Spinal dopaminergic involvement in the antihyperalgesic effect of antidepressants in a rat model of neuropathic pain.

Antidepressants such as tricyclic antidepressants, and serotonin noradrenaline reuptake inhibitors are a first-line treatment for neuropathic pain. Here, we aimed to determine the involvement of the spinal dopaminergic system in the antihyperalgesic effects of antidepressants in a rat model of neuropathic pain induced by spinal nerve ligation (SNL). The right L5 spinal nerve of male Sprague-Dawley rats was ligated under inhalation anesthesia to induce hyperalgesia. Behavioral testing was performed by measuring ipsilateral hindpaw withdrawal thresholds after intraperitoneal injection of amitriptyline, duloxetine, milnacipran, and fluoxetine. D2-like receptors were blocked by intrathecal administration of sulpiride. We also determined the concentrations of dopamine in the spinal cord using microdialysis after injection of antidepressants. The dopamine contents in the spinal dorsal horn were also measured in normal and SNL rats at 2, 3, 4, and 8 weeks after SNL surgery. Intraperitoneal injection of amitriptyline, duloxetine, milnacipran, and fluoxetine (3-30mg/kg) produced antihyperalgesic effects, and prevented by intrathecal pre-injection of sulpiride (30µg). Microdialysis revealed the dopamine levels in the spinal cord were increased after intraperitoneal injection of each antidepressant (10mg/kg). Furthermore, the dopamine content in homogenized spinal cord tissue were increased at 2 weeks after SNL and then subsequently declined. Our results suggest that the effect of antidepressants against neuropathic pain is related to modulation of not only noradrenalin and serotonin but also dopamine levels in the spinal cord.

Planarian shows decision-making behavior in response to multiple stimuli by integrative brain function.

INTRODUCTION: Planarians belong to an evolutionarily early group of organisms that possess a central nervous system including a well-organized brain with a simple architecture but many types of neurons. Planarians display a number of behaviors, such as phototaxis and thermotaxis, in response to external stimuli, and it has been shown that various molecules and neural pathways in the brain are involved in controlling these behaviors. However, due to the lack of combinatorial assay methods, it remains obscure whether planarians possess higher brain functions, including integration in the brain, in which multiple signals coming from outside are coordinated and used in determining behavioral strategies. RESULTS: In the present study, we designed chemotaxis and thigmotaxis/kinesis tracking assays to measure several planarian behaviors in addition to those measured by phototaxis and thermotaxis assays previously established by our group, and used these tests to analyze planarian chemotactic and thigmotactic/kinetic behaviors. We found that headless planarian body fragments and planarians that had specifically lost neural activity following regeneration-dependent conditional gene knockdown (Readyknock) of synaptotagmin in the brain lost both chemotactic and thigmotactic behaviors, suggesting that neural activity in the brain is required for the planarian's chemotactic and thigmotactic behaviors. Furthermore, we compared the strength of phototaxis, chemotaxis, thigmotaxis/kinesis, and thermotaxis by presenting simultaneous binary stimuli to planarians. We found that planarians showed a clear order of predominance of these behaviors. For example, when planarians were simultaneously exposed to 400 lux of light and a chemoattractant, they showed chemoattractive behavior irrespective of the direction of the light source, although exposure to light of this intensity alone induces evasive behavior away from the light source. In contrast, when the light intensity was increased to 800 or 1600 lux and the same dose of chemoattractant was presented, planarian behaviors were gradually shifted to negative phototaxis rather than chemoattraction. These results suggest that planarians may be capable of selecting behavioral strategies via the integration of discrete brain functions when exposed to multiple stimuli. CONCLUSIONS: The planarian brain processes external signals received through the respective sensory neurons, thereby resulting in the production of appropriate behaviors. In addition, planarians can adjust behavioral features in response to stimulus conditions by integrating multiple external signals in the brain.

Antihyperalgesic effect of duloxetine and amitriptyline in rats after peripheral nerve injury: Influence of descending noradrenergic plasticity.

Antidepressants such as serotonin-noradrenaline reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs) are frequently used for the management of neuropathic pain. Noradrenaline (NA) and serotonin (5-HT) increase in the spinal cord by reuptake inhibition is considered to be main mechanism of the therapeutic effect of antidepressants in neuropathic pain. In the present study, we examined the analgesic effects of duloxetine (SNRI) and amitriptyline (TCA) in a rat model of neuropathic pain induced by spinal nerve ligation (SNL). Intraperitoneal administration of duloxetine and amitriptyline dose-dependently (3,10 and 30 mg/kg) suppressed hyperalgesia induced by SNL. In vivo microdialysis in the lumbar spinal dorsal horn revealed that NA and 5-HT concentrations increased after intraperitoneal administration of duloxetine and amitriptyline (10 mg/kg, respectively). We further determined NA and 5-HT contents in homogenized samples from the ipsilateral dorsal spinal cord after SNL. Although the NA content in SNL rats 2 weeks after ligation was higher than that in SNL rats 4 weeks after ligation, the analgesic efficacy of duloxetine and amitriptyline was similar between two groups. The present study suggests that NA/5-HT increase in the spinal cord is crucial in the antihyperalgesic effect of duloxetine and amitriptyline. The plastic change of the descending noradrenergic system does not obviously affect the analgesic efficacy of duloxetine and amitriptyline.

