Inhibitory gamma-aminobutyric acidergic neurons in the anterior cingulate cortex participate in the comorbidity of pain and emotion

Pain is often comorbid with emotional disorders such as anxiety and depression.Hyperexcitability of the anterior cingulate cortex has been implicated in pain and pain-related negative emotions that arise from impairments in inhibitory gamma-aminobutyric acid neurotransmission.This review primarily aims to outline the main circuitry(including the input and output connectivity)of the anterior cingulate cortex and classification and functions of different gamma-aminobutyric acidergic neurons;it also describes the neurotransmitters/neuromodulators affecting these neurons,their intercommunication with other neurons,and their importance in mental comorbidities associated with chronic pain disorders.Improving understanding on their role in pain-related mental comorbidities may facilitate the development of more effective treatments for these conditions.However,the mechanisms that regulate gamma-aminobutyric acidergic systems remain elusive.It is also unclear as to whether the mechanisms are presynaptic or postsynaptic.Further exploration of the complexities of this system may reveal new pathways for research and drug development.

The sexually dimorphic expression of glutamate transporters and their implication in pain after spinal cord injury

In addition to the loss of motor function,~60% of patients develop pain after spinal cord injury.The cellular-molecular mechanisms are not well understood,but the data suggests that plasticity within the rostral,epicenter,and caudal penumbra of the injury site initiates a cellularmolecular interplay that acts as a rewiring mechanism leading to central neuropathic pain.Sprouting can lead to the formation of new connections triggering abnormal sensory transmission.The excitatory glutamate transporters are responsible for the reuptake of extracellular glutamate which makes them a critical target to prevent neuronal hyperexcitability and excitotoxicity.Our previous studies showed a sexually dimorphic therapeutic window for spinal cord injury after treatment with the selective estrogen receptor modulator tamoxifen.In this study,we investigated the anti-allodynic effects of tamoxifen in male and female rats with spinal cord injury.We hypothesized that tamoxifen exerts anti-allodynic effects by increasing the expression of glutamate transporters,leading to reduced hyperexcitability of the secondary neuron or by decreasing aberrant sprouting.Male and female rats received a moderate contusion to the thoracic spinal cord followed by subcutaneous slow-release treatment of tamoxifen or matrix pellets as a control(placebo).We used von Frey monofilaments and the“up-down method”to evaluate mechanical allodynia.Tamoxifen treatment decreased allodynia only in female rats with spinal cord injury revealing a sexdependent effect.The expression profile of glutamatergic transporters(excitatory amino acid transporter 1/glutamate aspartate transporter and excitatory amino acid transporter 2/glutamate transporter-1)revealed a sexual dimorphism in the rostral,epicenter,and caudal areas of the spinal cord with a pattern of expression primarily on astrocytes.Female rodents showed a significantly higher level of excitatory amino acid transporter-1 expression while male rodents showed increased excitatory amino acid transporter-2 expression compared with female rodents.Analyses of peptidergic(calcitonin gene-related peptide-α)and non-peptidergic(isolectin B4)fibers outgrowth in the dorsal horn after spinal cord injury showed an increased calcitonin gene-related peptide-α/isolectin B4 ratio in comparison with sham,suggesting increased receptive fields in the dorsal horn.Although the behavioral assay shows decreased allodynia in tamoxifen-treated female rats,this was not associated with overexpression of glutamate transporters or alterations in the dorsal horn laminae fibers at 28 days post-injury.Our findings provide new evidence of the sexually dimorphic expression of glutamate transporters in the spinal cord.The dimorphic expression revealed in this study provides a therapeutic opportunity for treating chronic pain,an area with a critical need for treatment.

Mechanism of persistent hyperalgesia in neuropathic pain caused by chronic constriction injury

