This mouse model utilizes a dual approach by combining a monosodium iodoacetate (MIA) injection into the knee joint to induce chronic osteoarthritis pain with an Unpredictable Chronic Mild Stress (UCMS) protocol to evoke depression and anxiety-like behaviors. Designed for both male and female mice, this system enables comprehensive investigation of cellular, molecular, and genetic mechanisms under conditions that mimic the co-occurrence of chronic pain and negative affect. The model addresses the progression of chronic, inflammatory joint pain over several weeks while concurrently applying mild, unpredictable stressors that provoke measurable behavioral symptoms.