Platelet-rich plasma alleviates neuropathic pain in osteoarthritis by downregulating microglial activation.

BACKGROUND: The development of neuropathic pain (NP) is one of the reasons why the pain is difficult to treat, and microglial activation plays an important role in NP. Recently, platelet-rich plasma (PRP) has emerged as a novel therapeutic method for knee osteoarthritis (KOA). However, it's unclarified whether PRP has analgesic effects on NP induced by KOA and the underlying mechanisms unknown. PURPOSE: To observe the analgesic effects of PRP on NP induced by KOA and explore the potential mechanisms of PRP in alleviating NP. METHODS: KOA was induced in male rats with intra-articular injections of monosodium iodoacetate (MIA) on day 0. The rats received PRP or NS (normal saline) treatment at days 15, 17, and 19 after modeling. The Von Frey and Hargreaves tests were applied to assess the pain-related behaviors at different time points. After euthanizing the rats with deep anesthesia at days 28 and 42, the corresponding tissues were taken for subsequent experiments. The expression of activating transcription factor 3 (ATF3) in dorsal root ganglia (DRG) and ionized-calcium-binding adapter molecule-1(Iba-1) in the spinal dorsal horn (SDH) was detected by immunohistochemical staining. In addition, the knee histological assessment was performed by hematoxylin-eosin (HE) staining. RESULTS: The results indicated that injection of MIA induced mechanical allodynia and thermal hyperalgesia, which could be reversed by PRP treatment. PRP downregulated the expression of ATF3 within the DRG and Iba-1 within the SDH. Furthermore, an inhibitory effect on cartilage degeneration was observed in the MIA + PRP group only on day 28. CONCLUSION: These results indicate that PRP intra-articular injection therapy may be a potential therapeutic agent for relieving NP induced by KOA. This effect could be attributed to downregulation of microglial activation and reduction in nerve injury.

Transcranial direct current stimulation attenuates chronic pain in knee osteoarthritis by modulating BDNF/TrkB signaling in the descending pain modulation system.

Knee osteoarthritis (KOA) is the most common cause of chronic pain, but its pain mechanisms are complex and may be closely related to the descending pain modulation system. Transcranial direct current stimulation (tDCS) is used for relieving pain, but its analgesic mechanisms are still being explored. The purpose of this study was to investigate the role of BDNF/TrkB signaling in chronic pain in KOA and to investigate whether this signaling is related to the analgesic effect of tDCS. Rats were injected with monosodium iodoacetate (MIA) into the left knee joint to establish a chronic pain model and then received 20 min of tDCS for 8 days. Rats were respectively administered the TrkB inhibitor ANA-12 after MIA modeling and exogenous BDNF after tDCS treatment. Behaviors testing was assessed by hot plate and von Frey hairs using the up-down method. In addition, the expression levels of BDNF and TrkB on the periaqueductal gray (PAG)-the rostral ventromedial medulla (RVM)-the spinal dorsal horn (SDH) axis were detected by Western blot and Immunohistochemistry staining. Behavioral results show that tDCS treatment and ANA-12 injection reversed MIA-induced allodynia while reducing BDNF and TrkB expression levels. Furthermore, injection of exogenous BDNF reversed the therapeutic effect of tDCS on pain. These results indicate that upregulation of the BDNF/TrkB signaling in the descending pain modulation system may play an important role in KOA-induced chronic pain in rats, and tDCS may reduce KOA-induced chronic pain by inhibiting the BDNF/TrkB signaling in the descending pain modulation system.

Botulinum toxin type a combined with transcranial direct current stimulation reverses the chronic pain induced by osteoarthritis in rats.

Osteoarthritis (OA) is the most common cause to lead to chronic pain. Sensitization of pain pathways including central sensitization and peripheral sensitization has been regarded as a major cause of OA pain refractory to treatment. Addressing peripheral sensitization or central sensitization alone may not adequately treat OA pain. In our previous studies, botulinum toxin type A (BoNT/A) has been shown to reduce peripheral sensitization for analgesic effects. In addition, transcranial direct current stimulation (tDCS) has also been suggested to reduce central sensitization for analgesia. The present study was designed to investigate whether BoNT/A in combination with tDCS has better analgesic effects than isolated treatment to alleviate OA-induced chronic pain in rats. The Von Frey and hot plate tests were applied to assess the pain-related behaviors at different time points. The expression level of N-methyl-D-aspartate receptor-2B (NMDAR2B) was evaluated in midbrain periaqueductal gray (PAG) by Western blot the Immunohistochemistry staining after different treatments. The results showed that the combined treatment of BoNT/A and tDCS better improved the pain-related behaviors and significantly increased the expression level of NMDAR2B protein in PAG than each isolated treatment. These results suggested that the combined treatments for relief of chronic pain were more obvious than each isolated treatment. The combination of BoNT/A and tDCS may relieve pain by increasing N-methyl-D-aspartate (NMDA) receptors in the PAG, and then the descending inhibitory systems were activated to modulate peripheral and central sensitization.