Transmembrane member 16 A(TMEM16 A) is involved in many physiological functions, such as epithelial secretion, sensory conduction, nociception, control of neuronal excitability, and regulation of smooth muscle contraction, and may be important in peripheral pain transmission. To explore the role of TMEM16 A in the persistent hyperalgesia that results from chronic constriction injury-induced neuropathic pain, a rat model of the condition was established by ligating the left sciatic nerve. A TMEM16 A selective antagonist(10 μg T16 Ainh-A01) was intrathecally injected at L5–6. For measurement of thermal hyperalgesia, the drug was administered once at 14 days and thermal withdrawal latency was recorded with an analgesia meter. For measurement of other indexes, the drug was administered at 12 days,once every 6 hours, totally five times. The measurements were performed at 14 days. Western blot assay was conducted to analyze TMEM16 A expression in the L4–6 dorsal root ganglion. Immunofluorescence staining was used to detect the immunoreactivity of TMEM16 A in the L4–6 dorsal root ganglion on the injured side. Patch clamp was used to detect electrophysiological changes in the neurons in the L4–6 dorsal root ganglion. Our results demonstrated that thermal withdrawal latency was shortened in the model rats compared with control rats.Additionally, TMEM16 A expression and the number of TMEM16 A positive cells in the L4–6 dorsal root ganglion were higher in the model rats, which induced excitation of the neurons in the L4–6 dorsal root ganglion. These findings were inhibited by T16 Ainh-A01 and confirm that TMEM16 A plays a key role in persistent chronic constriction injury-induced hyperalgesia. Thus, inhibiting TMEM16 A might be a novel pharmacological intervention for neuropathic pain. All experimental protocols were approved by the Animal Ethics Committee at the First Affiliated Hospital of Shihezi University School of Medicine, China(approval No. A2017-170-01) on February 27, 2017.

Drugs used for pain management in gastrointestinal surgery and their implications

Pain is the predominant symptom troubling patients.Pain management is one of the most important aspects in the management of surgical patients leading to early recovery from surgical procedures or in patients with chronic diseases or malignancy.Various groups of drugs are used for dealing with this;however,they have their own implications in the form of adverse effects and dependence.In this article,we review the concerns of different pain-relieving medicines used postoperatively in gastrointestinal surgery and for malignant and chronic diseases.

Research Findings Using Mindfulness-Based Interventions for Chronic Pain

Chronic pain is a complex condition that is very detrimental to physical and psychological wellbeing. It carries a significant level of disability and economic burden. Pain patients frequently experience comorbid mental illness (e.g. depression, anxiety, PTSD, insomnia) and often require psychotherapeutic interventions in addition to medication management. Mindfulness-based interventions (MBIs) have emerged as a means to treat several chronic conditions (e.g. chronic pain, depression, anxiety, substance abuse, stress, insomnia). The objective of this review is to evaluate the current research on the use of MBIs in chronic pain managment. Although there are several controlled trials on the use of MBIs in chronic pain management, only a few studies were found that demonstrated significant effects on pain intensity, quality of life, as well as physical and psychological functioning. Therefore, the current evidence is mixed and there are insufficient data to definitively confirm the full impact of the use of MBIs in chronic pain conditions such as fibromyalgia, chronic low back pain, rheumatoid arthritis, and chronic musculoskeletal pain. The lack of compelling evidence at this time signals a demand for higher quality investigations in this area. Research examining MBIs and concomitant CBT may be of great value in order to synergize and strengthen patient outcomes.

Rose Hip Powder That Contains the Natural Amount of Shells and Seeds Alleviates Pain in Osteoarthritis of the Dominant Hand—A Randomized, Double-Blind, Placebo-Controlled, Cross-Over Clinical Trial

Aim: A standardized preparation of seeds and shells of selected sub-species of Rosa canina L, trade name Hyben Vital, reduces discomfort from osteoarthritis of the knee and hip. This study aims to investigate the impact of the same rose-hip powder (RHP) on discomfort and the consumption of rescue medication, in patients with osteoarthritis of the hand. Methods: The double blind, placebo-controlled, crossover trial included 30 patients with osteoarthritis of the dominant hand. Patients were randomly allocated to treatment with either five gram encapsulated RHP or placebo, for three months (Phase 1), after which they switched to the corresponding treatment for a further three months period (Phase 2). Before entering the study, after 3 weeks and following three months of each of the study phases, scores for pain, stiffness and general feeling of discomfort were evaluated using a 10 step categorical scale, focusing on 16 different daily activities of the hand. The consumption of rescue medication was also calculated at the beginning and at the end of each study phase. Data are based on the intention to treat. Results: At the end of Phase 1, 90% of patients in the group receiving RHP first (group A), showed a reduction in pain, as compared to 36% in the group B initially given placebo (p 0.029). In line with this observation, stiffness and the general feeling of discomfort from the disease declined during RHP treatment (p 0.032). In group A, symptom reduction was still indicated by the study subjects 3 weeks after the switch to placebo. The consumption of rescue medication such as paracetamol, codeine and tramadol also declined significantly in group A when compared to group B (p 0.013). Conclusion: The present data suggest that administration of RHP, containing seeds and shells can reduce symptoms of osteoarthritis of the hand and consumption of rescue medication.

