Differential Contribution of 5-HT4, 5-HT5, and 5-HT6 Receptors to Acute Pruriceptive Processing Induced by Chloroquine and Histamine in Mice.

The involvement of serotonin (5-HT) and/or noradrenaline in acute pruriceptive processing in the central nervous system (CNS) has been reported using antidepressants, such as milnacipran, a serotonin and noradrenaline reuptake inhibitor, and mirtazapine, a noradrenergic and specific serotonergic antidepressant; however, the roles of 5-HT receptor family in acute pruriceptive processing have not been fully elucidated in the CNS. In the present study, scratching behavior induced by chloroquine (CQ) was ameliorated by milnacipran or mirtazapine, and these effects were reversed by SB207266, a 5-HT4 antagonist, or SB258585, a 5-HT6 antagonist, but not by SB258585, a 5-HT5 antagonist. Moreover, CQ-induced scratches were mitigated by intrathecal injection of 5-HT4 agonists, such as BIMU8 and ML10302, and the 5-HT6 agonist, WAY208466. Conversely, histamine-induced scratches were not affected by the 5-HT4 agonists or a 5-HT6 agonist. Similarly, the amelioration of histamine-induced scratches by these antidepressants was not reversed by the 5-HT4, 5-HT5, or 5-HT6 receptor antagonist. Therefore, 5-HT is involved in the amelioration of CQ-induced scratches by milnacipran and mirtazapine, and 5-HT4, 5-HT5, and 5-HT6 receptors play differential roles in acute pruriceptive processing after administration of CQ or histamine.

Role of kainate receptors in pruriceptive processing in the mouse spinal cord.

Pruritus, including neuropathic and psychogenic pruritus, is an unpleasant feeling that causes a desire to scratch, which negatively impacts physical and psychological aspects of daily life. Nonetheless, little is known about the neural mechanisms involved in pruritus. Glutamate is a predominant excitatory neurotransmitter in the mammalian central nervous system and exerts its effects by binding to various glutamate receptors, including kainate (KA) receptors; however, the precise involvement of each glutamate receptor in pruriceptive processing remains unclear, particularly that of KA receptors. Therefore, the roles of KA receptors in histamine-dependent and -independent itch were investigated using CNQX, an AMPA/KA receptors antagonist, UBP310 and UBP302, antagonists of KA receptors, and small interfering (si)RNAs against KA receptor subunits in mice with acute and chronic pruritus. The effects of KA receptor antagonists on histamine-induced c-Fos expression in the spinal cord were also examined. The intrathecal administration of CNQX reduced the number of scratching events induced by histamine and chloroquine. On the other hand, UBP310 or UBP302 and the siRNAs of KA receptor subunits 1-3 significantly inhibited the induction of scratching events in mice treated with histamine, while no significant change was observed in the induction of spontaneous scratching events in mice with chronic pruritus. In addition, antagonists of KA receptors attenuated c-Fos expression in the superficial layers of the dorsal horn induced by histamine. These results indicate that KA receptors are involved in acute pruriceptive processing in the spinal cord induced by histamine, but not chloroquine or chronic itch.

Roles of 5-HT3 and 5-HT7 receptors in acute pruriceptive processing in mice.

The roles of serotonin (5-HT) and/or noradrenaline in acute pruriceptive processing have been demonstrated using antidepressants, such as milnacipran, a serotonin and noradrenaline reuptake inhibitor, and mirtazapine, a noradrenergic and specific serotonergic antidepressant; however, the involvement of 5-HT in acute pruriceptive processing has not yet been elucidated in detail. Scratching events induced by chloroquine (CQ) were attenuated by the administration of milnacipran or mirtazapine, and these effects were reversed by a treatment with ondansetron, a 5-HT3 antagonist, or SB26970, a 5-HT7 antagonist. CQ-induced scratching events were also ameliorated by the intrathecal administration of 5-HT, SR572227A and RS56812 (5-HT3 agonists), and LP211 and LP44 (5-HT7 agonists), indicating the modulation of CQ-induced scratching events by 5-HT and noradrenaline. By contrast, histamine-induced scratching events were not markedly affected by the administration of 5-HT and 5-HT7 agonists, whereas 5-HT3 agonists exerted attenuating effects. Similarly, they were not clearly reversed by the administration of the 5-HT7 antagonist, unlike a 5-HT3 antagonist. Therefore, 5-HT is involved in the attenuating effects of milnacipran and mirtazapine on CQ- and histamine-induced scratching events, and 5-HT3 and 5-HT7 receptors play different roles in pruriceptive processing induced by histamine or CQ.

Serotonin and noradrenaline modulate chronic itch processing in mice.

The roles of serotonin and noradrenaline in the modulation of chronic pruriceptive processing currently remain unclear. To clarify the contribution of serotonin and noradrenaline to chronic itch, the effects of the administration of antidepressants or noradrenaline reuptake inhibitors were evaluated in the present study. A pretreatment with milnacipran, a serotonin and noradrenaline reuptake inhibitor, and mirtazapine, a noradrenergic and specific serotonergic antidepressant, attenuated the induction of spontaneous scratching behavior in mice with chronic itch. The administration of a serotonin reuptake inhibitor, such as fluvoxamine and paroxetine, but not escitalopram, or a noradrenaline reuptake inhibitor, such as atomoxetine and nisoxetine, ameliorated the induction of spontaneous scratching behavior in mice with chronic itch. Furthermore, this attenuation was reversed by the administration of yohimbine, a selective α2-adrenoceptor antagonist, or methysergide, a non-selective serotonin receptor antagonist. These results suggest that elevated serotonin and noradrenaline levels are involved in the attenuation of scratching behavior induced by chronic itch, and serotonin receptors and an α2-adrenoceptor play a crucial role in chronic pruriceptive processing.