Therapeutic effect of paeoniflorin on chronic constriction injury of the sciatic nerve via the inhibition of Schwann cell apoptosis.

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.

Ameliorative effects of escin on neuropathic pain induced by chronic constriction injury of sciatic nerve.

ETHNOPHARMACOLOGY RELEVANCE: Escin is a natural mixture of triterpene saponins extracted from the seeds of Aesculus wilsonii Rehd. And has been reported to possess the therapeutic effects against neuropathic pain (NP). However, the underlying mechanisms remain unclear. AIM OF THE STUDY: The present study aimed to investigate the therapeutic effects and explore the underlying mechanisms of escin on rats of NP induced by chronic constriction injury (CCI) of sciatic nerve. MATERIALS AND METHODS: Rats were treated with escin (7, 14, and 28 mg/kg, i. g.) daily from the third day after the surgery (day 0) for consecutive 14 days. Regular behavior and thermal threshold were measured on days 0, 3, 5, 7, 10 and 14. Investigations into mechanisms involved measurement of inflammatory factors and biochemical factors in dorsal root ganglion (DRG). Inflammatory pain responses and nerve injuries were induced by the CCI model. Tonic pain model and acute inflammatory model induced by formalin or carrageenan were established to evaluated the pharmacological effects of escin on acute inflammatory pain. Corresponding behaviors were monitored and relevant gene expression such as c-fos, mu opioid receptor (MOR) and KCNK1 were detected by qRT-PCR. Investigate the neuroprotective effects of escin on PC12 cell injury induced by lipopolysaccharide (LPS). Cell morphology was observed under inverted microscope and neuroprotective effect of escin on cell activity was assessed by MTT assay. RESULTS: Escin could widen thermal threshold, downregulate the concentration of inflammatory factors like tumor necrosis factor (TNF)-α and interleukin (IL)-1ß, suppress the gene expression of toll-like receptor 4 (TLR4), nuclear factor κB (NF-κB), decrease the level of glial fibrillary acidic protein (GFAP) and nerve growth factor (NGF) remarkably. In addition, escin significantly lowered the duration of licking, numbers of flinches and increase in paw edema, showing great therapeutic effects on inflammatory pain responses. Moreover, the activity of injured PC12 cells was significantly improved after escin administrated. CONCLUSION: Escin exerted the ameliorative effects on NP induced by CCI which may be related to downregulating the release of pro-inflammatory cytokines, suppressing TLR-4/NF-κB signal pathway, thereafter decreasing the level of GFAP and NGF.

Effect of combined medicated thread moxibustion plus needle picking therapy of Zhuang nationality medicine on antioxidant levels in a rat model of sciatica.

OBJECTIVE: To investigate the effect and underlying mechanisms of combined medicated thread moxibustion therapy plus needle picking therapy of Zhuang nationality medicine on antioxidant levels in a rat model of sciatica. METHODS: One hundred Wistar rats, of specific pathogen free level, were randomly divided into five groups: normal control group, model group, medicated thread moxibustion group, needle picking group, and combination group. Each group contained 20 rats. In the model, medicated thread moxibustion, needle picking, and combination groups, sciatica models were established through chronic constriction injury of the sciatic nerve. After the model was established, the rats in the medicated thread moxibustion, needle picking, and combination groups were given the corresponding therapies for 21 days. The control and model groups received no treatment. Reactive oxygen species, superoxide dismutase, malondialdehyde, and total antioxidant capacity changes were determined. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit NADPH oxidases 4 (NOX4) mRNA expression and the morphology of cells were observed to detect apoptosis of gamma- aminobutyric acid ergic (GABAergic) neurons. RESULTS: Compared with control group, reactive oxygen species and malondialdehyde levels rose significantly in the model group (P < 0.01), while superoxide dismutase and total antioxidant capacity levels were lowered (P < 0.05). Compared with the model group, reactive oxygen species and malondialdehyde decreased in the needle picking group (P < 0.05), while superoxide dismutase levels were increased (P < 0.05); reactive oxygen species and malondialdehyde significantly decreased in the combination group (P < 0.01). In addition, the model group had higher NOX4 mRNA expression than that of the control group (P < 0.05), and the combination group had lower expression levels than that of the model group (P < 0.05). Apoptosis of GABAergic neurons was observed in the model group, and was attenuated after combined therapy. CONCLUSION: The medicated thread moxibustion therapy plus needle picking therapy of Zhuang nationality medicine can prevent oxidative damage in the rat model of sciatica via down-regulating NOX4 expression, improving antioxidant capacity, and inhibiting the oxidative damage pathway of GABAergic neurons.