Pathogenesis and managenent of pain in chronic pancreatitis

INTRODUCTIONOf the three cardinal manifestations of chronic pancreatitis-pain,diabetes mellitus and steatorrhea,it is pain thatbrings the patient to the physician and is the most difficultto manage.The intractabale pain that is quite

Using quality improvement methods to increase use of pain prevention strategies for childhood vaccination

AIM To increase evidence-based pain prevention strategy use during routine vaccinations in a pediatric primary care clinic using quality improvement methodology.METHODS Specific intervention strategies(i.e.,comfort positioning,nonnutritive sucking and sucrose analgesia,distraction) were identified,selected and introduced in three waves,using a Plan-Do-Study-Act framework.System-wide change was measured from baseline to post-intervention by:(1) percent of vaccination visits during which an evidence-based pain prevention strategy was reported as being used; and(2) caregiver satisfaction ratings following the visit.Additionally,self-reported staff and caregiver attitudes and beliefs about pain prevention were measured at baseline and 1-year post-intervention to assess for possible long-term cultural shifts.RESULTS Significant improvements were noted post-intervention.Use of at least one pain prevention strategy was documented at 99% of patient visits and 94% of caregivers were satisfied or very satisfied with the pain prevention care received.Parents/caregivers reported greater satisfaction with the specific pain prevention strategy used [t(143) = 2.50,P ≤ 0.05],as well as greater agreement that the pain prevention strategies used helped their children's pain [t(180) = 2.17,P ≤ 0.05] and that they would be willing to use the same strategy again in the future [t(179) = 3.26,P ≤ 0.001] as compared to baseline.Staff and caregivers also demonstrated a shift in attitudes from baseline to 1-year post-intervention.Specifically,staff reported greater agreement that the pain felt from vaccinations can result in harmful effects [2.47 vs 3.10; t(70) =-2.11,P ≤ 0.05],less agreement that pain from vaccinations is "just part of the process" [3.94 vs 3.23; t(70) = 2.61,P ≤ 0.05],and less agreement that parents expect their children to experience pain during vaccinations [4.81 vs 4.38; t(69) = 2.24,P ≤ 0.05].Parents/caregivers reported more favorable attitudes about pain prevention strategies for vaccinations across a variety of areas,including safety,cost,time,and effectiveness,as well as less concern about the pain their children experience with vaccination [4.08 vs 3.26; t(557) = 6.38,P ≤ 0.001],less need for additional pain prevention strategies [3.33 vs 2.81; t(476) = 4.51,P ≤ 0.001],and greater agreement that their doctors' office currently offers pain prevention for vaccinations [3.40 vs 3.75; t(433) =-2.39,P ≤ 0.05].CONCLUSION Quality improvement methodology can be used to help close the gap in implementing pain prevention strategies during routine vaccination procedures for children.

Interventional pain therapy in cervical post-surgery syndrome

Fifteen percent to forty percent of patients present with persistent disabling neck pain or radicular pain after cervical spine surgery. Persistent pain after cervical surgery is called cervical post-surgery syndrome(CPSS). This review investigates the literature about interventional pain therapy for these patients. Because different interventions with different anatomical targets exist, it is important to find the possible pain source. There has to be a distinction between radicular symptoms(radicular pain or radiculopathy) or axial pain(neck pain) and between persistent pain and a new onset of pain after surgery. In the case of radicular symptoms, inadequate decompression or nerve root adherence because of perineural scarring are possible pain causes. Multiple structures in the cervical spine are able to cause neck pain. Hereby, the type of surgery and also the number of segments treated is relevant. After fusion surgery, the so-called adjacent level syndrome is a possible pain source. After arthroplasty, the load of the facet joints in the index segment increases and can cause pain. Further, degenerative alterations progress. In general, two fundamentally different therapeutic approaches for interventional pain therapy for the cervical spine exist: Treatment of facet joint pain with radiofrequency denervation or facet nerve blocks, and epidural injections either via a transforaminal or via an interlaminar approach. The literature about interventions in CPSS is limited to single studies with a small number of patients. However, some evidence exists for these procedures. Interventional pain therapies are eligible as a target-specific therapy option. However, the risk of theses procedures(especially transforaminal epidural injections) must be weighed against the benefit.

