Mechanism Of Pain Relief Research Articles

Modulation of BDNF Expression by Bryophyllum pinnatum Extract: Implications for Oxidative Stress and Cognitive Function in Pain-induced Wistar Rats

This research work investigated modulatory effects of Bryophylum pinnatum extract on BDNF expression, and cognitive functions in repetitive pain-induced oxidative stress in Wistar rats. Animals weighing between 80–100g were acquired from the animal house of the Department of Human Physiology, Faculty of Basic Medical Sciences, University of Port Harcourt, and all animals received standard laboratory rat feeds and water ad libitum. The study was designed to assess the time dependent effects with a total of 30 rats divided into 6 groups. Group 1(Control), Group 2 (Pain Only), Group 3 (Pain + 5mg/kg Morphine), Group 4 (Pain + 10mg/kg Morphine), Group (Pain + 25mg/kg Bryophylumm Pinnatum), Group 6 (Pain + 50mg/kg Bryophylumm Pinnatum), Hydromethanolic extracts was prepared accordingly, and Gas Chromatography Mass Spectrometry (GC/MS) analysis were carried out. Neurobehavioral studies were conducted weekly to assess the effects of the interventions on cognitive and neurological parameters, using radial maze and navigational maze test. Assay of BDNF was done using the Elisa method. The Results showed that Morphine and Bryophyllum pinnatum both significantly improved BDNF expression, showed antioxidant effects, improved cognitive functions, and provided possible mechanisms of pain relief. Pharmacokinetic studies on the binding affinities and drug-likeness properties of the active compounds from these extracts revealed some favorable properties with regard to management of oxidative stress and promotion of cognitive function in states of pain. The study therefore provide indication of the therapeutic potential of Bryophyllum pinnatum in the effective management of Pain, oxidative stress and cognitive functions.

Unveiling the Scientific Mechanisms of Pain Relief through Marma Therapy as a Non-Pharmacological Intervention

Unveiling the Scientific Mechanisms of Pain Relief through Marma Therapy as a Non-Pharmacological Intervention

Clinical therapeutic effect of self-prescribed Sanhanchushi Tongbi on lumbar disc herniation

BACKGROUND Lumbar disc herniation (LDH) commonly occurs during spinal surgery; LDH is on the increase in younger patients and is classified as "paralysis" and "back pain.” Sanhanchushi Tongbi (SPST) is a customized prescription. It disperses cold, relieves pain, removes cold from the meridians and viscera, and treats neuropathic pain. However, few studies have investigated its mechanism of pain relief. AIM To observe the clinical therapeutic effects on LDH treated with self-prescribed SPST. METHODS A total of 211 patients with LDH syndrome were divided into two groups: 107 patients in the control group were treated with conventional massage combined with traction, and 104 patients in the observation group were treated with a combination of the control regimen and self-prescribed oral SPST. The patients were treated for 4 wk. Indices of traditional Chinese medicine (TCM) syndrome score and serum inflammatory factor levels were measured. RESULTS After therapy, the TCM syndrome score in the observation group was significantly lower than that in the control group (P < 0.05). The main symptoms, clinical signs, daily activities, and Japanese Orthopedic Association scores in the observation group were significantly higher than those in the control group after therapy (P < 0.05). The levels of tumor necrosis factor-α, interleukin-6, and C-reactive protein were lower in the observation group than in the control group (P < 0.05). In the observation group, superoxide dismutase levels were significantly higher, whereas malondialdehyde levels were significantly lower, compared with the control group (P < 0.05). The overall efficacy rate in the observation group was 96.15%, which was substantially higher than that in the control group (88.79%; P < 0.05). CONCLUSION Self-prescribed SPST can reduce the levels of inflammatory and pain-causing factors as well as lumbar pain in patients with LDH.

