Critical role of GRP receptor-expressing neurons in the spinal transmission of imiquimod-induced psoriatic itch

Abstract

Aim: Ample evidence indicates that gastrin-releasing peptide receptor (GRPR)-expressing neurons play a critical role in the transmission of acute itch. However, the pathophysiology of spinal mechanisms underlying intractable itch such as psoriasis remains unclear. In this study, we aimed to determine whether itch-responsive GRPR⁺ neurons contribute to the spinal transmission of imiquimod (IMQ)-induced psoriatic itch.

Methods: To generate a psoriasis model, C57BL/6J mice received a daily topical application of 5% IMQ cream on their shaved back skin for 7-10 consecutive days. GRP⁺ neurons were inhibited using Cre-dependent expression of Gi-designer receptors exclusively activated by designer drugs (DREADDs), while GRPR⁺ neurons were ablated by intrathecal administration of bombesin-saporin.

Results: Repeated topical application of IMQ elicited psoriasis-like dermatitis and scratching behaviors. The mRNA expression levels of GRP and GRPR were upregulated in the cervical spinal dorsal horn (SDH) on days 7 and 10 after IMQ application. Either chemogenetic silencing of GRP⁺ neurons by Gi-DREADD or ablation of GRPR⁺ neurons significantly attenuated IMQ-induced scratching behaviors.

Conclusion: The GRP-GRPR system might be enhanced in the SDH, and itch-responsive GRPR⁺ neurons largely contribute to intractable itch in a mouse model of psoriasis.

Keywords: AMPA; GRP; pruritus; psoriasis; spinal cord.

FIGURE 1

Imiquimod (IMQ)‐induced psoriasis and upregulation of GRP and GRPR in the spinal dorsal horn (SDH). A, Schedule of the IMQ application and photograph and psoriasis area and severity index (PASI) score of the IMQ‐treated mice on days 0, 4, 7, and 10. n = 5. ***P < .001 vs. control. B, Scratching bouts were observed on days 4, 7, and 10 before IMQ application up to 40 min, and the total number of scratching bouts is shown. n = 6‐10. **P < .01, *P < .05 vs. control. C, The mRNA expression levels of GRP and GRPR on days 0, 4, 7, and 10 in the cervical SDH were evaluated by RT‐qPCR. n = 5‐6. *P < .05 vs. control

FIGURE 2

Roles of GRP⁺ and GRPR⁺ neurons in IMQ‐induced psoriatic itch. A, Inhibition of scratching behaviors by intraperitoneally (i.p.; 0.3 mg/kg; left panel) or intrathecally (i.t.; 3 nmol, right panel) administration of clozapine‐N‐oxide (CNO, 30 min prior to observation) in GRP‐Gi‐DREADD mice on day 7 after IMQ application; n = 5‐7. ^# P < .05 vs. control. B, Prevention of scratching behaviors in bombesin‐saporin (Bom‐Sap)‐treated (250 ng, i.t., 14 days before experiment) mice on day 4 after IMQ application. n = 5‐6. ^## P < .01 vs. control. The mRNA expression levels of GRPR in the cervical SDH and PASI score were evaluated on day 7 after IMQ application. n = 5‐6. ^### P < .001 vs. control