Astrocytic Ror2-induced imbalance in brain and gut homeostasis contributes to chronic post-thoracotomy pain

Chaoqun Liu^1*Le Shen²Li Xu²Afang Zhu^2*Yuguang Huang^2*

• ¹National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Beijing, China
• ²Peking Union Medical College Hospital Department of Anesthesiology, Beijing, China

Receptor tyrosine kinase-like orphan receptor 2 (Ror2) plays an indispensable role in mediating acute and chronic pain. We previously demonstrated the involvement of spinal cord astrocyte-derived Ror2 in chronic post-thoracotomy pain (CPTP). Here, we further investigated the effect of spinal Ror2 on anterior cingulate cortex (ACC) Ror2 and gut microbiota in CPTP. We observed elevated astrocytic Ror2 levels in the ACC of male CPTP rats, with astrocytes predominantly polarised into the A1 phenotype, characterised by increased astrocytic CCL2 and CXCL1 secretion, and a concomitant reduction in gut-derived short-chain fatty acids (SCFAs). Knockdown of astrocytic Ror2 through intrathecal AAV2/9-GFAP-miR30-shRor2 administration significantly alleviated mechanical hyperalgesia and cold allodynia caused by thoracotomy, restored the ACC A1/A2 astrocytic balance, reduced its CCL2 and CXCL1 expression, and increased gut-derived SCFA production in CPTP rats. These findings suggest that the facilitation of CPTP development by Ror2 is associated with disruptions in the A1/A2 astrocytic balance, chemokine production in the ACC, and SCFA levels in the gut microbiota. Inactivation of astrocytic Ror2 may serve as a targeted treatment to restore the balance of reactive astrocytes and mitigate their pathogenic effects.