Andrographolide exhibits antinociceptive effects in neuropathic rats via inhibiting class Ⅱ MHC associated response and regulating synaptic plasticity

BackgroundNeuropathic pain (NP) due to nerve injury, disrupts neural plasticity by triggering the release of inflammatory mediators. Alongside the hypothesis that neuro-inflammation contributes to this disruption, Andrographolide (Andro), a traditional bioactive compound derived from Andrographis paniculata, has garnered attention for its potent anti-inflammatory properties. However, whether Andro could ameliorate NP by regulating neuroinflammation remains unknown. PurposeThis study aimed to investigate whether and how Andro regulates neuroinflammation and alleviates NP. MethodsThe analgesic effects of Andro on NP were evaluated using both the spinal nerve ligation (SNL) and formalin rat models. A combination of network pharmacology, RNA sequencing, and experimental validation was employed to elucidate the underlying mechanism behind Andro's analgesic effects. Additionally, various techniques such as functional ultrasound, immunohistochemistry, quantitative real-time polymerase chain reaction (qPCR), patch clamp, and electron microscopy were employed to investigate the specific neural cell types, neural functions, and changes in neural plasticity influenced by Andro. ResultsNetwork pharmacology analysis unveiled the crucial roles played by shared targets of Andro and pain in regulating pain-related inflammation, including microglia activation, neuroinflammation, immune modulation, and synaptic transmission. Furthermore, we confirmed Andro's superior efficacy in pain relief compared to the traditional analgesic drug, Gabapentin. In these models, Andro was observed to modulate the haemodynamic response triggered by SNL. Transcriptome analysis and molecular docking studies indicated the involvement of major histocompatibility complex class II (MHCII) genes (Db1, Da, and Bb). Electron microscopy revealed improvements in synaptic ultrastructure, and electrophysiological investigations showed a selective reduction in glutamatergic transmission in neuropathic rats after following Andro treatment. The integration of systems pharmacology analysis and biological validation collectively demonstrated that the mechanism of pain relief involves immune modulation, enhancement of synaptic plasticity, and precise regulation of excitatory neurotransmission. ConclusionIn conclusion, this study has demonstrated that Andro, by targeting MHCII genes, may serve as a promising therapeutic candidate for neuropathic pain.

Assessing Muscular Pain and Ergonomics Among Robotic Surgeons in China: A Validation.

Robotic surgery has transformed minimally invasive procedures, offering precision and efficiency. However, the ergonomic aspects of robotic consoles and their impact on surgeon health remain understudied. This review investigates the burden of ergonomics and muscle fatigue among robotic surgeons in China, comparing the findings to a multinational study. A literature review identified themes related to physical discomfort in robotic surgery. A questionnaire was administered to Chinese robotic surgeons, yielding 40 responses. The study assessed demographic characteristics, surgeon experience, ergonomic practices, reported discomfort, and pain-relief mechanisms. The study revealed that most surgeons experienced shoulder and neck pain, with mixed opinions on whether robotic surgery was the primary cause. Stretching exercises were commonly used for pain relief. Surgeons believed that case volume and surgery duration contributed to discomfort. Comparisons with a multinational study suggested potential demographic and experience-related differences. While the study has limitations, including a small sample size and potential translation issues, it underscores the importance of addressing ergonomic concerns and providing proper training to robotic surgeons to ensure their well-being and longevity in the field. Further research with larger cohorts and platform-specific analyses is warranted.

The Combined Intraosseous Administration of Orthobiologics Outperformed Isolated Intra-articular Injections in Alleviating Pain and Cartilage Degeneration in a Rat Model of MIA-Induced Knee Osteoarthritis

Background: Intra-articular (IA) platelet-rich plasma (PRP) and bone marrow aspirate concentrate (BMAC) injections have shown efficacy and safety in treating osteoarthritis (OA). However, the effectiveness and mechanisms of combined intraosseous (IO) administration of these orthobiologics have yet to be explored. Purpose/Hypothesis: The purpose of this study was to evaluate the effect on pain, cartilage, synovium/infrapatellar fat pad (IFP), and subchondral bone in rat knee OA, comparing isolated IA with combined IA and IO (IA+IO) injections of PRP or BMAC. It was hypothesized that combined injections would be superior to sole IA injections. Study Design: Controlled laboratory study. Methods: A total of 48 rats were divided into 6 groups: sham (only joint puncture during OA induction with IA+IO saline injection treatment) and 5 groups with OA induction, control (IA+IO saline injection), PRP (IA PRP+IO saline injection), BMAC IA (IA BMAC+IO saline injection), PRP IA+IO (IA+IO PRP injection), and BMAC IA+IO (IA+IO BMAC injection). OA was induced by IA injection of monosodium iodoacetate (MIA). Rats were administered different orthobiologics according to their grouping 3 weeks after the MIA injection. Pain changes were evaluated using the weightbearing ratio assay at weeks 3, 4, 5, 7, and 9 after OA induction. Rats were euthanized at week 9 for gross, radiological, histological, immunohistochemical, and immunofluorescence assessments of cartilage, synovium, and subchondral bone. Results: Compared with the control group, all orthobiologics injection groups had reduced joint pain. Compared with IA injection, IA+IO injections provided superior pain relief by suppressing calcitonin gene-related peptide and substance P in both the synovium/IFP and subchondral bone. IA+IO injections slowed the progression of subchondral bone lesions by inhibiting CD31hiEmcnhi vessel formation and excessive osteoclast and osteoblast turnover while preserving subchondral bone microarchitecture, slowing cartilage degeneration. However, IA+IO injections did not outperform isolated IA injections in reducing synovitis and synovium/IFP fibrosis. Compared with PRP, BMAC exhibited superior inhibition of pain-related mediators, but no significant differences were observed in synovitis suppression, infrapatellar fat pad fibrosis, and subchondral bone protection. Conclusion: IA+IO injections of orthobiologics were more effective in relieving pain, slowing cartilage degeneration, and inhibiting abnormal vascularization and remodeling compared with isolated IA injections. BMAC showed superior pain relief in the synovium/IFP and subchondral bone compared with PRP. Further research is needed to optimize PRP and BMAC components for enhanced efficacy in OA management. Clinical Relevance: Our findings contribute to advancing the understanding of pain relief mechanisms and support the endorsement of IO injection of orthobiologics for the treatment of OA and joint pain.

