Interleukin-6: an emerging regulator of pathological pain

Abstract

Interleukin-6 is an inflammatory cytokine with wide-ranging biological effects. It has been widely demonstrated that neuroinflammation plays a critical role in the development of pathological pain. Recently, various pathological pain models have shown elevated expression levels of interleukin-6 and its receptor in the spinal cord and dorsal root ganglia. Additionally, the administration of interleukin-6 could cause mechanical allodynia and thermal hyperalgesia, and an intrathecal injection of anti-interleukin-6 neutralizing antibody alleviated these pain-related behaviors. These studies indicated a pivotal role of interleukin-6 in pathological pain. In this review, we summarize the recent progress in understanding the roles and mechanisms of interleukin-6 in mediating pathological pain associated with bone cancer, peripheral nerve injury, spinal cord injury, chemotherapy-induced peripheral neuropathy, complete Freund's adjuvant injection, and carrageenan injection. Understanding and regulating interleukin-6 could be an interesting lead to novel therapeutic strategies for pathological pain.

Keywords: Bone cancer pain; Inflammatory pain; Interleukin-6; Neuropathic pain.

Fig. 1

Schematic representation of the downstream mechanism of IL-6 in the processing of bone cancer pain and neuropathic pain. IL-6 interleukin-6, IL-6R interleukin-6 receptor, JAK Janus-activated kinase, PI3K phosphoinositide 3-kinase, TRPV1 transient receptor potential vanilloid channel type 1, MAPK mitogen-activated protein kinase, STAT3 signal transducer activator of transcription 3

Fig. 2

Schematic representation of the possible upstream mechanism of IL-6 in the processing of neuropathic pain and inflammatory pain. PGE2 prostaglandin E2, EP4R prostaglandin E2 receptor 4, PKA protein kinase A, PKC protein kinase C, ERK extracellular signal-regulated kinase, MAPK mitogen-activated protein kinase, CREB cAMP-response element binding protein, NF-kB nuclear factor kappa B, TNF-α tumor necrosis factor-α, TNFR1 tumor necrosis factor receptor 1, IL-6 interleukin-6, CB2R cannabinoid CB2 receptor