The hyperalgesic activities in rats of interleukin‐1β (IL‐1β), IL‐6, IL‐8, tumour necrosis factor α (TNFα) and carrageenin were investigated. IL‐6 activated the previously delineated IL‐1/prostaglandin hyperalgesic pathway but not the IL‐8/sympathetic mediated hyperalgesic pathway. TNFα and carrageenin activated both pathways. Antiserum neutralizing endogenous TNFα abolished the response to carrageenin whereas antisera neutralizing endogenous IL‐1β, IL‐6 and IL‐8 each partially inhibited the response. The combination of antisera neutralizing endogenous IL‐1β + IL‐8 or IL‐6 + IL‐8 abolished the response to carrageenin. These results show that TNFα has an early and crucial role in the development of inflammatory hyperaglesia. The delineation of the roles of TNFα, IL‐1β, IL‐6 and IL‐8 in the development of inflammatory hyperalgesia taken together with the finding that the production of these cytokines is inhibited by steroidal anti‐inflammatory drugs provides a mechanism of action for these drugs in the treatment of inflammatory hyperalgesia.

Interleukin-1 (IL-1) describes two inflammatory proteins, IL-1 alpha and IL-1 beta, produced by activated macrophages and other cell types and encoded by two genes. Their amino acid sequences have only 26% similarity, but their biological activities are comparable, with a few exceptions; indeed, both molecules appear to act at the same receptor. As IL-1 release prostaglandins which sensitize nociceptors in man and in experimental animals, we tested IL-1 alpha and IL-1 beta in rats for hyperalgesic (nociceptive) activity. Our results show that IL-1 beta given systemically is an extremely potent hyperalgesic agent with a probable peripheral site of action; IL-1 alpha is approximately 3,000 times less active than IL-1 beta. We have delineated the region of IL-1 beta mediating the hyperalgesic effect and developed an analgesic tripeptide analogue of IL-1 beta which antagonizes hyperalgesia evoked by IL-1 beta and by the inflammatory agent carrageenan.

1 The hyperalgesic effects of interleukin-8 (IL-8), interleukin-1fi (IL-iIf) and carrageenin were measured in a rat paw pressure test.2 IL-8 evoked a dose-dependent hyperalgesia which was attenuated by a specific antiserum, the fiadrenoceptor antagonists atenolol and propranolol, the dopamine, receptor antagonist SCH 23390 and the adrenergic neurone-blocking agent guanethidine. The hyperalgesia was not attenuated by the cyclooxygenase inhibitor indomethacin or the IL-1,i analogue Lys-D-Pro-Thr.3 IL-1i/-evoked hyperalgesia was attenuated by indomethacin and Lys-D-Pro-Thr but not by atenolol or SCH 23390. 4 Carrageenin-evoked hyperalgesia was attenuated by atenolol, indomethacin and anti-IL-8 serum. The effects of atenolol and anti-IL-8 serum were not additive. The effects of indomethacin and anti-IL-8 serum were additive: this combination abolished carrageenin-evoked hyperalgesia. 5 A new biological activity of IL-8 is described, namely the capacity to evoke hyperalgesia by a prostaglandin-independent mechanism. IL-8 is the first endogenous mediator to be identified as evoking hyperalgesia involving the sympathetic nervous system. Since IL-8 is released by activated macrophages and endothelial cells it may be a humoral link between tissue injury and sympathetic hyperalgesia.

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