Chemokine CCL8 and its receptor CCR5 in the spinal cord are involved in visceral pain induced by experimental colitis in mice

•TNBS induced visceral pain and the upregulation of spinal CCL8 and CCR5 in mice.•CCL8 and CCR5 were expressed by neurons in the spinal dorsal horn after TNBS.•Inhibition of CCL8 or CCR5 attenuated pain by reducing spinal pERK expression. Visceral hypersensitivity induced by inflammatory bowel disease (IBD) is a clinical challenge since the underlying mechanisms remain elusive. Chemokines and their receptors have been suggested to modulate inflammatory pain and neuropathic pain. However, the exact chemokines involved in visceral pain remain to be determined. Here, we investigated the effects of spinal chemokine CCL8 and its major receptor CCR5 on the development of visceral hyperalgesia. We showed that intracolonic injection of 2,4,6-trinitrobenzene sulfonic acid (TNBS) in mice produced significant colonic inflammation and visceral hypersensitivity to colorectal distension. Moreover, the mRNA and protein expression of CCL8 and CCR5 in the lumbosacral spinal cord were significantly upregulated. Both of CCL8 and CCR5 were expressed in spinal neurons. Furthermore, TNBS induced the activation of extracellular signal-regulated kinase (ERK) in the spinal cord. The induction of visceral pain by TNBS was attenuated by injection of ERK upstream kinase (MEK) inhibitor PD98059. Finally, intrathecal CCL8 neutralizing antibody or CCR5 antagonist DAPTA dose-dependently suppressed TNBS-evoked visceral hyperalgesia and spinal ERK activation. Taken together, these data demonstrated that CCL8 and CCR5, expressed and upregulated in spinal neurons after colonic inflammation, are involved in the maintenance of visceral hyperalgesia via the activation of spinal ERK. Targeting CCL8/CCR5/ERK pathway in the spinal cord might provide a novel treatment for the relief of visceral pain.