Intrathecal ultra-low dose naloxone enhances the antihyperalgesic effects of morphine and attenuates tumor necrosis factor-α and tumor necrosis factor-α receptor 1 expression in the dorsal horn of rats with partial sciatic nerve transection.

BACKGROUND: Glutamate homeostasis and microglia activation play an important role in the development and maintenance of neuropathic pain. We designed this investigation to examine whether ultra-low dose naloxone administered alone or in combination with morphine could alter the concentration of the excitatory amino acids (EAAs) glutamate and aspartate, as well as the expression of tumor necrosis factor-α (TNF-α) and its receptors (TNFR1 and TNFR2) in the spinal cord dorsal horn of rats with partial sciatic nerve transection (PST). METHODS: Male Wistar rats underwent intrathecal catheter implantation for drug delivery and were divided in 7 groups: sham-operated + saline (sham), PST + saline (S), PST + 15 ng naloxone (n), PST + 15 µg naloxone (N), PST + 10 µg morphine (M), PST + 15 ng naloxone + 10 µg morphine (Mn), PST + 15 µg naloxone + 10 µg morphine (MN). Thermal withdrawal latency and mechanical withdrawal threshold, TNF-α and TNFR expression in the spinal cord and dorsal root ganglia, and EAAs glutamate and aspartate concentration in cerebrospinal fluid dialysates were measured. RESULTS: Ten days after PST, rats developed hyperalgesia (P < 0.0001) and allodynia (P < 0.0001), and increased TNF-α (P < 0.0001) and TNFR1 expression (P = 0.0009) were measured in the ipsilateral spinal cord dorsal horn. The antihyperalgesic and antiallodynic effects of morphine (10 µg) were abolished by high-dose naloxone (15 µg; P = 0.0031) but enhanced by ultra-low dose naloxone (15 ng; P = 0.0015), and this was associated with a reduction of TNF-α (P < 0.0001) and TNFR1 (P = 0.0009) expression in the spinal cord dorsal horn and EAAs concentration (glutamate: P = 0.0001; aspartate: P = 0.004) in cerebrospinal fluid dialysate. Analysis of variance (ANOVA) or Student t test with Bonferroni correction were used for statistical analysis. CONCLUSIONS: Ultra-low dose naloxone enhances the antihyperalgesia and antiallodynia effects of morphine in PST rats, possibly by reducing TNF-α and TNFR1 expression, and EAAs concentrations in the spinal dorsal horn. Ultra-low dose naloxone may be a useful adjuvant for increasing the analgesic effect of morphine in neuropathic pain conditions.

Repetitive treatment with diluted bee venom reduces neuropathic pain via potentiation of locus coeruleus noradrenergic neuronal activity and modulation of spinal NR1 phosphorylation in rats.