Scalp electroacupuncture targeting the VTADA neurons to relieve negative emotions and promote the alleviation of chronic pain.

Chronic pain and negative emotions are often linked, and both can impact the reward circuit. The use of electroacupuncture (EA) has been found to regulate and improve these conditions. This study explores the potential mechanism of chronic pain relief by adding acupoints with emotional regulation effect to the basis of routine EA analgesia, to optimize the acupoint compatibility scheme of EA in the treatment of analgesia. For this study, 42 male Wistar rats were used. Recombinant adeno-associated viruses were used to label and regulate the activity of dopamine (DA) neurons. The rat model was established by complete Freund's adjuvant (CFA). Lower limb electroacupuncture (LEA) was applied to the ST36 and BL60 acupoints. In addition, LEA + scalp EA (SEA) was given using the GV20 and GV24+ acupoints besides ST36 and BL60. To evaluate the pain threshold, we measured 50% paw withdrawal thresholds and thermal paw withdrawal latencies. Negative emotions were evaluated through the open field test, marble-burying test, sucrose preference test, and forced swimming test. Moreover, the conditional place preference test was conducted to measure the reward behavior in response to pain relief. Immunofluorescence staining, Western blotting, and qPCR were used to detect the activity of the VTADA-NAc reward circuit. The injection of CFA significantly lowered the pain threshold. As the pain persisted, the anxiety and depression-like behaviors escalated while the response to reward reduced. Meanwhile, the VTADA-NAc pathway was suppressed with pain chronification. However, activating DA neurons in VTA attenuated the effects induced by CFA. LEA could relieve chronic pain, negative emotions, and reward disorders, while also activating the VTADA-NAc pathway. In addition, LEA + SEA exhibited a more pronounced effect compared with LEA alone. Nevertheless, chemogenetic inhibition of DA neurons decreased the efficacy of LEA + SEA in the treatment of chronic pain and associated comorbidities. Adding SEA to conventional LEA effectively alleviates negative emotions and chronic pain, potentially due to the activation of the VTADA-NAc reward neural circuit. Thus, LEA + SEA is a more effective treatment for hyperalgesia and associated negative emotions compared with LEA alone.

