peoniflorin and Neuralgia

Therapeutic drugs of chronic neuralgia have a high risk of addiction, making it crucial to identify novel drugs for chronic neuralgia. This study aimed to explore the therapeutic effect of paeoniflorin on chronic sciatica via inhibiting Schwann cell apoptosis. 28 SD rats were randomly divided into four groups, including the sham operation group, chronic constriction injury (CCI) group, mecobalamin group, and paeoniflorin group. The therapeutic effect and mechanism of paeoniflorin were evaluated via rat and cell experiments. Mechanical, hot, or cold hyperalgesia was induced in the rats after CCI operation, while paeoniflorin relieved chronic neuralgia. Besides, paeoniflorin decreased the levels of IL1, IL6, TNF-α, CRP, and LPS and increased the level of IL10 in serum. As for the sciatic nerve, the number of inflammatory cells was decreased, and Schwann cells were present after paeoniflorin treatment, and paeoniflorin promoted the recovery of nerve structure. In cell experiments, LPS induced Schwann cell apoptosis via the TLR4/NF-kB pathway. And paeoniflorin attenuated LPS-induced Schwann cell apoptosis by decreasing the levels of TLR4, p-NF-kB, caspase3, cleaved-caspase3, and cleaved-caspase7. Overall, these results suggest that paeoniflorin alleviates chronic sciatica by decreasing inflammatory factor levels and promotes the repair of damaged nerves by reducing Schwann cell apoptosis.

Topics: Animals; Apoptosis; Constriction; Glucosides; Hyperalgesia; Lipopolysaccharides; Monoterpenes; Neuralgia; NF-kappa B; Rats; Rats, Sprague-Dawley; Schwann Cells; Sciatic Nerve; Sciatica; Toll-Like Receptor 4

Wu-tou decoction (WTD), a classic Traditional Chinese medicine formula, has been extensively used in the treatment of neuropathic pain (NP) such as chronic inflammatory pain, trigeminal neuralgia, and cancer-induced pain. Our previous studies have shown that the severity of mechanical allodynia and thermo hypersensitivity in NP rats are reduced by WTD, of which analgesic candidates are paeoniflorin (Pae) and liquiritin (Liq). The aim of this study was to clarify the molecular mechanisms of WTD, Pae and Liq against NP based on the primary rat glial cells in vitro. The gene expression levels of neurotrophic factors such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and Artemin and C-C chemokine receptor type 5 (CCR5) were augmented by inflammatory cytokines, while chemokines increased only CCR5 gene expression. The constitutive and cytokine-augmented neurotrophic factor gene expression was enhanced by WTD, Pae, and Liq through PI3K- and PKA-dependent pathways in rat glial cells, leading to the increase of NGF and BDNF production. Furthermore, the CCR5 gene expression under basal and chemokine-treated conditions was suppressed by these reagents, in which signal pathway(s) was independent on the activation of PI3K and PKA. Moreover, there was no cytotoxicity in the WTD, Pae, and Liq treatments in glial cells. Thus, these results provide a novel evidence that WTD may exert the anti-NP actions by predominantly increasing the production of neurotrophic factors through PI3K- and PKA-signaling pathways in rat glial cells. Furthermore, Pae and Liq may play as analgesic candidates in WTD-mediated NP management.

Topics: Animals; Cells, Cultured; Cytokines; Drugs, Chinese Herbal; Flavanones; Gene Expression Regulation; Glucosides; Inflammation Mediators; Monoterpenes; Nerve Growth Factors; Neuralgia; Neuroglia; Rats, Sprague-Dawley; Receptors, CCR5; RNA, Messenger; Signal Transduction

Topics: Animals; Chemokines; Disease Models, Animal; Drug Discovery; Drug Therapy, Combination; Flavanones; Glucosides; Humans; Monoterpenes; Neuralgia; Rats; Signal Transduction