Transcranial Direct Current Stimulation Alleviates the Chronic Pain of Osteoarthritis by Modulating NMDA Receptors in Midbrain Periaqueductal Gray in Rats.

PURPOSE: Osteoarthritis (OA) is the most common cause to lead to chronic pain. Transcranial direct current stimulation (tDCS) has been widely used to treat nerve disorders and chronic pain. The benefits of tDCS for chronic pain are apparent, but its analgesic mechanism is still unclear. This study observed the analgesic effects of tDCS on OA-induced chronic pain and the changes of NMDA receptor levels in PAG after tDCS treatment in rats to explore the analgesic mechanism of tDCS. METHODS: After establishing chronic pain by injecting monosodium iodoacetate (MIA) into the rat ankle joint, the rats received tDCS for 14 consecutive days (20 min/day). Before tDCS treatment, Ifenprodil (the selective antagonist of NMDAR2B) was given to rats in different ways: intracerebroventricular (i.c.v.) injection or intraperitoneal (i.p.) injection. The Von Frey and hot plate tests were applied to assess the pain-related behaviors at different time points. The expression level of NMDAR2B was evaluated in midbrain periaqueductal gray (PAG) by Western blot. In addition, NMDAR2B and c-Fos were observed by the Immunohistochemistry staining after tDCS treatment. RESULTS: The mechanical allodynia and thermal hyperalgesia were produced after MIA injection. However, tDCS treatment reverted the mechanical allodynia and thermal hyperalgesia. Moreover, tDCS treatment significantly increased the expression of NMDAR2B and the proportion of positive stained cells of NMDAR2B. Besides that, the tDCS treatment also decreased the proportion of positive stained cells of c-Fos in PAG. However, these changes did not occur in the rats given the Ifenprodil (i.c.v.). CONCLUSION: These results indicate that tDCS may increase the expression of NMDA receptors in PAG and strengthen the NMDA receptors-mediated antinociception to alleviate OA-induced chronic pain in rats.

Anti-Inflammatory Effects of BoNT/A Against Complete Freund's Adjuvant-Induced Arthritis Pain in Rats: Transcriptome Analysis.

Arthritis is the most common cause to lead to chronic pain. Botulinum toxin type A (BoNT/A) has been widely used to treat chronic pain. In our previous study, we confirmed the anti-inflammatory and antinociceptive effects of BoNT/A in the Complete Freund's Adjuvant (CFA)-induced arthritis model, but the underlying anti-inflammatory mechanism was not fully elucidated. The purpose of this study was to investigate the anti-inflammatory effects and mechanisms of BoNT/A on arthritis using transcriptomic analysis. The BoNT/A was injected into the rat ankle joint on day 21 after CFA injection. The von Frey and hot plate tests were applied to assess the pain-related behaviors at different time points. Five days after BoNT/A treatment, gene expression profiling in dorsal root ganglion (DRG) was performed using RNA sequencing (RNA-seq). The differentially expressed genes (DEGs) were analyzed by various tools. The mechanical allodynia and thermal hyperalgesia were significantly reversed after BoNT/A injection. RNA-seq revealed 97 DEGs between the CFA group and Sham group; these DEGs were enriched inflammatory response, IL-17 signaling pathway, etc. There are 71 DEGs between the CFA+BoNT/A group and the CFA group; these DEGs related to response to peptide, PI3K-Akt signaling pathway, ECM-receptor interactions, etc. Three key genes were significantly decreased after CFA-induced arthritis pain, while BoNT/A increased the expression of these genes. The identification of S100A9, S100A8, and MMP8 genes can provide new therapeutic targets for arthritis pain and affect the signaling pathway to play an anti-inflammatory role after the treatment of BoNT/A.