Enhancing postoperative pain control by surgically-initiated rectus sheath block in abdominal aortic aneurysm open repair: A case report

BACKGROUND Abdominal aortic aneurysm(AAA)repair often involves significant postoperative pain,traditionally managed with systemic opioids,which can cause undesirable side effects.This case report explores the novel use of a surgically-initiated rectus sheath block with a catheter-over-needle assembly for pain management in AAA repair.CASE SUMMARY A 67-year-old female with hypertension and previous aortic dissection underwent elective open repair of an infrarenal AAA,which had grown from 3.4 cm to 4.3 cm over 14 months.A rectus sheath block was initiated surgically for postoperative pain control.The patient reported low pain scores and did not require systemic intravenous opioids,enabling early ambulation and discharge on postoperative day seven without complications.By preventing complications of systemic opi-oids,the method indicating a promising direction for postoperative pain management in major vascular surgeries.CONCLUSION Surgically-initiated rectus sheath block as a valuable tool for managing postoperative pain in AAA repair.

The hypothalamic-spinal dopaminergic system:a target for pain modulation

Nociceptive signals conveyed to the dorsal horn of the spinal cord by primary nociceptors are subject to extensive modulation by local neurons and by supraspinal descending pathways to the spinal cord before being relayed to higher brain centers. Descending modulatory pathways to the spinal cord comprise,among others, noradrenergic, serotonergic, γ-aminobutyric acid(GABA)ergic, and dopaminergic fibers.The contributions of noradrenaline, serotonin, and GABA to pain modulation have been extensively investigated. In contrast, the contributions of dopamine to pain modulation remain poorly understood.The focus of this review is to summarize the current knowledge of the contributions of dopamine to pain modulation. Hypothalamic A11 dopaminergic neurons project to all levels of the spinal cord and provide the main source of spinal dopamine. Dopamine receptors are expressed in primary nociceptors as well as in spinal neurons located in different laminae in the dorsal horn of the spinal cord, suggesting that dopamine can modulate pain signals by acting at both presynaptic and postsynaptic targets. Here, I will review the literature on the effects of dopamine and dopamine receptor agonists/antagonists on the excitability of primary nociceptors, the effects of dopamine on the synaptic transmission between primary nociceptors and dorsal horn neurons, and the effects of dopamine on pain in rodents. Published data support both anti-nociceptive effects of dopamine mediated by D2-like receptors and pro-nociceptive effects mediated by D1-like receptors.

Estrogen affects neuropathic pain through upregulating N-methyl-D-aspartate acid receptor 1 expression in the dorsal root ganglion of rats

Estrogen affects the generation and transmission of neuropathic pain,but the specific regulatory mechanism is still unclear.Activation of the N-methyl-D-aspartate acid receptor 1（NMDAR1） plays an important role in the production and maintenance of hyperalgesia and allodynia.The present study was conducted to determine whether a relationship exists between estrogen and NMDAR1 in peripheral nerve pain.A chronic sciatic nerve constriction injury model of chronic neuropathic pain was established in rats.These rats were then subcutaneously injected with 17β-estradiol,the NMDAR1 antagonist D（-）-2-amino-5-phosphonopentanoic acid（AP-5）,or both once daily for 15 days.Compared with injured drug na？ve rats,rats with chronic sciatic nerve injury that were administered estradiol showed a lower paw withdrawal mechanical threshold and a shorter paw withdrawal thermal latency,indicating increased sensitivity to mechanical and thermal pain.Estrogen administration was also associated with increased expression of NMDAR1 immunoreactivity（as assessed by immunohistochemistry） and protein（as determined by western blot assay） in spinal dorsal root ganglia.This 17β-estradiol-induced increase in NMDAR1 expression was blocked by co-administration with AP-5,whereas AP-5 alone did not affect NMDAR1 expression.These results suggest that 17β-estradiol administration significantly reduced mechanical and thermal pain thresholds in rats with chronic constriction of the sciatic nerve,and that the mechanism for this increased sensitivity may be related to the upregulation of NMDAR1 expression in dorsal root ganglia.

