High-intensity interval training (HIIT) is a physical therapy that may benefit patients with osteoarthritis (OA). Cacna2d1 is a calcium channel subunit protein that plays an important role in the activity of nerve cells. However, there is currently no evidence on HIIT relieving OA-associate hyperalgesia by decreased Cacna2d1. Our study established the OA rat models with intra-articular injection of monosodium iodoacetate (MIA). This experiment was divided into two stages. The first stage comprised three groups: the control, OA, and OA-HIIT groups. The second stage comprised two groups, including the AAV-C and AAV-shRNA-Cacna2d1 groups. OA rats were positioned at the L5–L6 segments, and 20 µl of AAV virus was injected intrathecally. The pain threshold, cartilage analysis, Cacna2d1, and pain neurotransmitters were measured and compared. The pain threshold was significantly lower in OA rats than in control rats from the first to the tenth week. Starting from the sixth week, OA-HIIT rats exhibited significantly increased pain thresholds. The expression of Cacna2d1 increased in OA rats. Moreover, the knockdown of Cacna2d1 significantly down-regulated the expression of c-Fos, SP, and Vglut2 in the posterior horn of the spinal cord. In conclusion, HIIT attenuates OA-associated hyperalgesia, which may be related to the down-regulation of Cacna2d1.

Objective: Osteoarthritis (OA)-induced neuropathic pain is closely related to microglial polarization in the central nervous system. This study aimed to determine whether high-intensity interval training (HIIT) could relieve neuropathic pain and promote the polarization of M1 to M2 in microglia through the Jak2/Stat3 pathway in OA rats. Methods: Wistar rats received intra-articular injection of monosodium iodoacetate for an OA model. After four weeks, moderate-intensity continuous training (MICT) or HIIT was conducted consecutively for six weeks. Pain threshold was measured by the von Frey test. The degree of cartilage damage was analyzed by magnetic resonance imaging and safranin-O staining. Tmem119, substance P (SP), Vglut2, c-Fos, and IL6 were detected by immunofluorescence. The CD68 and CD163 were analyzed by flow cytometry. The proteomics sequencing and quantitative real-time polymerase chain reaction analyzed the differences in protein and mRNA expression levels between MICT and HIIT groups. Intraperitoneal injection of C-A1 activated the Jak2/Stat3 pathway in OA rats, followed by HIIT treatment, and pain neurotransmitters were detected by Western blotting. Results: The pain threshold was significantly decreased from third weeks to tenth weeks in OA rats. HIIT treatment promoted the polarization of M1 to M2 in microglia and down-regulated Tmem119, SP, Vglut2, c-Fos, and IL6. Moreover, HIIT suppressed Jak2 and Stat3 expression levels when compared with MICT rats. The pain threshold and pain neurotransmitters were lower in C-A1+HIIT rats than in C-A1 rats. Conclusions: HIIT relieves OA-induced neuropathic pain and promotes the polarization of M1 to M2 in microglia through the Jak2/Stat3 pathway.