2025 Volume 48 Issue 2 Pages 184-187
Itch is described as an unpleasant sensation, and chronic itch, such as that in atopic dermatitis (AD), often decreases a patient’s QOL. There are few effective treatments for various chronic pruritic disorders that are not limited to inflammation. Selective serotonin reuptake inhibitors (SSRIs) are antidepressants used to treat some chronic pruritus disorders. However, there is little evidence from clinical and basic studies using animal models. In this study, we found that paroxetine suppressed acute and chronic itch in mouse models. Single administration of paroxetine (10 mg/kg) inhibited scratching behavior caused by histamine-dependent or histamine-independent itch. Moreover, paroxetine (10 mg/kg) inhibited spontaneous scratching behavior in AD model using NC/Nga mice without affecting locomotor function. These results suggest that paroxetine suppresses chronic itch caused by AD via histamine-dependent and -independent pathways. This study provides one of the few pieces of evidence that SSRIs suppress itch.
Itch is defined as an unpleasant sensation that provokes the desire to scratch.1) It is typically described as more excruciating than pain. For example, chronic itch including atopic dermatitis (AD), causes discomfort that is not normally experienced and significantly reduces the QOL of patients.2) In recent years, the advent of treatments such as interleukin (IL) -4, IL-13 inhibitors, and Janus kinase inhibitors has greatly advanced the development of treatments for inflammatory and immune-mediated chronic itch.3) However, as there are cases of chronic itch that do not have an inflammatory component, it is necessary to develop treatments that target the nerves rather than the immune system.4)
The itch-scratch cycle is a feature of the mechanism underlying the worsening of chronic itch conditions.5) Scratching with persistent itch releases itch mediators in the skin by disrupting the skin barrier and causing inflammation, which leads to further itch. In addition, the itch-anxiety cycle has recently been proposed, in which itch and anxiety/stress are mutually exacerbated.6) Acute itch induce anxiety-like behavior in mice.7) Conversely, stress caused by restraint increases scratching behavior.8) Moreover, many patients with chronic itch report that psychological stress aggravates itch. Therefore, it may be important to break the itch-anxiety cycle during the treatment of chronic itch.
Selective serotonin reuptake inhibitors (SSRIs), such as paroxetine are used to treat depression. SSRIs selectively inhibit serotonin reuptake, potentiating serotonergic neurotransmission.9) SSRIs have been reported to be effective in the treatment of some chronic pruritus disorders.10–12) However, these are often not reported in studies and are only cited by experts.13) Especially, basic research using animal models is rare, and what type of itch is effective remains unknown.
In this study, we analyzed the antipruritic effects of a single systemic dose of paroxetine, the most potent antidepressant, on acute itch and AD in chronic itch models.
In acute itch study, male ICR mice were purchased from Japan SLC, Inc. (Shizuoka, Japan) and used for the experiments at 11–13 weeks of age. For the chronic itch study, male NC/Nga mice were purchased from Japan SLC, Inc. and used at 12–14 weeks of age. As reported previously, we used conventional (CV) mice that developed AD after mite infection.14) All animals were housed at a temperature of 25 ± 1 °C with a 12-h light–dark cycle (light from 7:00–19:00) and fed food (CE-2, CLEA Japan, Inc., Tokyo, Japan) and water ad libitum. All animal experiments were conducted in accordance with relevant national and international guidelines, as outlined in the “Act on Welfare and Management of Animals” (Ministry of Environment of Japan). The procedures used for animal experiments were approved by the Committee for Animal Experiments at the University of Toyama (A2019PHA-12, A2019PHA-13, A2022PHA-2, and A2023PHA-13). Efforts were made to minimize animal suffering and ensure accurate counts.
DrugsParoxetine hydrochloride hemihydrate was purchased from Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan). The drug was dissolved in saline (Otsuka Pharmaceutical Factory Inc., Tokushima, Japan). Paroxetine was administered intraperitoneally (i.p.) in a volume of 0.1 mL/10 g body weight to mice at a dose of 5, 10, or 20 mg/kg. These doses are listed as free-body doses. Histamine dihydrochloride (200 nmol/site, 085–03554; Wako, Osaka, Japan) and chloroquine diphosphate (625 nmol/site, 038–17971; Wako) were used. The drugs were dissolved in saline and administered intradermally (i.d.) in a volume of 50 µL per site into the rostral back of ICR mice.
Behavioral TestsAccording to the previous report, the scratching behavior and total distance moved was recorded using the SCLABA®-Next (Noveltec Inc., Kobe, Japan) real-time scratch counting system.14) The animals were placed in an acrylic cage (approximately 150 mm wide, 200 mm deep, and 350 mm high) for 30 min before the scratching behavior was measured. The scratching behavior of ICR mice treated with i.p. administration of the drugs was measured for 30 min after i.d. injection of pruritogens. The scratching behaviors of NC mice were treated with saline or paroxetine, and spontaneous scratching behaviors and total distance moved were measured for 90 min.
Statistical AnalysisData are presented as the mean ± standard error (S.E.M). “n” in each graph stands for the number of animals. Statistical differences between the two groups for various behavioral tests were analyzed using the unpaired t-test or Mann–Whitney test. Multiple comparison tests were conducted with a one way ANOVA followed by Dunnett’s test or Kruskal–Wallis test followed by Dunn’s test. The significance level was set at 5% (p < 0.05). Prism 5 (GraphPad Software Inc., La Jolla, CA, U.S.A.) was used for these analyses.