The antihyperalgesic effects of intrathecal bupropion, a dopamine and noradrenaline reuptake inhibitor, in a rat model of neuropathic pain.

BACKGROUND: Antidepressants are often used for the treatment of neuropathic pain, and their analgesic effects rely on increased noradrenaline and serotonin levels in the spinal cord. Clinical studies have also shown that bupropion, a dopamine and noradrenaline reuptake inhibitor, has strong efficacy in neuropathic pain; however, the role of spinal cord dopamine in neuropathic pain is unknown. We hypothesized that bupropion inhibits neuropathic pain by increasing noradrenaline and dopamine in the spinal cord. In the present study, we determined the efficacy and underlying mechanisms of intrathecal administration of bupropion in a rat model of neuropathic pain. METHODS: Male Sprague-Dawley rats were anesthetized, and right L5 spinal nerve ligation (SNL) was performed to produce mechanical hyperalgesia of the hindpaw. Withdrawal threshold to a paw pressure test was measured before and after intrathecal administration of bupropion, without or with intrathecal antagonists for α2-adrenoceptors and dopamine D2 receptors. In vivo microdialysis was performed in the dorsal horn of the lumbar spinal cord to measure noradrenaline and dopamine concentrations after intrathecal injection of bupropion. We also measured the noradrenaline and dopamine contents in the ipsilateral dorsal lumbar spinal cord in normal rats and in rats 2, 3, and 4 weeks after SNL. RESULTS: Intrathecal injection of bupropion produced a dose-dependent antihyperalgesic effect (3, 10, 30, and 100 µg, P < 0.001). The effect (30 µg) was dose-dependently reversed by intrathecal pretreatment (15 minutes before bupropion injection) with the α2-adrenoceptor antagonist idazoxan (3, 10, and 30 µg, P < 0.001) and D2 receptor antagonist sulpiride (3, 10, and 30 µg, P < 0.001). Microdialysis revealed that noradrenaline and dopamine concentrations in the spinal dorsal horn were increased after intrathecal injection of bupropion (30 µg, P < 0.001 and P = 0.001, respectively). Furthermore, the noradrenaline and dopamine contents in the spinal dorsal horn were increased 2 weeks after SNL (P < 0.001 and P = 0.044, respectively) and then decreased gradually. CONCLUSIONS: These findings suggest that plasticity of descending inhibitory pathways such as the noradrenaline and dopamine systems contributes to the maintenance of neuropathic pain and that spinal cord noradrenaline and dopamine both play an inhibitory role in neuropathic pain.

Clozapine but not haloperidol suppresses the changes in the levels of neuropeptides in MK-801-treated rat brain regions.

Noncompetitive NMDA receptor antagonist (+)MK-801 is known to induce neurotoxicity and schizophrenia-like symptomatology where atypical neuroleptic clozapine is effective in contrast to typical neuroleptic, haloperidol. Although neuropeptides are implicated in memory and cognition, their roles in schizophrenia are not well understood. In the present study, we therefore examined the possible roles of neuropeptides, cholecystokinin (CCK) and somatostatin (SS) in the posterior cingulate/retrosplenial cortices (PC/RSC), frontal cortex, and hippocampus of a MK-801-induced schizophrenia-like model rat brain. This study further investigated the pretreated effect of atypical versus typical neuroleptics on the peptidergic system. SS mRNA and peptide levels significantly decreased in the PC/RSC and hippocampus but not in the frontal cortex 3 days after 0.5 mg/kg MK-801 treatment whereas CCK mRNA and peptide levels significantly decreased in all of the brain regions examined. Pretreatment with clozapine but not haloperidol completely recovered the changes in both mRNA and peptide levels of SS and CCK in those brain regions. These data suggest that peptidergic system in the brain presumably plays an important role in the control of negative schizophrenia.

[Anesthetic management for cerebral aneurysm surgery in a patient with aortitis syndrome accompanied by lung edema].

A 48-year-old woman with aortitis syndrome underwent clipping of dissecting aneurysm of the left posterior inferior cerebellar artery following subarachnoid hemorrhage. Preoperative echocardiography demonstrated moderate aortic regurgitation and pulmonary hypertension. Intravenous infusion (1900 ml.day-1) was performed to avoid cerebral vasospasm, but the patient developed lung edema. She received delayed surgical treatment after the improvement of lung symptoms. Anesthesia was induced with fentanyl (0.1 mg), propofol (90 mg) and vecuronium (6 mg). Radial arterial flow was judged to be insufficient for cannulation, and a cannulation was therefore performed on the dorsal pedis artery. During induction of anesthesia, there was a significant decrease in the arterial pressure, that required a total of 32 mg of intravenous ephedrine. Following tracheal intubation, a central venous catheter was inserted and dopamine was continuously administered. The patient was positioned in the park bench position. We thought that the placement of the introducer for Swan-Ganz catheter was difficult under the position and Swan-Ganz catheter was not inserted. Anesthesia was maintained with sevoflurane, air, and oxygen. We continuously monitored the central venous pressure as an indicator of fluid balance. In this case, we monitored dorsal pedis arterial pressure directly, which might not be sufficiently reliable to predict the decrease in cerebral blood flow.