Ž . European Journal of Pharmacology 329 1997 17–26 Intrathecally administered c-fos antisense oligodeoxynucleotide decreases formalin-induced nociceptive behavior in adult rats Wen-Yeong Hou a , Bai-Chuang Shyu d , Tzer-Ming Chen b , Jai-Wei Lee a , Jeng-Yung Shieh c , Wei-Zen Sun a, ) a Department of Anesthesiology, Medical College of the National Taiwan UniÕersity, No. 7, Chung-Shan South Road, Taipei, Taiwan, ROC b Department of Obstetrics and Gynecology, Medical College of the National Taiwan UniÕersity, Taipei, Taiwan, ROC c Department of Anatomy, Medical College of the National Taiwan UniÕersity, Taipei, Taiwan, ROC d Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, ROC Received 10 October 1996; revised 7 April 1997; accepted 8 April 1997 Abstract c-fos antisense strategy was applied as a pharmacological approach to characterize its dose-dependent role and reversibility in the Ž . reduction of formalin-induced hyperalgesia. Nociceptive behavioral responses weighted score, flinching response, lickingrbiting Ž . Ž . following formalin 50 ml 5% injection were assessed in adult Wistar rats receiving different doses 50 nM, 250 nM of intrathecally administered c-fos antisense oligodeoxynucleotides at different times prior to formalin injections. The treatments dose dependently decreased both Fos immunoreactivity expression in dorsal horn of rat lumbar spinal cord and all nociceptive measures in the tonic phase of the formalin test. c-Fos correlated well with weighted pain score andror flinching responses, but not with lickingrbiting behavior. With the exception of a 48–120 h period required for lickingrbiting behavior to be restored to its normal status, the suppressive effect on c-fos expression and other nociceptive behaviors disappeared 48 h following c-fos antisense oligodeoxynucleotide treatment. The results suggest a pharmacological potential of c-fos antisense oligodeoxynucleotides in the central nervous system to block immediate-early genes and their resulting physiological consequence following noxious stimulus. q 1997 Elsevier Science B.V. Ž . Keywords: c-fos; Formalin test; Hyperalgesia; Intrathecal ; Nociception; Antisense oligodeoxynucleotide 1. Introduction The immediate-early gene, c-fos, is transiently induced in the central nervous system by a variety of stimuli. Fos-like protein is produced within the cortex and hip- Ž pocampus following seizure activity White and Gall, 1987; . Munglani et al., 1989 , within the hypothalamus following Ž . water deprivation Sagar et al., 1988 and within the dorsal Ž . horn following peripheral stimulation Hunt et al., 1987 . c-Fos protein forms leucin-zipper heterodimers with mem- bers of the jun family as a transcriptional factor in vitro, which regulates the expression of the secondary response Ž gene, suggesting a major role in neuronal activity Naranjo ) Ž . Ž . Corresponding author. Tel.: 886-2 397-0800, ext. 5521; Fax: 886-2 394-9681; e-mail: wzsun@ccms.ntu.edu.tw . et al., 1991 . c-fos expression following peripheral inflam- mation has been shown to correlate well with behavioral Ž . hyperalgesia Dubner and Ruda, 1992 . Pretreatment with Ž . drugs like opioids Gogas et al., 1991 , NMDA receptor Ž . antagonists Kehl et al., 1991 and nitric oxide synthase Ž . inhibitors Chapman et al., 1995 can inhibit both c-fos expression and the noxious stimulus-evoked hyperalgesia. Furthermore, the time course of c-fos expression and be- havioral hyperalgesia have also been shown to coincide Ž . Draisci and Iadarola, 1989 . c-fos expression has thus been widely accepted as a marker of neuronal activation, leading to its long-term change after peripheral stimulation Ž . Bullitt, 1990 . However, since a causal relationship be- tween peripheral stimulation, immediate-early gene activa- tion, and behavioral hyperalgesia is still lacking, direct evidence based on selective inhibition of c-fos expression is necessary to demonstrate the immediate-early gene acti- vation leading to its physiological consequences. 0014-2999r97r$17.00 q 1997 Elsevier Science B.V. All rights reserved. Ž . PII S0014-2999 97 00116-7