Tumour necrosis factor-a, interleukin-1b and interleukin-8 induce persistent mechanical nociceptor hypersensitivity Daniela Sachs a , Fernando Queiroz Cunha a , Stephen Poole b , Se ´rgio Henrique Ferreira a, * a Department of Pharmacology, Faculty of Medicine of Ribeira ˜o Preto, University of Sa ˜o Paulo, Avenida Bandeirantes, 3900, 14049-900- Ribeira ˜o Preto, Sao Paulo, Brazil b Division of Endocrinology, National Institute for Biological Standards and Control, Blanche Lane, South Mimms, Potters Bar, Herts EN6 3QG, UK Received 27 March 2001; received in revised form 19 September 2001; accepted 2 October 2001 Abstract 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 inflamma- tion, the release of these hyperalgesic agents are mediated by cytokines, we investigated in the present study whether interleukin-1b (IL-1b), IL-8 and tumour necrosis factor-a (TNF-a) are able to induce persistent mechanical nociceptor hypersensitivity. Daily i.pl. administration of TNF-a, IL-1b 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-1b 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-a 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-a. 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-a, IL-1b 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 due to an ongoing immunological response against the cytokines. In conclusion, our results support the suggestion that IL-1b- and IL-8-induced persistent mechanical nociceptor hypersensitivity results from the endogenous release of eicosanoids and sympathetic amines, respectively. However, TNF-a-induced mechanical nociceptor hypersensitivity results from the concomitant endogenous release of eicosanoids and sympathomimetic mediators. q 2002 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved. Keywords: Persistent inflammatory hyperalgesia; Interlukin-1b; Interlukin-8; Tumour necrosis factor-a 1. Introduction The sensitisation of pain receptors is the common denominator of inflammatory pain. This functional up-regu- lation of pain receptors leads to a state known as hyperal- gesia/allodynia. Following such sensitisation, previously mildly effective or ineffective stimuli cause ‘overt pain’ in humans, or a characteristic behaviour response that is used as an end point in animal nociceptive tests (Handwerker, 1976; Perl et al., 1976). There are two groups of directly acting hyperalgesic mediators that satisfy the experimental and clinical criteria for agents that directly sensitise noci- ceptors: eicosanoids and sympathomimetic amines. The capacity of prostaglandins and sympathomimetic amines (noradrenaline and dopamine) to sensitise pain receptors has been shown in man and in animals using both beha- vioural and electrophysiological techniques (Hannington- Kiff, 1974; Lol and Nathan, 1978; Lol et al., 1980; Ferreira, 1983; Nakamura and Ferreira, 1987; Duarte et al., 1988). Nociceptor hypersensitivity may be classified as immedi- ate, delayed or persistent depending upon the duration of its plateau. Prostacyclin (PGI 2 ) produces an immediate sensiti- sation, peaking at 30 min and subsiding within 1 h of its injection, with no hyperalgesic plateau. Delayed hyperalge- sia can be evoked by prostaglandin E 2 (PGE 2 ) and sympathomimetic amines (Ferreira et al., 1978b; Nakamura and Ferreira, 1987); it has a slow onset, reaches a peak after 2–3 h followed by a plateau lasting 2 h and declines after- wards. Persistent hyperalgesia is generated by frequent peri- ods of sensitisation of the pain receptor and has a duration of Pain 96 (2002) 89–97 0304-3959/02/$20.00 q 2002 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved. PII: S0304-3959(01)00433-X www.elsevier.com/locate/pain * Corresponding author. Tel.: 155-16-602-3222; fax: 155-16-633-2301. E-mail address: shferrei@fmrp.usp.br (S.H. Ferreira).