Characterization of cytokine-induced hyperalgesia

Brain Res. 1994 Aug 15;654(1):15-26. doi: 10.1016/0006-8993(94)91566-0.


Agents which induce symptoms of illness, such as lipopolysaccharide (LPS), cause diverse effects including hyperalgesia. While previous studies have examined central pathways mediating LPS hyperalgesia, the initial steps in activating this system remain unknown. Since LPS induces the release of various cytokines and eicosinoids from immune cells, the present series of experiments examined the potential involvement of these substances in LPS hyperalgesia. This work demonstrates that: (a) Interleukin-1 beta (IL-1 beta) can produce hyperalgesia following either intraperitoneal or intracerebroventricular injection. In contrast, IL-1 beta delivered intrathecally did not affect pain responsivity. (b) Liver macrophages (Kupffer cells) appear to be critically involved, and relay signals to the brain via hepatic vagal afferents. (c) Both IL-1 beta and tumor necrosis factor appear to be critical mediators of LPS hyperalgesia. In contrast, prostaglandins do not appear to be involved. Taken together, these studies suggest that substances classically thought of as products of the immune system may dynamically enhance pain responsivity via actions either on the hepatic vagus or at central sites.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Cytokines / administration & dosage
  • Cytokines / pharmacology*
  • Hyperalgesia / chemically induced*
  • Hyperalgesia / physiopathology
  • Inflammation / physiopathology
  • Injections, Intraventricular
  • Injections, Spinal
  • Interleukin-1 / administration & dosage
  • Interleukin-1 / pharmacology
  • Kupffer Cells / drug effects
  • Lipopolysaccharides / pharmacology
  • Macrophages / drug effects
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Tumor Necrosis Factor-alpha / administration & dosage
  • Tumor Necrosis Factor-alpha / pharmacology
  • Vagotomy
  • Vagus Nerve / physiology


  • Anti-Inflammatory Agents, Non-Steroidal
  • Cytokines
  • Interleukin-1
  • Lipopolysaccharides
  • Tumor Necrosis Factor-alpha