Efficacy of radial shock wave therapy on rat models of adjuvant arthritis

BackgroundExtracorporeal shock wave therapy (ESWT) is an effective treatment for musculoskeletal pain, tendinopathy, and fasciitis with an anti-inflammatory effect. ESWT can be categorized into two groups: radial pressure wave (RPW) and focused shock wave (FSW). Although there have been several studies on the inflammation and pain-improvement mechanisms of FSW, there are few studies on the pain-improvement mechanisms of RPW. This study aimed to elucidate the efficacy of RPW in a rat model of adjuvant arthritis. MethodsNinety-six rats were randomly categorized into three groups: RPW, control, and sham as follows: (I) RPW group, which received RPW application after complete Freund's adjuvant (CFA) injection; (II) Control group, which received only CFA injection; and (III) Sham group, which received only saline injection. All rats were evaluated at 0, 4, 7, 14, 28, and 56 days post-RPW application based on foot circumference, von Frey test, and immunohistochemistry of nerve fibers for calcitonin gene-related peptide (CGRP) and protein gene product (PGP) 9.5 in plantar skins. ResultsThere were no significant differences in foot circumference between the RPW and control groups at any time point. The RPW group showed significant improvements in the von Frey test results on days 7 and 14. The total CGRP-immunoreactive (ir) and PGP9.5-ir nerve fiber lengths in the RPW group decreased on day 0; however, both were increased in the control group. The CGRP-ir and PGP9.5-ir nerve fibers in the RPW group were significantly shorter than those in the control group until day 14 after RPW. ConclusionsRPW improved the mechanical hypersensitivity between days 7 and 14 after application. Like FSW, RPW also induced the degeneration of sensory nerve fibers in the skin in the early period after irradiation, and reinnervation occurred between 14 and 28 days. Thus, our results demonstrate one of the pain relief mechanisms after RPW application.

Ibuprofen modulates tetrodotoxin-resistant persistent Na+ currents at acidic pH in rat trigeminal ganglion neurons

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to relieve various symptoms such as headache, arthralgia, and dental pain. While the primary mechanism of NSAID-based pain relief is the inhibition of cyclooxygenase-2, several NSAIDs also modulate other molecular targets related to nociceptive transmission such as voltage-gated Na+ channels. In the present study, we examined the effects of NSAIDs on persistent Na+ current (INaP) mediated by tetrodotoxin-resistant (TTX-R) Na+ channels in small-to medium-sized trigeminal ganglion neurons using a whole-cell patch-clamp technique. At clinically relevant concentrations, all propionic acid derivatives tested (ibuprofen, naproxen, fenoprofen, and flurbiprofen) preferentially inhibited the TTX-R INaP. The inhibition was more potent at acidic extracellular pH (pH 6.5) than at normal pH (pH 7.4). Other NSAIDs, such as ketorolac, piroxicam, and aspirin, had a negligible effect on the TTX-R INaP. Ibuprofen both accelerated the onset of inactivation and retarded the recovery from inactivation of TTX-R Na+ channels at acidic extracellular pH. However, all NSAIDs tested in this study had minor effects on voltage-gated K+ currents, as well as hyperpolarization-activated and cyclic nucleotide-gated cation currents, at both acidic and normal extracellular pH. Under current-clamp conditions, ibuprofen decreased the number of action potentials elicited by depolarizing current stimuli at acidic (pH 6.5) extracellular pH. Considering that extracellular pH falls as low as 5.5 in inflamed tissues, TTX-R INaP inhibition could be a mechanism by which ibuprofen and propionic acid derivative NSAIDs modulate inflammatory pain.

Effect of spinal cord stimulation for thermal noxious stimulus pain threshold in Parkinson's disease

BackgroundParkinson's disease (PD)-related pain or PD pain is a frequent non-motor symptom and is treated with pharmacotherapy and non-pharmacologic therapies such as deep brain stimulation (DBS) and spinal cord stimulation (SCS). The mechanism of PD pain relief by DBS is thought to involve increased pain threshold to nociceptive stimulation, whereas the mechanism of SCS has not been elucidated. ObjectivePD pain relief by SCS may involve modulation of the pain thresholds in the spinal cord segments and supra-spinal actions. Therefore, we investigated the effect of SCS in patients who underwent SCS for intractable PD pain in the lower extremities by measuring pain thresholds to thermal nociceptive stimulation of the lower (leg) and upper (hand) parts of the stimulated spinal segment during SCS-off and SCS-on using quantitative sensory testing to determine the pain threshold. MethodsSeven PD patients with SCS in the lower thoracic spinal cord underwent measurements of cold sensory threshold, warm sensory threshold, cold pain threshold (CPT), and heat pain threshold (HPT). ResultsIn upper part of the stimulated spinal segment, CPT was significantly decreased during SCS-on compared to SCS-off (p < 0.01); whereas HPT was not significantly different. In lower part of the stimulated spinal segment, CPT was significantly increased during SCS-on compared to SCS-off (p < 0.05); and HPT was also increased (p < 0.05). ConclusionThis study shows that SCS raises the pain threshold to thermal nociception in PD patients. The primary mechanism of pain relief by SCS is thought to be segmental inhibition at the level of the stimulated spinal segments.

