Interleukin-1b increases spinal cord wind-up activity in normal but not in monoarthritic rats Luis Constandil a , Teresa Pelissier b , Rube ´n Soto-Moyano c , Mauricio Mondaca a , Herna ´n Sa ´ez a , Claudio Laurido a , Carlos Mun ˜oz c , Nandy Lo ´pez a , Alejandro Herna ´ndez a, * a Laboratory of Neurobiology, Department of Biological Sciences, Faculty of Chemistry and Biology, University of Santiago of Chile, Casilla 40 Correo 33, Santiago, Chile b Program of Molecular and Clinical Pharmacology, Biomedical Sciences Institute, Faculty of Medicine, University of Chile, Santiago, Chile c Institute of Nutrition and Food Technology (INTA), University of Chile, Santiago, Chile Received 28 August 2002; received in revised form 30 January 2003; accepted 30 January 2003 Abstract Cytokines produced by spinal cord glia after peripheral inflammation, infection or trauma have a relevant role in the maintenance of pain states. The effect of intrathecally administered interleukin-1b (IL-1b) on spinal cord nociceptive transmission was studied in normal and monoarthritic rats by assessing wind-up activity in a C-fiber-mediated reflex paradigm evoked by repetitive (1 Hz) electric stimulation. Low i.t. doses of IL-1b (0.03, 0.12, 0.5 and 2.0 ng) dose-dependently enhanced wind-up activity in normal rats, while higher doses (8.0 ng) only produced a marginal unsignificant effect. IL-1b administration to monoarthritic rats did not significantly change wind-up scores at any dose. Adaptive changes developed in the spinal cord during chronic pain may underlie the ineffectiveness of exogenous IL-1b to up-regulate nociceptive transmission. q 2003 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Interleukin-1b; Cytokine; C-fiber reflex; Wind-up; Spinal cord; Monoarthritis; Rat Pro-inflammatory cytokines of peripheral tissues, such as interleukins and tumor necrosis factor (TNF), are known to influence behavioral responses to sensory stimuli leading to development of hyperalgesia and allodynia [5]. Glial cells of the spinal cord dorsal horn can also produce cytokines in response of a variety of conditions that produce hyperalge- sia, including inflammation, infection, and trauma of the skin or viscera, of peripheral nerves, and of the central nervous system; thus, spinal cytokines are thought to be involved in central mechanisms underlying the maintenance and exaggeration of pain states [17,18]. In this context, it has been reported that neurons of the central nervous system normally express receptors for interleukin-1 (IL-1) and TNF and therefore they could serve as targets for these centrally produced mediators [16]; besides, intrathecal administration of IL-1 in normal mice [14] and IL-6 in normal rats [2] induces hyperalgesia and allodynia; finally, intrathecal administration of IL-1b and TNF in normal rats enhances both the acute response and the wind-up activity of dorsal horn neurons [11]. Since, on the one hand, cytokines produced by spinal cord glia may have a relevant role in the development and maintenance of pain states [17,18] and, on the other hand, the expression of mRNAs encoding for both cytokines and cytokine receptors in the central nervous system appears to upregulate after sustained activity of central neurons [10], it seems important to investigate the effects of the intrathecal administration of some of these mediators in animal models of chronic pain, where spinal cord cytokine expression is abnormally high [18] and maintained activity in pain afferent pathways is expected to be occurring. The present study was aimed to address this question by comparing the effects of intrathecally adminis- tered IL-1b on spinal wind-up activity elicited in both normal and monoarthritic rats, as revealed by changes in potentiation of C-fiber nociceptive reflex responses evoked by repetitive electric stimulation of the sural nerve receptive field. As already reported, wind-up activity in dorsal horn neurons is a synaptic potentiation phenomenon of particular importance for the development and maintenance of chronic 0304-3940/03/$ - see front matter q 2003 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0304-3940(03)00278-7 Neuroscience Letters 342 (2003) 139–142 www.elsevier.com/locate/neulet * Corresponding author. Tel.: þ 56-2-681-1366; fax: þ56-2-681-2108. E-mail address: ahernand@lauca.usach.cl (A. Herna ´ndez).