UNLABELLED: We previously demonstrated that a single injection of diluted bee venom (DBV) temporarily alleviates thermal hyperalgesia, but not mechanical allodynia, in neuropathic rats. The present study was designed to determine whether repetitive injection of DBV produces more potent analgesic effects on neuropathy-induced nociception and whether those effects are associated with increased neuronal activity in the locus coeruleus (LC) and with the suppression of spinal NMDA receptor NR1 subunit phosphorylation (pNR1). DBV (.25 mg/kg) was administered subcutaneously twice a day for 2 weeks beginning on day 15 post-chronic constrictive injury surgery. Pain responses were examined and potential changes in LC Fos expression and spinal pNR1 expression were determined. Repetitive DBV administration significantly reduced mechanical allodynia, as well as thermal hyperalgesia. The activity of LC noradrenergic neurons was increased and spinal pNR1 expression was significantly suppressed by repetitive DBV as compared with those of vehicle or single DBV injection. These suppressive effects of repetitive DBV on neuropathic pain and spinal pNR1 were prevented by intrathecal pretreatment of idazoxan, an alpha-2 adrenoceptor antagonist. These results indicate that repetitive DBV produces potent analgesic effects on neuropathic pain and this is associated with the activation of the LC noradrenergic system and with a reduction in spinal pNR1. PERSPECTIVE: The results of current study demonstrate that repetitive administration of DBV significantly suppresses neuropathic pain. Furthermore, this study provides mechanistic information that repetitive treatment of DBV can produce more potent analgesic effect than single DBV treatment, indicating a potential novel strategy for the management of chronic pain.

[Deep Oscillation: therapeutic-rehabilitative experiences with a new electrostatic device]. / Deep Oscillation®: esperienze terapeutico-riabilitative con un nuovo innovativo strumento ad azione elettrostatica.

AIM: Deep Oscillation® is an apparatus that produces low frequency electromagnetic radiations able to modulate immune reactions and, therefore, applicable to pain, tumour and inflammation treatments. The aim of this study is to evaluate how the Deep Oscillation® therapy works on conventional therapy resistant patients as the apparatus can be applied either to trauma derived fom surgical wounds or on sports post-traumatic oedema, low back pain and/or sciatalgic pain and cervicobrachial pain. METHODS: In the first part of the study, 34 cases of recent surgical wounds have been treated with Deep Oscillation® with 3 times a week visits for 20 minutes. In the same way 30 cases of sports post-traumatic oedema, 20 cases of low back pain and/or sciatalgic pain and 10 cases of cervicobrachial pain were treated. Among these patients, 15 cases had also undergone contemporaneous nonsteroidal anti-inflammatory drugs intravenous drip, electrolytes and vitamins to verify the probable synergetic efficacy of both treatments. RESULTS: The results confirm that in some cases the Deep Oscillation® treatment is effective since the first/third therapy up to the restitutio ad integrum. It has also been demonstrated that the maximum efficiency of the Deep Oscillation® and nonsteroidal anti-inflammatory drugs synergetic treatment is probably due to the electromagnetic radiations able to facilitate the pharmacological uptake. CONCLUSION: This study confirms the capacity of the electrostatic energy, released by Deep Oscillation®, to stimulate the patient's neurosensory system, raising his pain threshold and facilitating his pharmacological uptake and restoring his functional recovery more quickly.

Adenosine A1 receptors mediate local anti-nociceptive effects of acupuncture.

Acupuncture is an invasive procedure commonly used to relieve pain. Acupuncture is practiced worldwide, despite difficulties in reconciling its principles with evidence-based medicine. We found that adenosine, a neuromodulator with anti-nociceptive properties, was released during acupuncture in mice and that its anti-nociceptive actions required adenosine A1 receptor expression. Direct injection of an adenosine A1 receptor agonist replicated the analgesic effect of acupuncture. Inhibition of enzymes involved in adenosine degradation potentiated the acupuncture-elicited increase in adenosine, as well as its anti-nociceptive effect. These observations indicate that adenosine mediates the effects of acupuncture and that interfering with adenosine metabolism may prolong the clinical benefit of acupuncture.

Pain-relieving effects of processed Aconiti tuber in CCI-neuropathic rats.