Identifying pain-related concerns in routine follow-up clinics following oral and oropharyngeal cancer

AIM:To describe clinical characteristics of head and neck cancer(HNC)patients with pain and those wishing to discuss pain concerns during consultation.METHODS:Cross-sectional,questionnaire study using University of Washington Quality of Life,version 4(UWQOL)and the Patients Concerns Inventory(PCI)in disease-free,post-treatment HNC cohort.Significant pain on UW-QOL and indicating"Pain in head and neck"and"Pain elsewhere"on PCI.RESULTS:One hundred and seventy-seven patientscompleted UW-QOL and PCI.The prevalence of selfreported pain issues was 38%(67/177)comprising25%(44/177)with significant problems despite medications and 13%(23/177)with lesser or no problems but wishing to discuss pain.Patients aged under 65years and patients having treatment involving radiotherapy were more likely to have pain issues.Just over half,55%(24/44)of patients with significant pain did not express a need to discuss this.Those with significant pain or others wanting to discuss pain in clinic had greater problems in physical and social-emotional functioning,reported suboptimal QOL,and also had more additional PCI items to discuss in clinic compared to those without significant pain and not wishing to discuss pain.CONCLUSION:Significant HNC-related pain is prevalent in the disease-free,posttreatment cohort.Onward referral to a specialist pain team may be beneficial.The UW-QOL and PCI package is a valuable tool that may routinely screen for significant pain in outpatient clinics.

Regional anesthesia for acute pain management in elderly patients

Normal aging is a process that involves loss of functional reserve of most organ systems of the human body, most significantly: cardiovascular, pulmonary, renal and nervous systems. Advancements in both surgery and anesthesia have made it possible to operate more safely on the elderly population and those older patients with multiple severe co-morbidities that were not routinely possible in the recent past. Regional anesthesiologist have proven to be instrumental in this regard as regional anesthetic/analgesic techniques may now permit surgeons to operate on the elderly who were not ideal surgical candidates or unable to tolerate general anesthesia. In addition, regional techniques provide alternatives that may optimize acute pain control and reduce the incidence of devastating side effects during the perioperative period such as: myocardial infarction, pulmonary embolism, pneumonia, and also increases the opportunity to allow for early ambulation and shorter hospital stays. These anesthetic options now provide the elderly patient with better medical care alternatives, but also can show a significant financial impact on health care system resources. Further understanding on aging molecular biology, physiology and pathophysiology, together with technical improvements of regional anesthetic techniques will continue to make it safer and more efficacious to operate on the elderly population with evidence of reduced morbidity and mortality. Although there is only anecdotal evidence that regional anesthesia(RA) improves survival, there is little doubt that RA plays an important role in perioperative optimization of pain control and decreases pain management complications as well as a reduction in healthcare costs. Beyond traditional operating rooms, elderly patients may increasingly benefit from RA and acute pain management in Emergency Rooms, medical clinics and even within a patient's home. Therefore, the focus of this review is directed toward geriatric patients and beneficial effects of RA on outcomes in the elderly.

Comparison of perceived pain and patients’ satisfaction with traditional local anesthesia and single tooth anesthesia: A randomized clinical trial

BACKGROUND Contemporary innovations in the area of local anesthesia have attempted to provide an absolutely pain free experience for patients.Since the introduction of Computer-Controlled Local Anesthetic Delivery Systems to dentistry,many studies have compared its efficacy and safety to conventional anesthesia.However,very few studies have compared single tooth anesthesia(STA)and traditional local anesthesia.AIM To compare pain rating,changes in blood pressure,and heart rate during the local anesthetic injection.The secondary objectives were to measure the patients’level of satisfaction and the differences in anesthetic efficiency between the STA system and traditional local infiltration.METHODS A randomized controlled trial was conducted and a total of 80 patients with dental restorative needs were enrolled for the study.The patients were evaluated for their general physical status and oral clinical findings before enrollment.Information regarding perceived pain,changes in heart rate and blood pressure,and patients’satisfaction was collected using an electronic data form and was analyzed using paired and unpaired t-tests.RESULTS No significant difference was noted in perceived pain(P=0.59)and systolic blood pressure(P=0.09)during anesthetic injection using both traditional and STA techniques.STA patients had a significantly higher heart rate during anesthesia,although a statistically significant difference was noted among the traditional anesthesia and the STA groups even before anesthesia.During the restorative procedure,less pain was perceived by STA patients on the Wong-Baker FACES pain scale,which was statistically significant(P<0.001).Analyses of post-procedure patient responses showed that STA patients had a significantly better treatment experience and preferred to have the same method of injection in the future(P=0.04).CONCLUSION STA system can provide less painful and more comfortable restorative treatment procedures in comparison to the traditional infiltration technique.