Proteomic Analysis to Identify Prospective Biomarkers of Treatment Outcome After Microvascular Decompression for Trigeminal Neuralgia: A Preliminary Study

Trigeminal neuralgia (TN) is a severe neuropathic facial pain disorder, often caused by vascular or neuronal compression of the trigeminal nerve. In such cases, microvascular decompression (MVD) surgery can be used to treat TN, but pain relief is not guaranteed. The molecular mechanisms that affect treatment response to MVD are not well understood. In this exploratory study, we performed label-free quantitative proteomic profiling of plasma and cerebrospinal fluid samples from patients undergoing MVD for TN, then compared the proteomic profiles of patients graded as responders (n = 7) versus non-responders (n = 9). We quantified 1,090 proteins in plasma and 1,087 proteins in the cerebrospinal fluid, of which 12 were differentially regulated in the same direction in both sample types. Functional analyses of differentially regulated proteins in protein-protein interaction networks suggested pathways of the immune system, axon guidance, and cellular stress response to be associated with response to MVD. These findings suggest potential biomarkers of response to MVD, as well as possible mechanisms of variable treatment success in TN patients. PerspectiveThis exploratory study evaluates proteomic profiles in plasma and cerebrospinal fluid of patients undergoing microvascular decompression surgery for trigeminal neuralgia. Differential expression of proteins between surgery responders versus non-responders may serve as biomarkers to predict surgical success and provide insight into surgical mechanisms of pain relief in trigeminal neuralgia.

ID: 206155 Rapid Adaption of Dorsal Horn Inhibitory Populations to Dorsal Column Stimulation

Epidural spinal cord stimulation (SCS) has been used for over 50 years to treat refractory pain and avoid addictive opioid therapies. However, there is an incomplete understanding of how these neuromodulatory devices mediate pain relief, which has precluded effective clinical implementation. One of the mechanisms of SCS-mediated pain relief is through activation of inhibitory superficial dorsal horn circuits, as elegantly proposed in the Gate Control Theory (GCT). The properties of sustained Aβ-fiber stimulation evoked responses in molecularly defined inhibitory dorsal horn populations remain poorly defined and were investigated here using an optical approach.

α7- and α9-Containing Nicotinic Acetylcholine Receptors in the Functioning of Immune System and in Pain.

Nicotinic acetylcholine receptors (nAChRs) present as many different subtypes in the nervous and immune systems, muscles and on the cells of other organs. In the immune system, inflammation is regulated via the vagus nerve through the activation of the non-neuronal α7 nAChR subtype, affecting the production of cytokines. The analgesic properties of α7 nAChR-selective compounds are mostly based on the activation of the cholinergic anti-inflammatory pathway. The molecular mechanism of neuropathic pain relief mediated by the inhibition of α9-containing nAChRs is not fully understood yet, but the role of immune factors in this process is becoming evident. To obtain appropriate drugs, a search of selective agonists, antagonists and modulators of α7- and α9-containing nAChRs is underway. The naturally occurring three-finger snake α-neurotoxins and mammalian Ly6/uPAR proteins, as well as neurotoxic peptides α-conotoxins, are not only sophisticated tools in research on nAChRs but are also considered as potential medicines. In particular, the inhibition of the α9-containing nAChRs by α-conotoxins may be a pathway to alleviate neuropathic pain. nAChRs are involved in the inflammation processes during AIDS and other viral infections; thus they can also be means used in drug design. In this review, we discuss the role of α7- and α9-containing nAChRs in the immune processes and in pain.

Knockdown of PAC1 improved inflammatory pain in mice by regulating the RAGE/TLR4/NF-κB signaling pathway

The development of inflammatory pain seriously affects the activities and general functions of patients in daily life. At present, the research on the mechanism of pain relief is still insufficient. This study aimed to investigate the influence of PAC1 on the progression of inflammatory pain and its molecular mechanism. Lipopolysaccharide (LPS) was used to induce BV2 microglia activation to establish an inflammation model, and CFA injection was used to establish a mouse inflammatory pain model. The results showed that PAC1 was highly expressed in BV2 microglia induced by LPS. Knockdown of PAC1 significantly reduced LPS-induced inflammation and apoptosis in BV2 cells, and RAGE/TLR4/NF-κB signaling pathway was involved in the regulation of BV2 cells by PAC1. What's more, knockdown of PAC1 alleviated CFA-induced mechanical allodynia and thermal hyperalgesia in mice, as well as reduced the development of inflammatory pain to a certain extent. Therefore, Knockdown of PAC1 relieved inflammatory pain in mice by inhibiting the RAGE/TLR4/NF-κB signaling pathway. Targeting PAC1 may be a new direction for the treatment of inflammatory pain.

