162 Yimam et al. DISCUSSIONS Anti-inflammatory and analgesic activities of NSAIDs have been extensively em- ployed for decades. The mechanism of action is widely believed to involve inhibi- tion of COX-mediated biosynthesis of prostacyclin (PGI2) and prostaglandin E2 (PGE2) (Moncada, Ferreira, & Vane, 1973). These prostanoids exhibit both proin- flammatory and pronociceptive activity by potentiating the biological effects of other proinflammatory mediators including kinins, histamine, and serotonin during acute inflammation. Nevertheless, the side effects of these commonly prescribed or over-the-counter drugs in the gastric mucosa and cardiovascular system limit their clinical utilization (Wallace, McKnight, Wilson, Del Soldato, & Cirino, 1997). In this regard, the search for anti-inflammatory and/or antinociceptive natural alternatives with reduced side effect is urgent and necessary. UP446, a unique and well-defined bioflavonoid composition standardized with two major active compounds, baicalin and catechin originated from S. baicalensis and A. catechu, respectively, reduces production of eicosanoids through inhibition of COX-1, COX-2, and LOX enzymes (Burnett et al., 2007) and also decreases gene and protein expressions of proinflammatory iNOS, NF-kB, and TNF-α (Al- tavilla et al., 2009). The safety profiles of individual bioflavonoids and the stan- dardized composition, UP446, have already been reported (Burnett et al., 2007; Chou et al., 2003; Isbrucker & Burdock, 2006). Burnett et al. concluded in their study that daily administration of UP446 by oral gavage at dose levels of 0, 250, 500, and 1,000 mg/kg/day to rats for 90 days produced no evidence of toxicity. As a result, a dose of 1,000 mg/kg/day was identified as the no observed adverse effect level (NOAEL). He also reported drowsiness, stomach upset, nausea, and irritabil- ity in 9 out of 29 subjects treated with UP446 at 250 mg/day and 6 out of 39 placebo subjects after 60 days of double blind placebo-controlled human clinical study. In the current study, bioflavonoid composition, UP446, exhibited antinocicep- tive activity in all three animal models and also reduced carrageenan-induced paw edema. The hyperalgesia and edema caused by the carrageenan are cardinal signs of inflammation, which commonly considered as most reliable signs when assess- ing a compound with a potential anti-inflammatory and antinociceptive activity. Carrageenan-induced acute inflammation involves the synthesis and release of va- soactive substances at the injured site. The role of PGE2 in the carrageenan-induced edema test has been well established in the literature (Flower, 1974). The early re- leased bradykinin and the late PGE2 in this model are believed to be responsible for the development of edema and also for the sustained pain that accompanies the in- flammatory reaction as they are able to sensitize primary afferent neurons (Tjolsen et al., 1992). Therefore, the analgesic and antiedema activity of UP446 observed in this study could partially attribute to the ability of these bioflavonoid compounds to block COX-mediated biosynthesis of PGE2 and reduce proinflammatory cytokines. In agreement with our findings, Chou et al. reported that the anti-inflammatory and analgesic mechanism of baicalin may be associated with the inhibition of critical in- flammatory mediators, including reduction gene expressions of COX-2 enzyme and proinflammatory cytokines (Chou, et al. 2003). Other studies conducted in aqueous extract of Acacia karroo stem bark, a similar class of A. catechu, have also shown the antinociceptive activity of bioflavonoids in carrageenan-induced rat pain model (Adedapo et al., 2008).