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.

Hoshino H ，Obata H ，Saito S 《-》

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.

Chen M ，Hoshino H ，Saito S ，Yang Y ，Obata H ... -  《-》

Repeated Administration of Amitriptyline in Neuropathic Pain: Modulation of the Noradrenergic Descending Inhibitory System.

Hiroki T ，Suto T ，Saito S ，Obata H ... -  《-》

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

Hoshino H ，Obata H ，Nakajima K ，Mieda R ，Saito S ... -  《-》

An increase in spinal cord noradrenaline is a major contributor to the antihyperalgesic effect of antidepressants after peripheral nerve injury in the rat.

Antidepressants are often used for the treatment of neuropathic pain. Clinical studies suggest that the efficacy of serotonin (5-HT) and noradrenaline (NA) reuptake inhibitors (SNRIs) for neuropathic pain is greater than that of selective 5-HT reuptake inhibitors (SSRIs). In the present study, we determined the efficacy and mechanisms involved in the antihyperalgesic effects of milnacipran, an SNRI, compared with paroxetine, an SSRI, and maprotiline, a selective NA reuptake inhibitor, using a rat model of neuropathic pain. Male Sprague-Dawley rats underwent spinal nerve ligation (SNL), and the withdrawal threshold to paw pressure was measured. Intraperitoneal injection of milnacipran (3-30mg/kg) produced a dose-dependent antihyperalgesic effect. The effect was reversed by intrathecal injection of the α(2)-adrenoceptor antagonist idazoxan (30μg), but not by various 5-HT receptor antagonists. Paroxetine produced an antihyperalgesic effect only at the highest dose tested (10mg/kg). This effect was reversed by intrathecal injection of both idazoxan and ondansetron (30μg), a 5-HT3 receptor antagonist. Maprotiline produced an antihyperalgesic effect (10 and 30mg/kg), and the effect was reversed by intrathecal idazoxan. In microdialysis studies, NA and 5-HT concentrations in the spinal dorsal horn were increased after injection of either milnacipran or paroxetine, and only NA was increased after maprotiline. Furthermore, the NA content in the spinal cord of SNL rats was greater than that in normal animals. These findings suggest that an increase in NA in the spinal cord plays an important role in the antihyperalgesic effects of not only NA reuptake inhibitors but also SSRIs.

Nakajima K ，Obata H ，Iriuchijima N ，Saito S ... -  《-》