHODS: Brain microdialysis was performed in awake rats. Dialysates were analyzed for NA. RESULTS: NA in the LC decreased via local infusion of Ca2+-free medium (-42+/-5%) or the sodium channel blocker tetrodotoxine (TTX) (-47+/-8%) but increased (333+/-40%) via KCl-induced depolarization. The tyrosine hydroxylase (TH) inhibitor alpha-methyl-p-tyrosine (250 mg kg(-1), i.p.) and the vesicle depletory drug reserpine (5 mg kg(-1), i.p.) decreased NA. Therefore, extracellular NA in the LC satisfies the criteria for an impulse flow-dependent vesicular exocytosis of neuronal origin. Local perfusion of the alpha2-adrenoceptor agonist clonidine (0.1-100 microM) decreased NA (E(max)=-79+/-5%) in the LC, whereas the opposite effect (E(max)=268+/-53%) was observed with the alpha2A-adrenoceptor antagonist BRL44408 (0.1-100 microM). This suggests a tonic modulation of NA release through local alpha2A-adrenoceptors. The selective NA reuptake inhibitor desipramine (DMI) (0.1-100 microM) administered into the LC increased NA in the LC (E(max)=223+/-40%) and simultaneously decreased NA in the cingulate cortex, confirming the modulation exerted by NA in the LC on firing activity of noradrenergic cells and on the subsequent NA release in noradrenergic terminals. CONCLUSION: Synaptic processes underlying NA release in the LC are similar to those in noradrenergic terminal areas. NA in the LC could represent local somatodendritic release, but also the presence of neurotransmitter release from collateral axon terminals.
Sujet(s)
Locus ceruleus/métabolisme , Microdialyse , Norépinéphrine/métabolisme , Agonistes alpha-adrénergiques/pharmacologie , Antagonistes alpha-adrénergiques/pharmacologie , Animaux , Neuroleptiques/pharmacologie , Liquide cérébrospinal/composition chimique , Clonidine/pharmacologie , Solutions de dialyse/administration et posologie , Solutions de dialyse/composition chimique , Liquide extracellulaire/composition chimique , Liquide extracellulaire/effets des médicaments et des substances chimiques , Imidazoles/pharmacologie , Indoles/pharmacologie , Isoindoles , Locus ceruleus/effets des médicaments et des substances chimiques , Mâle , Activité motrice/physiologie , Chlorure de potassium/pharmacologie , Rats , Rat Sprague-Dawley , Réserpine/pharmacologie , Vésicules synaptiques/effets des médicaments et des substances chimiques , Vésicules synaptiques/métabolisme , Tétrodotoxine/administration et posologie , Tétrodotoxine/pharmacologie , Vigilance/physiologie , alpha-Méthyltyrosine/pharmacologieRÉSUMÉ
The regulation of noradrenaline release in the rat cingulate cortex by somatodendritic alpha(2)-adrenoceptors placed in the locus coeruleus was evaluated by dual-probe microdialysis. The alpha(2)-adrenoceptor antagonists BRL44408 (2-[2H-(1-methyl-1,3-dihydroisoindole)methyl]-4,5-dihydroimidazole), RS79948 ((8,12,13)-decahydro-3methoxy-12-(ethylsulphonyl)-6H-isoquino[2,1-g][1,6]-naphthyridine) and RX821002 (2-methoxyidazoxan) administered by reverse dialysis into the locus coeruleus increased concentration-dependently (0.01-100 microM) noradrenaline release in the cortex (maximal effects 170+/-30%, 543+/-17%, 195+/-26%, respectively). Administration of the alpha(2)-adrenoceptor antagonist idazoxan increased at lower (0.1-10 microM) but decreased at the highest dose (100 microM) noradrenaline in the cortex. These data demonstrate that somatodendritic alpha(2)-adrenoceptors in the locus coeruleus exert an inhibitory tonic modulation on noradrenaline release in noradrenergic terminal areas.