Sevoflurane suppresses noxious stimulus-evoked expression of Fos-like immunoreactivity in the rat spinal cord via activation of endogenous opioid systems

doi:10.1016/S0024-3205(02)01704-6

Life Sciences

Volume 71, Issue 5, 21 June 2002, Pages 571-580

https://doi.org/10.1016/S0024-3205(02)01704-6 Get rights and content

Abstract

We investigated the antagonism of sevoflurane antinociception by opioid antagonists in the rat formalin test. Formalin injection into the hindpaw of the rat induces the nocifensive flinching behavior and the expression of Fos-like immunoreactivity (Fos-LI) in the spinal cord. Sevoflurane significantly suppressed the flinching behavior and decreased the number of Fos-LI neurons in the dorsal horn of spinal cord compared with the control group. Moreover, pretreatment with intraperitoneal naloxone plus naltrexone antagonized the suppression of flinching behavior and the decrease of the number of Fos-LI neurons produced by 3% sevoflurane. Intraperitoneal opioid antagonists themselves had no effects on both the behavior response and the expression of Fos-LI induced by formalin injection. This study supports the hypothesis that sevoflurane suppresses the nociceptive response, at least in part, by activating endogenous opioid systems.

Introduction

Subcutaneous injection of formalin into the hindpaw of the rat results in a biphasic nocifensive behavior; phase 1 reflects an acute noxious response and phase 2 reflects the injury-induced spinal sensitization [1]. In the spinal dorsal horn, noxious stimulation evokes Fos-like immunoreactivity (Fos-LI) predominantly in laminae I, II and V. The topographic distribution of neurons with induced Fos-LI coincides with the distribution of central axon terminals of the stimulated primary nociceptors [2], [3], [4]. Previous study showed that the expression of Fos-LI in the spinal cord was a function of the intensity and duration of the noxious stimulus [2] and that the expression of Fos-LI correlated with the nocifensive behavior in the rat formalin test [3]. Furthermore, a reduction in Fos-LI by supraspinal, intrathecal, or systemic administration of opioid agonists has also been reported [5], [6], [7]. Previous studies showed that the suppression of Fos-LI by opioid receptor agonists in the spinal cord was dose-dependent and naloxone-reversible [6], [7] and that there was a correlation between the magnitude of antinociception and the extent to which Fos-LI is suppressed [5], [6]. Thus, expression of Fos-LI has been widely used as a reliable marker to identify populations of neurons that are activated by noxious stimuli, to trace pain pathways [8], and to permit both neuroanatomical localization and quantification of analgesic effects [6].

The ability of general anesthetics to influence nociceptive processes has not been investigated thoroughly. Inasmuch as a principal function of general anesthetics is to disrupt the normal process by which peripheral stimuli are perceived by and registered in the CNS, one would predict that these agents maybe influence nociceptive processes. However, it is controversial whether inhalation anesthetics block formalin-induced behavioral hyperalgesia [9], [10], [11]. Collins et al. demonstrated that the pharmacological actions of general anesthetics on the pain-evoked responses were agent- and site-selective and not the result of a unitary mechanism of action [12]. Sevoflurane, a volatile anesthetic, has the characteristics of both rapid induction and recovery from inhalation anesthesia. To our knowledge, no study has explored the effect of sevoflurane blocking the formalin-induced Fos-LI expression. In the present study, we examined the effect of sevoflurane on the spinal expression of Fos-LI evoked by injection of formalin into the rat hindpaw. Moreover, we also examined if sevoflurane produced antinociception in the rat inflammatory model through activating endogenous opioid systems. The ability of sevoflurane to inhibit formalin-induced flinching behavior in the same animals was also determined.

Section snippets

Animals

The study was approved by the Animal Care Committee of Asahikawa Medical College. Male Sprague-Dawley rats (250–350 g) were housed in individual cages with free access to food and water and maintained on a 12-h light-dark cycle at an ambient temperature of 20 ± 1 °C. The behavior study was carried out from 9:00 AM to 5:00 PM.

Formalin test

In the formalin test, 50 μl of 5% formalin was injected subcutaneously into the dorsal surface of the right hind paw using 27-G needle. Animals were then placed in a clear

Effects of sevoflurane on formalin-induced flinching

In the control group, rats showed a biphasic flinching behavior after injection of formalin into the hindpaw. Animals receiving 1.5% or 3% of sevoflurane lost the righting reflex and did not vocalized or did not became agitated by formalin injection during phase 1 (Fig. 1A), and these animals recovered within 1–3 min of discontinuing the anesthetic. Rats receiving either 1.5 % sevoflurane or 3% sevoflurane exhibited a significant decrease in phase 2 activity (P < 0.01) (Fig. 1B). In the group

Discussion

Compared with halothane, enflurane or isoflurane, sevoflurane has a low solubility in blood and tissue and thus possesses favorable kinetic property, which allow a precise control over delivery of anesthesia; sevoflurane lacks pungency and airway irritability so that induction of anesthesia can be easily achieved in children and adults [15]. The present study clearly demonstrated (1) that sevoflurane inhibited the nocifensive behavior response induced by formalin injection into the hindpaw,

Acknowledgments

This work was supported in part by Sasakawa Health Science Foundation of Japan to S. Hao. Dr. S. Hao also acknowledged the support of Professors of M. Mata and DJ. Fink (Department of Neurology, University of Pittsburgh, PA, USA) and their useful comments. Authors thank Professor H. Kiyama (Department of Anatomy, Asahikawa Medical College, Japan) for his help of the immunohistochemistry.