## 1 Introduction  
Knee osteoarthritis (KOA) is a chronic joint disease that affects more than 300 million people worldwide and results in a limited range of motion and dysfunction of the knee joint with alteration in the alignment of the kneee joint [1]. Obesity, aging, metabolic syndrome, inheritance, trauma, and infection are the risk factors for KOA [2, 3, 4]. The pathophysiology of KOA involves not only the \"wear and tear principle\" in the articular cartilage [5] but also the disorders of the peri- or intra-articular tissue caused by synovitis, sclerosis of the subchondoral bone, and contracture of the ligamentous structure [6]. KOA is known to impair activities of daily living due to pain and swelling associated with chronic inflammation and degenerative changes in the articular joints [7, 8]. Surgical and nonsurgical treatments are available for KOA. Surgical treatments such as around knee osteotomy and total knee arthroplasty are performed for terminal KOA [1]. Although they are beneficial with excellent pain-relieving effects and functional recovery,they are not absolutely recommended for everyone due to their large physical and economic burden. In some cases, postoperative pain becomes chronic, and not all patients are completely satisfied [9]. The Osteoarthritis Research Society International (OARSI) strongly recommends arthritis education, land-based exercise, and mind-body exercise such as tai-chi and yoga as a conservative treatment for KOA [10]. However, the current KOA conservative treatment only alleviates clinical symptoms and cannot improve the pathophysiological condition. Although various disease-modifying osteoarthritis drugs have undergone clinical trials [6], none have been clinically used. In fact, there is a need for treatments that have both an analgesic effect and a preventive effect on KOA. Studies have reported that herbal medicines reduce inflammation in the knee joint and suppress the progression of KOA [11; 12]. Boiogito (BO), a traditional Japanese herbal medicine (Kampo medicine), has been found to be effective for patients with swelling and pain of the knee, and its prescription has been approved by the Japanese Ministry of Health, Labor and Welfare [13]. According to oriental medicine, BO improves water metabolism and eliminates swelling and pain in the knee joint [14] and hence may prevent KOA. Oral administration of BO has been found to relieve gait pain in patients with KOA, and some basic research has reported that it suppresses the inflammatory response in the knee joint [15; 16]. We had earlier clarified that BO suppressed the progression of KOA in rats with surgically induced KOA; moreover, BO could also improve locomotive function in the early stage of the disease [17]. The maintenance of motor function despite the induction of KOA suggests that BO has an analgesic effect. However, the mechanism underlying this analgesic effect remains unclear. The pain associated with KOA has been classified as chronic in which dull pain or a throbbing sensation is exacerbated by long-term morbidity [18]. The development of chronic pain is involved in pain sensitization in peripheral tissues and/or the central nervous system, and it has been reported that pain-related stimuli are also enhanced in the spinal cord in patients with KOA [19]. One pathology underlying central sensitivities is the phosphorylation of extracellular signal-regulated kinase (ERK)1/2 in the dorsal horn of the spinal cord. Pain stimuli in the peripheral tissues ascend myelinated A6 fibers and unmyelinated C fibers and are then projected onto layers I and II in the dorsal horn of the spinal cord [20]. Neurotransmission in the spinal cord is enhanced by the activation of ERK1/2 [21]. The number of phosphorylated ERK1/2 (pERK1/2)-positive cells was found to increase in rats with hyperalgesia and allodynia [20; 21]. In this present study, we examined the analgesic effect of BO on acute postoperative pain and osteoarthritis associated pain as well as the involvement of ERK1/2 underlying the effect.