A central role for spinal dorsal horn neurons that express neurokinin-1 receptors in chronic itch

Akiyama, Tasuku; Nguyen, Tony; Curtis, Eric; Nishida, Katsuko; Devireddy, Jahnavi; Delahanty, Jeremy; Carstens, Mirela Iodi; Carstens, Earl

doi:10.1097/j.pain.0000000000000172

Cited by 77 publications

(91 citation statements)

References 36 publications

(53 reference statements)

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“…It is well‐established that GRP/GRPR plays a key role in the acute, chronic, and contagious itch. Loss of the function of GRP or GRPR has been demonstrated to reduce chronic itch, including ovalbumin‐induced chronic atopic dermatitis model (Akiyama et al, ), DCP‐induced contact dermatitis model (Sun et al, ), and the AEW model (Pereira et al, ). In the present study, we further confirmed the role of GRPR in DNFB induced chronic itch by using the GRPR inhibitor RC‐3095.…”

Section: Discussionmentioning

confidence: 99%

Spinal IL‐33/ST2 signaling mediates chronic itch in mice through the astrocytic JAK2‐STAT3 cascade

Yang

et al. 2019

Glia

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Interleukin‐33 (IL‐33) and its receptor ST2 contribute to spinal glial activation and chronic pain. A recent study showed that peripheral IL‐33 plays a pivotal role in the pathogenesis of chronic itch induced by poison ivy. However, how IL‐33/ST2 signaling in the spinal cord potentially mediates chronic itch remains elusive. Here, we determined that St2−/− substantially reduced scratching behaviors in 2,4‐dinitrofluorobenzene (DNFB)‐induced allergic contact dermatitis (ACD) as well as acetone and diethylether followed by water‐induced dry skin in mice. Intrathecal administration of the neutralizing anti‐ST2 or anti‐IL‐33 antibody remarkably decreased the scratching response in DNFB‐induced ACD mice. Expression of spinal IL‐33 and ST2 significantly increased in ACD mice, as evidenced by increased mRNA and protein levels. Immunofluorescence and in situ hybridization demonstrated that increased expression of spinal IL‐33 was predominant in oligodendrocytes and astrocytes, whereas ST2 was mainly expressed in astrocytes. Further studies showed that in ACD mice, the activation of astrocytes and increased phosphorylation of signal transducer and activator of transcription 3 (STAT3) were markedly attenuated by St2−/−. Intrathecal injection of Janus Kinase 2 Inhibitor AG490 significantly alleviated scratching behaviors in ACD mice. rIL‐33 pretreatment exacerbated gastrin‐releasing peptide (GRP)‐evoked scratching behaviors. This increased gastrin‐releasing peptide receptor (GRPR) expression was abolished by St2−/−. Tnf‐α upregulation was suppressed by St2−/−. Our results indicate that the spinal IL‐33/ST2 signaling pathway contributes to chronic itch via astrocytic JAK2‐STAT3 cascade activation, promoting TNF‐α release to regulate the GRP/GRPR signaling‐related itch response. Thus, these findings provide a potential therapeutic option for treating chronic pruritus.

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Section: Discussionmentioning

confidence: 99%

Spinal IL‐33/ST2 signaling mediates chronic itch in mice through the astrocytic JAK2‐STAT3 cascade

Yang

et al. 2019

Glia

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“…Although many animal models for itch in atopic dermatitis have been reported, the availability of animal models of itch related to other diseases is limited [8]. We previously reported that mouse models for itch associated with other skin diseases, such as atopic dermatitis and dry skin, exhibited spontaneous scratching and alloknesis, common manifestations of chronic itch [3; 4; 7]. However, the present study represents the first time that itch has been characterized in a model of psoriasis.…”

Section: Discussionmentioning

confidence: 99%

“…A scratch bout was defined as one or more rapid back-and-forth hind paw motions directed toward and contacting the treated area, ending with licking or biting of the toes or placement of the hind paw on the floor. Hind paw movements directed away from the treated area (e.g., ear-scratching) and grooming movements were not counted [2; 6; 7]. Following the 60-min recording period, alloknesis was assessed as follows: the mouse received five separate innocuous mechanical stimuli delivered using a von Frey filament (bending force: 0.7 mN) to five randomly selected sites along the border of the cream application area.…”