Management of lumbar zygapophysial (facet) joint pain

AIM: To investigate the diagnostic validity and therapeutic value of lumbar facet joint interventions in managing chronic low back pain.METHODS: The review process applied systematic evidence-based assessment methodology of controlled trials of diagnostic validity and randomized controlled trials of therapeutic efficacy. Inclusion criteria encompassed all facet joint interventions performed in a controlled fashion. The pain relief of greater than 50% was the outcome measure for diagnostic accuracy assessment of the controlled studies with ability to perform previously painful movements, whereas, for randomized controlled therapeutic efficacy studies, the primary outcome was significant pain relief and the secondary outcome was a positive change in functional status. For the inclusion of the diagnostic controlled studies, all studies must have utilized either placebo controlled facet joint blocks or comparative local anesthetic blocks. In assessing therapeutic interventions, short-term and long-term reliefs were defined as either up to 6 mo or greater than 6 mo of relief. The literature search was extensive utilizing various types of electronic search media including Pub Med from 1966 onwards, Cochrane library, National Guideline Clearinghouse, clinicaltrials.gov, along with other sources includingprevious systematic reviews, non-indexed journals, and abstracts until March 2015. Each manuscript included in the assessment was assessed for methodologic quality or risk of bias assessment utilizing the Quality Appraisal of Reliability Studies checklist for diagnostic interventions, and Cochrane review criteria and the Interventional Pain Management Techniques- Quality Appraisal of Reliability and Risk of Bias Assessment tool for therapeutic interventions. Evidence based on the review of the systematic assessment of controlled studies was graded utilizing a modified schema of qualitative evidence with best evidence synthesis, variable from level Ⅰ to level Ⅴ.RESULTS: Across all databases, 16 high quality diagnostic accuracy studies were identified. In addition, multiple studies assessed the influence of multiple factors on diagnostic validity. In contrast to diagnostic validity studies, therapeutic efficacy trials were limited to a total of 14 randomized controlled trials, assessing the efficacy of intraarticular injections, facet or zygapophysial joint nerve blocks, and radiofrequency neurotomy of the innervation of the facet joints. The evidence for the diagnostic validity of lumbar facet joint nerve blocks with at least 75% pain relief with ability to perform previously painful movements was level Ⅰ, based on a range of level Ⅰ to Ⅴ derived from a best evidence synthesis. For therapeutic interventions, the evidence was variable from level Ⅱ to Ⅲ, with level Ⅱ evidence for lumbar facet joint nerve blocks and radiofrequency neurotomy for long-term improvement(greater than 6 mo), and level Ⅲ evidence for lumbosacral zygapophysial joint injections for short-term improvement only.CONCLUSION: This review provides significant evidence for the diagnostic validity of facet joint nerve blocks, and moderate evidence for therapeutic radiofrequency neurotomy and therapeutic facet joint nerve blocks in managing chronic low back pain.

Therapeutic effect of neurogrowth factor in the treatment of gingival pain and swelling in patients with dental pulp necrosis after root canal therapy

Objective: To explore the clinical efficacy of neurogrowth factor in the treatment of gingival pain and swelling in patients with dental pulp necrosis after root canal therapy and the effect on the serum inflammatory cytokines. Methods: A total of 156 patients with gingival pain and swelling after root canal therapy due to dental pulp necrosis were included in the study and randomized into the control group (n=78) and teh treatment group (n=78). The patients in the control group were given metronidazole tablets. On the above basis, the patients in the treatment group were given local injection of neurogrowth factors. 10-day treatment was regarded as one course, and the patients were continuously treated for 2 courses. The improvement of clinical symptoms before and after treatment in the two groups was evaluated. Gingival sulcus index and serum inflammatory cytokines before and after treatment in the two groups were detected and compared. Results: When compared with before treatment, the periodontal soft tissue swelling, tooth mobility, and periapical pain scores after treatment in the two groups were significantly reduced, and those in the treatment group were significantly lower than those in the control group. When compared with before treatment, the gingival sulcus bleeding index 1 and 2 courses after treatment in the two groups was significantly reduced, and that 2 courses after treatment was significantly lower than that after 1 course treatment. The gingival sulcus bleeding index 1 and 2 courses after treatment in the treatment group was significantly lower than that in the control group. When compared with before treatment, the serum IL-8 and IL-6 levels after treatment in the two groups, and TNF-α level after treatment in the treatment group were significantly reduced, and the above indicators in the treatment group were significantly lower than those in the control group. Conclusions: The neurogrowth factors in the treatment of gingival pain and swelling in patients with dental pulp necrosis after root canal therapy can effectively improve the clinical symptoms, and inhibit the inflammatory reaction, with a significant efficacy.

