C-C motif chemokine receptor 7 (CCR7) in the spinal cord inhibits chronic itch through the neuropeptide NPY

Background

Studies showed that C-C motif chemokine receptor 7 (CCR7) contributes to the maintenance of neuropathic pain. However, whether CCR7 is involved in chronic itch remains unclear.

Objective

To explore the relationship between CCR7 and chronic itch.

Methods

The scratching behavior of wild-type (WT) and Ccr7^-/- mice in acute and chronic itch models, or of WT mice in chronic itch after intrathecal injection of CCR7 neutralizing antibody was compared. Mechanical, thermal, and inflammatory pain responses of Ccr7^-/- mice and WT mice were examined. The expression of CCR7, some known lamina-specific markers, and itch-related mediators in the spinal cord of WT and Ccr7^-/- mice with chronic itch were detected by immunostaining and qRT-PCR respectively. Finally, to explore the possible relationship between CCR7 and Neuropeptide Y (NPY), intrathecal injection of CCR7-siRNA for in vivo knockdown and neurotoxin bombesin-saporin for GRPR-expressing cells ablation were used.

Results

Ccr7^-/- mice displayed increasing scratching in chronic itch models. CCR7 neutralizing antibody elevated, while CCR7 ligands CCL19/CCL21 alleviated the scratching behavior in chronic itch models. However, the responses of Ccr7^-/- mice to mechanical, thermal, and inflammatory pain did not differ from their WT controls. Also, CCR7⁺ interneurons co-express NPY, and CCR7 expression was enhanced in the spinal cord of mice with chronic itch. Furthermore, spinal NPY expression was down-regulated in Ccr7^-/- mice or after CCR7-siRNA. Finally, GRPR⁺ neuron ablation eliminated scratching behavior in chronic itch mice regardless of whether the mice lacked CCR7.

Conclusion

Spinal CCR7 mediates persistent itch through a neural network with the inhibitory neuropeptide NPY.