Section: Methodsmentioning

confidence: 99%

Mouse model of imiquimod-induced psoriatic itch

Sakai

Sanders

Youssef

et al. 2016

PAIN

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Itch is a major indicator of psoriasis, but the underlying mechanisms behind this symptom are largely unknown. To investigate the neuronal mechanisms of psoriatic itch, we tested whether mice subjected to the imiquimod-induced psoriasis model exhibit itch-associated behaviors. Mice received daily topical applications of imiquimod to the rostral back skin for seven days. Imiquimod-treated mice exhibited a significant increase in spontaneous scratching behavior directed to the treated area as well as touch-evoked scratching (alloknesis). To characterize this model, we measured the mRNA expression levels of pruritogens and itch-relevant receptors/channels using real-time RT-PCR. The mRNA expression of MrgprA3, MrgprC11, and MrgprD decreased gradually over time in the dorsal root ganglion (DRG) cells. There was no significant change in the mRNA expression of TRPV1 or TRPA1 in DRG cells. TRPV4 mRNA expression was transiently increased in the DRG cells, while TRPM8 mRNA was significantly decreased. The mRNA expression levels of histidine decarboxylase and tryptophan hydroxylase 1, as well as the intensity of histamine and serotonin immunoreactivity, were transiently increased in the skin on day 2, returning to baseline by day 7. Histamine H1 receptor (H1R) antagonists, chlorpheniramine and olopatadine, significantly inhibited spontaneous scratching on day 2, but not day 7. Neither chlorpheniramine nor olopatadine affected alloknesis on day 2 or day 7. These results may reflect the limited antipruritic effects of H1R antagonists on human psoriasis. The imiquimod-induced psoriasis model appears to be useful for the investigation of itch and its sensitization in psoriasis.

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“…A scratch bout was defined as one or more rapid back-and-forth hind paw motions directed toward and contacting the treated area and ending with licking or biting of the toes or placement of the hind paw on the floor. Hind paw movements directed away from the treated area (e.g., ear-scratching) and grooming movements were not counted [2–4]. Scratch bouts were counted for mice treated with imiquimod alone, imiquimod plus goat IgG control, imiquimod plus low-dose NRTN-neutralizing antibody, and imiquimod plus high-dose NRTN-neutralizing antibody at Days 0, 2, and 7.…”

Section: Methodsmentioning

confidence: 99%

Role of neurturin in spontaneous itch and increased nonpeptidergic intraepidermal fiber density in a mouse model of psoriasis

Sakai

Sanders

Youssef

et al. 2017

PAIN

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Psoriasis is often accompanied by itch, but the mechanisms behind this symptom remain elusive. Dynamic changes in epidermal innervation have been observed under chronic itch conditions. Therefore, we investigated whether epidermal innervation is altered in the imiquimod-induced psoriasis mouse model, whether blockade of neurotrophic growth factor signaling can reduce these changes, and whether this system can impact psoriatic itch. Over the 7-day time course of imiquimod treatment, the density of epidermal nonpeptidergic nerves significantly increased, whereas the density of peptidergic nerves significantly decreased. The nonpeptidergic epidermal nerves expressed glial cell line–derived neurotrophic factor (GDNF) family receptor GFRα-1 and GFRα-2, the ligand-binding domains for GDNF and neurturin (NRTN). The NRTN mRNA expression was elevated in the skin of imiquimod-treated mice, whereas the GDNF mRNA expression was decreased. Treatment of imiquimod-challenged mice with an NRTN-neutralizing antibody significantly reduced nonpeptidergic nerve density as well as spontaneous scratching. These results indicate that NRTN contributes to an increase in the epidermal density of nonpeptidergic nerves in the imiquimod-induced psoriasis model, and this increase may be a factor in chronic itch for these mice. Therefore, inhibition of NRTN could be a potential treatment for chronic itch in psoriasis.

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A central role for spinal dorsal horn neurons that express neurokinin-1 receptors in chronic itch

Cited by 77 publications

References 36 publications

Spinal IL‐33/ST2 signaling mediates chronic itch in mice through the astrocytic JAK2‐STAT3 cascade

Spinal IL‐33/ST2 signaling mediates chronic itch in mice through the astrocytic JAK2‐STAT3 cascade

Mouse model of imiquimod-induced psoriatic itch

Role of neurturin in spontaneous itch and increased nonpeptidergic intraepidermal fiber density in a mouse model of psoriasis

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