Research advances on the application of music therapy in pain management of children with burns

Pain after burns is a very common problem in children. Severe pain will not only hinder treatment, but also damage children's mental health if not handled in time. Therefore, pain management is very important in treating children with burns. As a safe, effective, and convenient non-drug therapy, music therapy has great advantages in relieving pain and is widely used in a variety of clinical fields. This paper focused on music therapy and its mechanism of pain relief, the current status of research on pain management of pediatric burns, the application and prospect of music therapy in pain management of pediatric burns, etc., to provide reference for clinical application.

The Effect of Hypnoanesthesia on Serotonin

Background: Every minor and major surgical procedure requires anesthesia to relieve pain during surgery. The neuro-biomolecular mechanism of pain relief in hypnoanesthesia remains uncomprehended. Objective: This study aims to observe the effect of hypnoanesthesia on several neurotransmitters, including serotonin, glutamic acid, and substance P, which play a role in the mechanism of pain. Methods: The study subjects included patients with benign soft tissue tumors consisting of 40 people who were divided into two groups, namely treatment and control groups. Minor surgery with hypnoanesthesia was performed in the treatment group, whereas in the control group, minor surgery was performed with 2% lidocaine local anesthetic. Pain in both groups was measured by FPS (Face Pain Scale) and monitored by a vital sign monitor. The processes of the study were recorded with a camcorder. Changes in serum levels of excitatory (glutamic acid and substance P) and inhibitory (serotonin) neurotransmitters before and after the intervention were analyzed using ELISA (Enzym-Link Immunosorbent Assay) in both groups. Results: The control and treatment groups had the same end result, which was pain relief. The results of regression and ANOVA analysis indicated that serotonin simultaneously had a significant effect on substance P at 98.4% and glutamic acid at 98.2%. Conclusion: There was no statistically significant change in serotonin levels before and after hypnoanesthesia. Serotonin, as an inhibitory neurotransmitter, simultaneously has a significant effect on both excitatory neurotransmitters, namely Glutamate Acid and Substance P, in the mechanism of nociceptive pain relief with hypnosis.

Spinal Cord Stimulation in Chronic Low Back Pain Syndrome: Mechanisms of Modulation, Technical Features and Clinical Application.

Chronic low-back pain (CLBP) is a common disease with several negative consequences on the quality of life, work and activity ability and increased costs to the health-care system. When pharmacological, psychological, physical and occupational therapies or surgery fail to reduce CLBP, patients may be a candidate for Spinal Cord Stimulation (SCS). SCS consists of the transcutaneous or surgical implantation of different types of electrodes in the epidural space; electrodes are then connected to an Implanted Pulse Generator (IPG) that generates stimulating currents. Through spinal and supraspinal mechanisms based on the “gate control theory for pain transmission”, SCS reduces symptoms of CLBP in the almost totality of well-selected patients and its effect lasts up to eight years in around 75% of patients. However, the evidence in favor of SCS still remains weak, mainly due to poor trial methodology and design. This narrative review is mainly addressed to those professionals that may encounter patients with CLBP failing conventional treatments. For this reason, we report the mechanisms of pain relief during SCS, the technical features and some clinical considerations about the application of SCS in patients with CLBP.

Electroacupuncture relieves neuropathic pain by inhibiting degradation of the ecto-nucleotidase PAP in the dorsal root ganglions of CCI mice.

