232 www.anesthesia-analgesia.org January 2013 • Volume 116 • Number 1 T he spinal cord is the center that controls orthodromic (nociception) as well as antidromic (peripheral vasodilation) traffic in the nociceptive pathway. 1 Therefore, the spinal cord could be considered a potential site for the modulation of inflammation and not just a simple transmission line from the periphery to the brain. There have been significant advances elucidating the cellular and molecular processes that mediate neuronal hyperexcitability at the periphery and in the spinal cord during an inflammatory insult. 2–4 A growing body of experimental evidence 5–9 suggests that the spinal cord may be an important therapeutic tar- get for the treatment of peripheral inflammatory diseases as an alternative to systemic treatments similar to strategies already in practice for the control of some types of chronic pain. 10 This evidence supports, in theory, the anti-inflam- matory use of anesthetics. In line with this idea, a previous report by our laboratory 7 showed that intrathecal morphine could prevent peripheral inflammatory edema by acting on opioid receptors and through the activation of the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway. Because cGMP can ultimately lead to neuron hyperpolarization by stimulating potassium channel open- ing, there is a reasonable possibility that the observed mor- phine antiedematogenic effect could be the result of the opening of potassium channels, in agreement with reported findings in nociceptive studies. 11–14 The present availability of drugs that open potassium channels for clinical use offers the possibility of strengthening the concept of administra- tion of anti-inflammatory anesthesia. Thus, the aim of the present study was to investigate the main types of K + chan- nels involved in the antiedematogenic effect of intrathecally administered morphine and its enhancement by a K + chan- nel opener in an effort to provide a clearer pharmacologic identity for this potential therapeutic strategy. METHODS Animals The male Wistar rats (weighing 250–350 g) used in this study were housed in a temperature-controlled (20°C ± 2°C) and light-controlled (12-hour light/dark cycle) room, with free access to water and food. All experimental proce- dures were conducted according to the ethical guidelines of the International Association for the Study of Pain 15 and approved by the local ethics committee for animal research (CEUA-UFSC). Inflammatory Model and Edema Measurement We used the classical model of carrageenan (CG)-induced rat paw edema. 16 Briefly, CG was diluted in physiological saline at a concentration of 3 mg/mL. This solution was boiled for 1 to 2 seconds and cooled to room temperature. The animals received 50 µL (150 µg of CG) of this solution in the hind right footpads. Inflammatory edema was measured before and at 4 timepoints after (hourly) CG injection by immers- ing the injected paw into a cuvette (10 mL) filled with a 2.5% The Involvement of Potassium Channels in the Peripheral Antiedematogenic Effect of Intrathecally Injected Morphine in Rats Vanessa R.S. Foletto, DVetMed, MSc, Maria A. Martins, DVetMed, ScD, and Carlos R. Tonussi, ScD Copyright © 2012 International Anesthesia Research Society DOI: 10.1213/ANE.0b013e31826f5cc5 From the Departamento de Farmacologia, CCB, Universidade Federal de Santa Catarina, Florianópolis, Brasil. Accepted for publication August 03, 2012. Reprints will not be available from the authors. The authors declare no conflicts of interest. Funded by Brazilian government funding agencies CAPES and FAPESC- CNPq/PRONEX. VRSF and MAM were the recipients of a master and doc- toral fellowships, respectively, from CNPq. Address correspondence to Carlos Rogério Tonussi, ScD, Departamento de Farmacologia, CCB, Universidade Federal de Santa Catarina, Florianópolis, SC, 88040–900, Brazil. Address e-mail to tonussi@farmaco.ufsc.br. BACKGROUND: A previous study indicated that intrathecal administration of morphine reduces experimental infammatory edema in rats by activating the nitric oxide/cyclic guanosine mono- phosphate pathway. This evidence supports the hypothesis that potassium channel opening may play an important role in mediating morphine’s effect under such conditions. METHODS: Male Wistar rats received intrathecal injections of drugs (20 μL) 30 minutes before paw stimulation with carrageenan (150 µg). Edema was measured as paw volume increase (in milliliters), and plasma leakage was measured by Evans blue dye leakage. Neutrophil migra- tion was evaluated indirectly by myeloperoxidase assay. The infammatory infltration and vascu- lar congestion were observed by histologic examination. RESULTS: Morphine (37 nmol) inhibited infammatory edema, plasma leakage, and vascu- lar congestion but had no effect on myeloperoxidase activity or neutrophil content compared with phosphate-buffered saline. Coinjection with 4-aminopyridine (10 nmol), glibenclamide (5 nmol), and dequalinium (10 pmol) reversed, but nicorandil (0.03 nmol) enhanced the effect of morphine. CONCLUSIONS: These results support the hypothesis that the peripheral antiedemato- genic effect produced by intrathecal morphine is mediated by potassium channel activation. Furthermore, this opioid effect does not involve the inhibition of acute neutrophil migration but does involve a reduction in capillary recruitment. (Anesth Analg 2013;116:232–8)