Neuropathic pain is often refractory to conventional pain therapies and thus requires exploration of effective drugs. We evaluated if processed Aconiti tuber (PAT), a traditional oriental herbal medicine that has been used as an analgesic, relieves neuropathic pain in the rat chronic constriction injury (CCI) model. Ten to 14 days after CCI in the right hind paw, six groups of rats received oral placebo, or PAT at 0.5, 1, 2, 3, or 5 g/kg. Additional groups received oral PAT, 2 g/kg, after pretreatment with intraperitoneal naloxone; intraperitoneal nor-binaltorphimine (norBNI); or intrathecal norBNI. As indicators of mechanical allodynia and thermal hyperalgesia, the pressure threshold of paw withdrawal (PWT) in response to linearly increasing pressure, and latency to paw withdrawal (PWL) in response to radiant heat, were measured before and after drug administration. Oral PAT dose-dependently increased PWT and PWL, which had been decreased due to CCI. The increases in PWT and PWL by oral PAT were inhibited by intraperitoneal and intrathecal norBNI: a selective kappa-opioid receptor antagonist, but not by intraperitoneal naloxone. These results indicate that oral PAT can alleviate mechanical allodynia and thermal hyperalgesia, dose-dependently, via spinal kappa-opioid receptor mechanisms in a rat CCI neuropathic pain model.

Infliximab attenuates immunoreactivity of brain-derived neurotrophic factor in a rat model of herniated nucleus pulposus.

STUDY DESIGN: The effect of infliximab, a chimeric monoclonal antibody to TNF-alpha, on induction of brain-derived neurotrophic factor (BDNF) was examined using an experimental herniated nucleus pulposus (NP) model. OBJECTIVES: To investigate whether treatment of infliximab could attenuate an induction of BDNF, which functions as a modulator of pain, following NP application to the nerve root. SUMMARY OF BACKGROUND DATA: Evidence from basic scientific studies proposes that TNF-alpha is involved in the development of NP-induced nerve injuries. However, the therapeutic mechanisms of infliximab against pain have not been elucidated experimentally. METHODS: Twenty rats were used in this study. In the test groups, the animals underwent application of NP to the L4 nerve roots and received a single systemic (intraperitoneal) injection of infliximab at the time of surgery (Infli-0 group, n = 5) or at 1 day after operation (Infli-1 group, n = 5). As a control treatment, sterile water was administered intraperitoneally to 5 rats with NP application (NP group) and to 5 sham-operated rats (sham group). On day 3 after surgery, the L4 dorsal root ganglion (DRG) and L4 spinal segment were harvested and assessed regarding BDNF immunoreactivity. RESULTS.: Application of NP induced a marked increase of BDNF immunoreactivity in number in the DRG neurons and within the superficial layer in the dorsal horn compared with the sham group (P < 0.01). Infliximab treatment in the Infli-0 and Infli-1 groups reduced the BDNF induction in both DRG and spinal cord (P < 0.05). CONCLUSION: These findings indicate that infliximab attenuates the elevated BDNF levels induced by NP. The present study therefore further indicates the importance of TNF-alpha in sciatica due to disc herniation and the possible therapeutic use of a TNF-alpha inhibitor for this condition.

Heme oxygenase type 2 participates in the development of chronic inflammatory and neuropathic pain.

Heme oxygenase (HO) catalyzes the conversion of heme to biliverdin, iron, and carbon monoxide. Recent studies have demonstrated that inhibitors of HO are analgesic in a number of different pain models. In these studies we attempted to define the role of HO type 2 (HO-2) in the development of chronic inflammatory and neuropathic pain. To do this both wild type and C57Bl/6 HO-2 null mutant mice were either injected with complete Freund[apos ]s adjuvant in 1 hind paw or underwent unilateral partial sciatic nerve ligation. The resulting thermal hyperalgesia and mechanical allodynia were monitored for up to 14 days afterward. In both models of chronic pain it was observed that the extent of hyperalgesia and allodynia was significantly less for the HO-2 null mutants than the wild type mice. Additional studies quantified spinal cord dorsal horn Fos expression after brushing of the affected hind paw for both complete Freund[apos ]s adjuvant and partial sciatic nerve ligation treated mice. These studies showed that HO-2 null mutants had less Fos expression after stimulation by brushing than did their wild type counterparts. Our results indicate that HO-2 participates in the thermal hyperalgesia and mechanical allodynia that occur in 2 commonly used models of chronic inflammatory and neuropathic pain.