Although electroacupuncture is widely used in chronic pain management, it is quite controversial due to its unclear mechanism. We hypothesised that EA alleviates pain by inhibiting degradation of the ecto-nucleotidase prostatic acid phosphatase (PAP) and facilitating ATP dephosphorylation in dorsal root ganglions (DRGs). We applied EA in male C57 mice subjected to chronic constriction injury (CCI) and assessed extracellular ATP and 5'-nucleotidease expression in DRGs. Specifically, we used a luminescence assay, quantitative reverse transcriptase-polymerase chain reaction, Western blotting, immunohistochemistry and nociceptive-related behavioural changes to gather data, and we tested for effects after PAP expression was inhibited with an adeno-associated virus (AAV). Moreover, membrane PAP degradation was investigated in cultured DRG neurons and the inhibitory effects of EA on this degradation were assessed using immunoprecipitation. EA treatment alleviated CCI surgery-induced mechanical pain hypersensitivity. Furthermore, extracellular ATP decreased significantly in both the DRGs and dorsal horn of EA-treated mice. PAP protein but not mRNA increased in L4-L5 DRGs, and inhibition of PAP expression via AAV microinjection reversed the analgesic effect of EA. Membrane PAP degradation occurred through a clathrin-mediated endocytosis pathway in cultured DRG neurons; EA treatment inhibited the phosphorylation of adaptor protein complex 2, which subsequently reduced the endocytosis of membrane PAP. EA treatment alleviated peripheral nerve injury-induced mechanical pain hypersensitivity in mice by inhibiting membrane PAP degradation via reduced endocytosis and subsequently promote ATP dephosphorylation in DRGs. In a mouse model of chronic pain, electroacupuncture treatment increased levels of prostatic acid phosphatase (PAP: an ecto-nucleotidase known to relieve pain hypersensitivity) by inhibiting PAP degradation in dorsal root ganglions. This promoted extracellular ATP dephosphorylation, inhibited glia activation and eventually alleviated peripheral nerve injury-induced mechanical pain hypersensitivity in mice. Our findings represent an important step forward in clarifying the mechanisms of pain relief afforded by acupuncture treatment.

Analgesic effects of a 5-HT3 receptor antagonist in an animal model of complex regional pain syndrome.

Complex regional pain syndrome (CRPS) is caused by injuries from fracture after trauma and orthopaedic surgical procedures in the hind limbs. The symptoms of CRPS include warmth, pain, allodynia, and hyperalgesia. It is known that 5-hydroxytryptamine 3 (5-HT3) receptors contribute to hyperalgesia, but their role has not yet been fully elucidated. This study investigated the mechanism of pain relief when a 5-HT3 receptor antagonist was administered in a CRPS animal model. To establish a CRPS animal model, 10-week-old Sprague-Dawley rats were used in the experiment. On the fourth week post tibial fracture surgery, we performed the von Frey test to measure mechanical allodynia. After performing behavioural tests, we collected blood and tissue samples after sacrificing the animals. Enzyme-linked immunosorbent assay and western blot were also performed. The experimental tibia fracture model-induced CRPS animals elicited increased 5-HT3 receptor expression, and the 5-HT transporter was decreased in the brain stem after 4 weeks of surgical intervention. Additionally, in CRPS-induced animals, both the concentration of substance P and the level of interleukin 6 were increased peripherally and centrally. Treatment with the 5-HT3 receptor antagonist, ramosetron, exerted an analgesic effect in the paw withdrawal test and was dependent on the attenuation of the 5-HT3 receptor population with inflammatory pain mediators. These data suggest that treatment with the 5-HT3 receptor antagonist, ramosetron, in experimental CRPS animal models alleviated pain-related behaviours and may be a new therapeutic option or potential therapeutic agent for patients with CRPS.

The Histamine H4 Receptor Participates in the Anti-Neuropathic Effect of the Adenosine A3 Receptor Agonist IB-MECA: Role of CD4+ T Cells.

A3 adenosine receptor (A3AR) agonists have emerged as potent relievers of neuropathic pain by a T cell-mediated production of IL-10. The H4 histamine receptor (H4R), also implicated in pain modulation, is expressed on T cells playing a preeminent role in its activation and release of IL-10. To improve the therapeutic opportunities, this study aimed to verify the hypothesis of a possible cross-talk between A3AR and H4R in the resolution of neuropathic pain. In the mouse model of Chronic Constriction Injury (CCI), the acute intraperitoneal co-administration of the A3AR agonist IB-MECA (0.5 mg/kg) and the H4R agonist VUF 8430 (10 mg/kg), were additive in counteracting mechano-allodynia increasing IL-10 plasma levels. In H4R−/− mice, IB-MECA activity was reduced, lower pain relief and lower modulation of plasma IL-1β, TNF-α, IL-6 and IL-10 were shown. The complete anti-allodynia effect of IB-MECA in H4R−/− mice was restored after intravenous administration of CD4+ T cells obtained from naïve wild type mice. In conclusion, a role of the histaminergic system in the mechanism of A3AR-mediated neuropathic pain relief was suggested highlighting the driving force evoked by CD4+ T cells throughout IL-10 up-regulation.