# CCR2 Regulates Referred Somatic Hyperalgesia by Mediating T-Type Ca2+ Channel Currents of Small-Diameter DRG Neurons in Gastric Ulcer Mice

## TL;DR

This study shows that CCR2 regulates referred pain by altering calcium channels in nerve cells of mice with stomach ulcers.

## Contribution

CCR2's role in modulating T-type Ca2+ channels to cause referred somatic hyperalgesia is newly identified.

## Key findings

- Gastric ulcers increase T-type Ca2+ channel and CCR2 co-expression in DRG neurons.
- Blocking CCR2 reduces neurogenic inflammation and referred pain in ulcer mice.
- CCR2 agonists mimic ulcer-induced changes in calcium channel behavior in normal neurons.

## Abstract

Background: Referred pain frequently co-exists with visceral pain. However, the exact mechanism governing referred somatic hyperalgesia remains elusive. Methods: By injecting 20% acetic acid into the stomach, we established a mouse model of gastric ulcer (GU). Hematoxylin and eosin (H&E) staining was used as the evaluation criterion for the gastric ulcer model. Evan’s blue (EB) and von Frey tests detected the somatic sensitized area. The DRG neurons distributed among the spinal segments of the sensitized area were prepared for biochemical and electrophysiological experiments. The CCR2 antagonist was intraperitoneally (i.p.) injected into GU mice to test the effect of blocking CCR2 on somatic neurogenic inflammation. Results: GU not only instigated neurogenic plasma extravasation and referred somatic allodynia in the upper back regions spanning the T9 to T11 segments but also augmented the co-expression of T-type Ca2+ channels and CCR2 and led to the gating properties of T-type Ca2+ channel alteration in T9–T11 small-diameter DRG neurons. Moreover, the administration of the CCR2 antagonist inhibited the T-type Ca2+ channel activation, consequently mitigating neurogenic inflammation and referred somatic hyperalgesia. The application of the CCR2 agonist to normal T9–T11 small-diameter DRG neurons simulates the changes in the gating properties of T-type Ca2+ channel that occur in the GU group. Conclusions: Therefore, these findings indicate that CCR2 may function as a critical regulator in the generation of neurogenic inflammation and mechanical allodynia by modulating the gating properties of the T-type Ca2+ channels.