There is strong evidence that spinal 5-HT3 receptor plays a facilitatory role in various pain states.Electrophysiological studies demonstrated that spinal 5-HT3 receptor is involved in nociception induced by intraplantar injection of formalin,but not carrageenan.Instead,spinal 5-HTi receptor was shown to exert a facilitatory effect on neuronal responses of carrageenan-injected rat although its role was not confirmed in behavioral studies.5-HT7 receptor,the lastly identified subtype,was shown to be inhibitory in descending modulation,but pronociceptive in formalin test.In addition,depletion of spinal serotonin has been shown to attenuate pain behavior in the formalin test,but there have been no such reports regarding the carrageenan model.This study compared the role of spinal 5-HTiR,5-HT3R and 5-HT7R and evaluated the direction of spinal serotonergic modulation in carrageenan-induced inflammatory pain.Male SD rats (220-250 g) were randomly administered with 8-OH-DPAT (5-HT1A agonist),CP-93,129 (5-HT1B agonist),AS-19 (5-HT7 agonist),SB-269970 (5-HT3 antagonist),mCPBG (5-HT3 agonist),or ondansetron (5-HT3 antagonist) through a intrathecal catheter 10 minutes prior to intraplantar injection of carrageenan.Paw withdrawal threshold was measured using von Frey test.In a second set of experiments,spinal serotonin was depleted by intrathecal injection of 5,7 dihydroxytryptamine (5,7-DHT) to evaluate the role of descending serotonergic pathway.Depletion of serotonin in spinal cord was examined by liquid chromatography tandem mass spectrometry.Results showed that intrathecal treatment with 5,7-DHT significantly reduced the concentration of serotonin compared to control (P < 0.001).Mechanical allodynia induced by intraplantar carrageenan in animals treated with 5,7-DHT was enhanced compared to control group (P < 0.01),suggesting that descending serotonergic modulation is mainly inhibitory in carrageenan-induced inflammatory pain.However,no significant difference was observed in animals treated with intrathecal agonist or antagonist of 5-HTt,5-HT3 and 5-HT7 receptor compared to control,suggesting no significant involvement of those receptors.This study suggests that dominant mechanism of descending serotonergic modulation on carrageenan-induced inflammatory pain is inhibitory,but spinal 5-HTi,5-HT3 or 5-HT7 receptors are not involved in descending inhibition.