Neuropathic pain remains one of the most common pain conditions worldwide. Accumulating evidence shows that activation of the NOD-like receptor protein 3 (NLRP3) inflammasome contributes to the pathogenesis of neuropathic pain, although the role of the NLRP3 inflammasome in neuropathic pain has not yet been fully elucidated. In animal models of neuropathic pain, paeoniflorin (PF) was shown to have analgesic, anti-inflammatory, and antidepressant effects. However, the role of the NLRP3 inflammasome in the analgesic properties of PF has not yet been studied. In this study, we aimed to confirm whether activation of the NLRP3 inflammasome in the spinal cord was involved in the development of neuropathic pain and whether PF could be an effective treatment for this type of pain. We found that activation of the NLRP3 inflammasome mediated the development of neuropathic pain following chronic constriction injury of the sciatic nerve and that PF attenuated neuropathic pain by inhibiting NLRP3 inflammasome activation. Moreover, PF enhanced the translocation of the transcription factor nuclear factor erythroid 2-related factor 2 into the nucleus and suppressed nuclear factor-kappa B activity in the spinal cord. These results suggest that PF may be a potential therapeutic agent for neuropathic pain.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Constriction; Glucosides; Hyperalgesia; Inflammasomes; Monoterpenes; Neuralgia; NF-E2-Related Factor 2; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Spinal Cord

Postoperative pain is a common form of acute pain that, if not managed effectively, can become chronic pain. Evidence has shown that glia, especially microglia, mediate neuroinflammation, which plays a vital role in pain sensitization. Moreover, toll-like receptor 4 (TLR4), the tumor necrosis factor receptor (TNF-R), the interleukin-1 receptor (IL-1R), and the interleukin-6 receptor (IL-6R) have been considered key components in central pain sensitization and neuroinflammation. Therefore, we hypothesized that activation of the body's endogenous "immune brakes" will inhibit these receptors and achieve inflammation tolerance as well as relieve postoperative pain. After searching for potential candidates to serve as this immune brake, we identified and focused on the suppressor of cytokine signaling 3 (SOCS3) gene. To regulate SOCS3 expression, we used paeoniflorin to induce heat shock protein 70 (HSP70)/TLR4 signaling. We found that paeoniflorin significantly induced SOCS3 expression both in vitro and in vivo and promoted the efflux of HSP70 from the cytoplasm to the extracellular environment. Furthermore, paeoniflorin markedly attenuated incision-induced mechanical allodynia, and this effect was abolished by small interfering RNAs targeting SOCS3. These findings demonstrated an effective and safe strategy to alleviate postoperative pain.

Topics: Animals; Cytokines; Drug Tolerance; Glucosides; HSP70 Heat-Shock Proteins; Hyperalgesia; Inflammation; Mice; Microglia; Monoterpenes; Neuralgia; Neuroglia; Neuroimmunomodulation; Pain, Postoperative; Rats; Rats, Sprague-Dawley; Signal Transduction; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Toll-Like Receptor 4

Neuropathic pain remains the most frequent cause of suffering and disability worldwide. Paeoniflorin (PF), a water‑soluble monoterpene glycoside extracted from the roots of Paeonia lactiflora Pall, has a wide range of pharmacological functions. Although the neuroprotective effect of PF has been reported in animal models of neuropathology, no systematic investigation has reported on the analgesic properties of PF in neuropathic pain. The aim of the present study was to investigate whether PF can alleviate neuropathic pain and to examine its possible mechanism. Neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve in rats. Following CCI surgery, the rats were administered with PF for 11 days. Mechanical withdrawal threshold and thermal withdrawal latency were assessed prior to surgery, and on days 3, 7 and 11 post‑surgery. The levels of interleukin (IL)‑1β and tumor necrosis factor (TNF)‑α in the spinal cord were analyzed using enzyme‑linked immunosorbent assays. The activation of astrocytes and microglia were observed using immunostaining. In addition, the phosphorylation of p38 mitogen‑activated protein kinase (p‑p38MAPK) and nuclear factor‑κB (NF‑κB) were examined using western blot analysis. The results indicated that PF significantly attenuated CCI‑induced neuropathic pain and decreased the levels of TNF‑α and IL‑1β proinflammatory cytokines in the spinal cord. Furthermore, PF inhibited the over‑activation of microglia and reduced the elevated expression levels of p‑p38 MAPK and NF‑κB in the spinal cord. These results indicated that PF offers potential as a therapeutic agent for neuropathic pain, which merits further investigation.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Glial Fibrillary Acidic Protein; Glucosides; Interleukin-1beta; Male; Microglia; Monoterpenes; Neuralgia; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Paeonia; Pain Threshold; Phosphorylation; Rats; Rats, Wistar; Sciatic Nerve; Spinal Cord; Tumor Necrosis Factor-alpha