Peripheral itch pathways are classically classified as histamine-dependent or histamine-independent.15) To investigate whether paroxetine has an antipruritic effect on acute itch, we used mouse models of acute itch induced by histamine or chloroquine, which activates a histamine-independent pathway. Figure 1A shows the drug administration schedule. When vehicle (saline) or paroxetine (5, 10, or 20 mg/kg) was administered intraperitoneally, paroxetine suppressed the histamine-induced scratching behaviors in application of 10 mg/kg (Fig. 1B). In addition, paroxetine (10 and 20 mg/kg) suppressed the chloroquine-induced scratching behavior (Fig. 1C). These results suggest that paroxetine has an antipruritic effect on acute itch, with the lowest effective dose being 10 mg/kg.
(A) Time schedule of intraperitoneal (i.p.) administration of vehicle or paroxetine, intradermal (i.d.) injection of each pruritogen and measurement of scratching behavior of ICR mice. (B) The number of histamine-induced scratching behavior. ** p < 0.01, Kruskal–Wallis test on Ranks–Dunn’s test (n = 8). (C) The number of chloroquine-induced scratching behavior. ** p < 0.01, *** p < 0.001, One way ANOVA on Dunnett’s test (n = 8).
To investigate whether paroxetine has an antipruritic effect on chronic itch, we used CV mice as the chronic itch model. Figure 2A shows the drug administration schedule. When vehicle (saline) or paroxetine (10 mg/kg) was administered intraperitoneally, paroxetine (10 mg/kg) suppressed spontaneous scratching behavior (Fig. 2B; Supplementary data). In addition, to investigate whether paroxetine has a sedative effect, we analyzed locomotor function. There were no significant changes in the locomotor activity (Fig. 2C). These results suggested that paroxetine (10 mg/kg) has an antipruritic effect on AD pruritus without affecting locomotor function.
(A) Time schedule of i.p. administration of vehicle or paroxetine (10 mg/kg), and measurement of scratching behavior and locomotor activity of CV mice. (B) The number of spontaneous scratching behavior. *** p = 0.0008, Mann–Whitney test (n = 8). (C) Total distance moved as locomotor activity (n = 8).
SSRIs and other antidepressants have been focused on as effective treatments for chronic pruritic disorders, but the evidence is insufficient.13) In this study, we analyzed the antipruritic effects of the SSRI, paroxetine using various mouse models. Systemic administration of paroxetine suppressed acute itch induced by histamine and chloroquine which activates histamine-independent pathway. Paroxetine increases serotonin levels by inhibiting the reuptake of serotonin at the synaptic cleft.9) In a previous study, intrathecal injection of fluvoxamine, an SSRI, did not suppress serotonin-induced itch-related responses.16) These results suggest that paroxetine primarily acts on the nervous system in the brain and exerts its antipruritic effects.
Systemic administration of paroxetine to AD-developed CV mice suppressed spontaneous scratching behavior. These results indicate that paroxetine suppresses chronic itch in AD by suppressing both histamine-dependent and histamine-independent itch. In previous study, intrathecal injection of paroxetine suppressed spontaneous scratching in chronic itch model caused by application of diphenylcyclopropenone.17) Considering results in acute itch as well, paroxetine may act on the spinal dorsal horn and the brain against chronic itch. However, the rule of serotonin (5-HT) in itch transduction in the spinal cord remains unclear. Intrathecal injection of 5-HT attenuated chloroquine-induced itch.18) Moreover, intrathecal injection of 5-HT4 and 5-HT6 agonists also attenuated chloroquine-induced itch.19) On the other hand, 5-HT1A receptor facilitated itch transmission in the neuron expressed gastrin releasing peptide receptor.20) Further studies are needed to investigate the mechanism underlying the antipruritic effect of paroxetine by identifying the specific subtype of the 5-HT receptors involved.
In a previous study, the repetitive administration of paroxetine (30 mg/kg) improved AD symptoms, including scratching, in NC/Nga mice.21) However, the mechanisms underlying this improvement remain unclear. In this study, a single application also suppressed the scratching behavior. These results supported the findings of a previous report indicating that the vicious itch-scratch cycle, in which scratching leads to further itch, can be disrupted by suppressing itch and improving AD pathology.
Furthermore, administration of paroxetine (10 mg/kg) did not affect locomotor activity in CV mice. This result might indicate that the dose of paroxetine exerts an antipruritic effect without affecting the sedative effect as a side effect. The itch caused by AD is intractable, and there are few treatments that directly target itch rather than inflammation, with few side effects. Moreover, pruritus in AD affects sleep and mood and can cause symptoms of anxiety and depression.4) Therefore, paroxetine, an antidepressant that directly suppresses itch, may be an effective treatment option for AD.
However, for the clinical utilization of paroxetine, it is necessary to conduct a more detailed examination of its side effects. One of the reasons SSRIs are not commonly utilized in dermatology is the challenge of managing their side effects.22) In particular, paroxetine reportedly has a greater sedative effect than other SSRIs.23) Further studies using naïve mice are necessary to determine the sedative effect of paroxetine (10 mg/kg).
In conclusion, a single systemic administration of paroxetine suppressed chronic itch in AD model mice via histamine-dependent and histamine-independent pathways without affecting locomotor function. In addition, this study is the first to show that SSRIs have an antipruritic effect on acute itch. Further investigations may reveal that SSRIs could be useful therapeutic agents for breaking the itch-scratch cycle and itch-anxiety cycle in various chronic pruritus disorders.
This work was supported by JSPS KAKENHI (Grant numbers: 19K09323 and 22K09020 to D. U., and 23KJ1021 to K. M.).
The authors declare no conflict of interest.
This article contains supplementary materials. This movie shows the scratching behavior of mice.
