Effects of Combined Shinbaro and Celecoxib in a Complete Freund’s Adjuvant-Induced Inflammatory Pain Mouse Model

Jae-Hwan Jang, Yurim Song, Seok Hee Han, Bo Ram Choi, Yoon Jae Lee, In-Hyuk Ha Jaseng Spine and Joint Research Institute, Jaseng Medical Foundation, Seoul, 05854, Republic of KoreaCorrespondence: In-Hyuk Ha, Jaseng Spine and Joint Research Institute, Jaseng Medical Foundation, Seoul, 05854, Republic of Korea, Tel +82232182740, Email [email protected]: Persistent inflammation resulting from injury, infection, or arthritis contributes to both peripheral and central sensitization. Various combinations of natural extracts have been explored to minimize the side effects associated with conventional medications. Shinbaro, which has traditionally been used in Eastern medicine to treat inflammatory conditions, was chosen due to its known anti-inflammatory properties. However, previous studies have not yet investigated the combined administration of celecoxib and Shinbaro for their anti-inflammatory and analgesic effects. In this study, we examined the anti-inflammatory and analgesic effects of combining celecoxib with Shinbaro in a complete Freund’s adjuvant (CFA)-induced inflammatory pain model.Methods: We randomly assigned 66 mice to 6 groups (n = 11 per group) and administered intraplantar injections of 100 μL CFA or saline into their right hind paw, followed by oral administration of Shinbaro (100 mg/kg), celecoxib (15 or 30 mg/kg), or both 30 minutes later. Behavioral assessments were conducted blindly at baseline and on days 1, 3, and 7 post-injection. The right hind paw and spinal cord were harvested 3 days post-injection to examine the molecular mechanisms, including macrophage infiltration in the right hind paw, as well as glial cell activation and inflammatory cytokine levels in the spinal cord. Statistical analysis was performed using Tukey’s post-hoc test.Results: The combination of Shinbaro (100 mg/kg) and celecoxib (15 mg/kg) synergistically reduced mechanical hyperalgesia and paw edema by preventing the conversion of monocytes to macrophages and inhibiting macrophage infiltration. Moreover, it decreased the expression of pro-inflammatory cytokines and mediators in the spinal cord by inhibiting spinal microglial activation.Conclusion: The combination of Shinbaro and celecoxib demonstrates significant anti-inflammatory and analgesic effects, suggesting its potential for managing inflammatory pain with fewer side effects than conventional therapies. Plain Language Summary: Why was the study done? We wanted to understand if combining two pain-relieving treatments—Shinbaro (an herbal medicine) and celecoxib (a common anti-inflammatory drug)—could work better together than using either one alone. We were particularly interested in treating inflammatory pain, like those experienced in rheumatoid arthritis and osteoarthritis.What did the researchers do and find? Our team used mice to model inflammatory pain by injecting a substance called CFA into their paw. This caused pain and swelling. We then tested how well Shinbaro and celecoxib worked separately and together to reduce these symptoms. We found that the combination of Shinbaro and celecoxib was more effective at reducing pain and swelling than either treatment alone. The combined treatment decreased the number of inflammatory cells (monocytes and macrophages) in the affected area. In the spinal cord, the combination therapy reduced the activity of cells (microglia and astrocytes) that contribute to ongoing pain. The treatment also lowered the levels of substances that promote inflammation in the body.What do these results mean? These findings suggest that combining Shinbaro and celecoxib could be a more powerful way to treat inflammatory pain than using either medication by itself. The combination appears to work on multiple levels - reducing inflammation at the site of injury, decreasing pain signals in the spinal cord, and lowering overall inflammation in the body. This approach could potentially allow for lower doses of celecoxib, which might reduce the risk of side effects associated with long-term use.Keywords: herbal medicine, analgesia, anti-inflammation, natural extracts, paw edema