Tumour necrosis factor-alpha, interleukin-1 beta and interleukin-8 induce persistent mechanical nociceptor hypersensitivity

It has been previously described that daily intraplantar (i.pl.) injections of prostaglandin E2 (PGE(2)) and dopamine in rats for 14 days cause the development of a persistent mechanical nociceptor hypersensitivity state lasting more than 30 days, Considering that during inflammation, the release of these hyperalgesic agents are mediated by cytokines, we investigated in the present study whether interleukin-1beta (IL-1beta). IL-8 and tumour necrosis factor-alpha (TNF-alpha) are able to induce persistent mechanical nociceptor hypersensitivity. Daily i.pl. administration of TNF-alpha, IL-1beta or IL-8 for 18 days led to persistent mechanical nociceptor hypersensitivity, which lasted at least 30 days after the cessation of treatment. The co-treatment of the animals with IL-1beta plus indomethacin, but not with atenolol, prevented the induction of persistent mechanical nociceptor hypersensitivity. The co-treatment of the animals with IL-8 plus atenolol, but not with indomethacin. prevented the induction of persistent mechanical nociceptor hypersensitivity, The daily co-treatment of TNF-alpha with either indomethacin or atenolol partially inhibited (+/-50%) the induction of persistent mechanical nociceptor hypersensitivity. However. the combined treatment with indomethacin plus atenolol abolished the induction of the persistent mechanical nociceptive hypersensitivity by TNF-alpha. A single injection of cytokines in the contralateral paws of the animals with persistent hypersensitivity caused only an acute nociceptive response. This observation. together with the demonstration of undetectable levels of immunoglobulins against TNF-alpha, IL-1beta or IL-8 in the sera of animals after the development of the persistent hypersensitivity induced by those cytokines, indicate that this event is not clue to an ongoing immunological response against the cytokines. In conclusion. our results support the suggestion that IL-1beta- and IL-8-induced persistent mechanical nociceptor hypersensitivity results from the endogenous release of eicosanoids and sympathetic amines, respectively. However, TNF-alpha-induced mechanical nociceptor hypersensitivity results from the concomitant endogenous release of eicosanoids and sympathomimetic mediators. (C) 2002 International Association for the Study of Pain, Published by Elsevier Science B.V. All rights reserved.