CHARACTERIZATION OF CYTOKINE-INDUCED HYPERALGESIA

Agents which induce symptoms of illness, such as lipopolysaccharide (L PS), cause diverse effects including hyperalgesia. While previous stud ies have examined central pathways mediating LPS hyperalgesia, the ini tial steps in activating this system remain unknown. Since LPS induces the release of various cytokines and eicosinoids from immune cells, t he 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 ei ther 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 o f LPS hyperalgesia. In contrast, prostaglandins do not appear to be in volved. Taken together, these studies suggest that substances classica lly thought of as products of the immune system may dynamically enhanc e pain responsivity via actions either on the hepatic vagus or at cent ral sites.