The chemotherapeutic agent paclitaxel (PTX) causes refractory peripheral neuropathy as a side effect. Prophylactic oral administration of the traditional herbal medicine Shakuyakukanzoto containing Paeoniae Radix and Glycyrrhizae Radix prevents the development of PTX-induced mechanical allodynia in mice via peripheral effects, mostly due to Paeoniae Radix. However, the bioactive component responsible for the prevention of PTX-induced neuropathic pain remains unknown.. To determine whether a monoterpene glycoside paeoniflorin (PF), which is the principal bioactive constituent of Paeoniae Radix, has inhibitory effects on PTX-induced mechanical allodynia and investigate the underlying mechanisms.. C57BL/6NCr mice received a single intraperitoneal injection of PTX and then were topically administered PF to the planar surface twice daily for 13 days. Mechanical allodynia was evaluated by the von Frey filament test, peripheral nerve activity was recorded using bipolar electrodes, and demyelination in peripheral nerves was analysed by electron microscopy. Schwann cell line LY-PPB6 pre-treated with PF and then treated with PTX was used to analyse the expression of the transcription factor CHOP, a marker of endoplasmic reticulum (ER) stress, by western blotting.. PTX caused mechanical allodynia and increased both spontaneous and mechanical stimuli-evoked peripheral nerve activities, whereas repetitive topical application of PF significantly attenuated PTX-induced allodynia, suppressed saphenous nerve firing, and inhibited demyelination in the plantar nerve. Moreover, in cultured Schwann cells, PF downregulated PTX-induced expression of CHOP, indicating the inhibition of ER stress. The attenuation of mechanical allodynia in mice and downregulation of CHOP levels in cell cultures was inhibited by adenosine A. These results suggest that prophylactic topical application of PF is effective in alleviating PTX-induced mechanical allodynia by protecting sensory nerves from demyelination via activation of the A1R.

Topics: Administration, Topical; Animals; Antineoplastic Agents; Benzoates; Demyelinating Diseases; Glucosides; Hyperalgesia; Male; Mice; Mice, Inbred C57BL; Monoterpenes; Neuralgia; Paclitaxel; Paeonia; Phytotherapy; Plant Extracts; Receptor, Adenosine A1

Neuropathic pain is frequently comorbid with sleep disturbances. Paeoniflorin, a main active compound of total glucosides of paeony, has been well documented to exhibit neuroprotective bioactivity.. The present study evaluated effects of paeoniflorin on neuropathic pain and associated insomnia and the mechanisms involved.. The analgesic and hypnotic effects of paeoniflorin were measured by mechanical threshold and thermal latency, electroencephalogram (EEG) and electromyogram, and c-Fos expression in a neuropathic pain insomnia model.. The data revealed that paeoniflorin (50 or 100 mg/kg, i.p.) significantly increased the mechanical threshold and prolonged the thermal latency in partial sciatic nerve ligation (PSNL) mice. Meanwhile, paeoniflorin increased non-rapid eye movement (NREM) sleep amount and concomitantly decreased wakefulness time. However, pretreatment with l,3-dimethy-8-cyclopenthylxanthine, an adenosine A1 receptor (R, A1R) antagonist, abolished the analgesic and hypnotic effects of paeoniflorin. Moreover, paeoniflorin at 100 mg/kg failed to change mechanical threshold and thermal latency and NREM sleep in A1R knockout PSNL mice. Immunohistochemical study showed that paeoniflorin inhibited c-Fos overexpression induced by PSNL in the anterior cingulate cortex and ventrolateral periaqueductal gray.. The present findings indicated that paeoniflorin exerted analgesic and hypnotic effects via adenosine A1Rs and might be of potential use in the treatment of neuropathic pain and associated insomnia.

Topics: Adenosine A1 Receptor Antagonists; Analgesics; Animals; Electroencephalography; Electromyography; Glucosides; Hypnotics and Sedatives; Mice; Mice, Knockout; Monoterpenes; Neuralgia; Neuroprotective Agents; Pain Threshold; Proto-Oncogene Proteins c-fos; Psychomotor Performance; Receptor, Adenosine A1; Sciatic Nerve; Sleep; Sleep Initiation and Maintenance Disorders