Muscovite nanoparticles mitigate neuropathic pain by modulating the inflammatory response and neuroglial activation in the spinal cord

Despite numerous efforts to overcome neuropathic pain,various pharmacological drugs often fail to meet the needs and have many side effects.Muscovite is an aluminosilicate mineral that has been reported to have an anti-inflammatory effect,but the efficacy of muscovite for neuropathic pain has not been investigated.Here,we assessed whether muscovite nanoparticles can reduce the symptoms of pain by controlling the inflammatory process observed in neuropathic pain.The analgesic effects of muscovite nanoparticles were explored using partial sciatic nerve ligation model of neuropathic pain,in which one-third to onehalf of the nerve trifurcation of the sciatic nerve was tightly tied to the dorsal side.Muscovite nanoparticles(4 mg/100μL)was given intramuscularly to evaluate its effects on neuropathic pain(3 days per week for 4 weeks).The results showed that the muscovite nanoparticle injections significantly alleviated partial sciatic nerve ligation-induced mechanical and cold allodynia.In the spinal cord,the muscovite nanoparticle injections exhibited inhibitory effects on astrocyte and microglia activation and reduced the expression of pro-inflammatory cytokines,such as interleukin-1β,tumor necrosis factor-α,interleiukin-6 and monocyte chemoattractant protein-1,which were upregulated in the partial sciatic nerve ligation model.Moreover,the muscovite nanoparticle injections resulted in a decrease in activating transcription factor 3,a neuronal injury marker,in the sciatic nerve.These results suggest that the analgesic effects of muscovite nanoparticle on partial sciatic nerve ligation-induced neuropathic pain may result from inhibiting activation of astrocytes and microglia as well as pro-inflammatory cytokines.We propose that muscovite nanoparticle is a potential anti-nociceptive candidate for neuropathic pain.All experimental protocols in this study were approved by the Institutional Animal Ethics Committee(IACUC)at Dongguk University,South Korea(approval No.2017-022-1)on September 28,2017.

Protein arginine methyltransferase-6 regulates heterogeneous nuclear ribonucleoprotein-F expression and is a potential target for the treatment of neuropathic pain

Protein arginine methyltransferase-6 participates in a range of biological functions,particularly RNA processing,transcription,chromatin remodeling,and endosomal trafficking.However,it remains unclear whether protein arginine methyl transferase-6 modifies neuropathic pain and,if so,what the mechanisms of this effect.In this study,protein arginine methyltransferase-6 expression levels and its effect on neuropathic pain were investigated in the spared nerve injury model,chronic constriction injury model and bone cancer pain model,using immunohistochemistry,western blotting,immunoprecipitation,and label-free proteomic analysis.The results showed that protein arginine methyltransferase-6 mostly co-localized withβ-tubulinⅢin the dorsal root ganglion,and that its expression decreased following spared nerve injury,chronic constriction injury and bone cancer pain.In addition,PRMT6 knockout(Prmt6~(-/-))mice exhibited pain hypersensitivity.Furthermore,the development of spared nerve injury-induced hypersensitivity to mechanical pain was attenuated by blocking the decrease in protein arginine methyltransferase-6 expression.Moreover,when protein arginine methyltransferase-6 expression was downregulated in the dorsal root ganglion in mice without spared nerve injury,increased levels of phosphorylated extracellular signal-regulated kinases were observed in the ipsilateral dorsal horn,and the response to mechanical stimuli was enhanced.Mechanistically,protein arginine methyltransferase-6 appeared to contribute to spared nerve injury-induced neuropathic pain by regulating the expression of heterogeneous nuclear ribonucleoprotein-F.Additionally,protein arginine methyltransfe rase-6-mediated modulation of hete rogeneous nuclear ribonucleoprotein-F expression required amino atids 319 to 388,but not classical H3R2 methylation.These findings indicated that protein arginine methyltransferase-6 is a potential therapeutic target fo r the treatment of peripheral neuro pathic pain.

Effect of esketamine on reducing postpartum pain and depression

In this editorial,we comment on a recent article by Chen et al,that addressed the effect of intraoperative injection of esketamine on postoperative analgesia and postoperative rehabilitation after cesarean section.Poor management of postcesarean pain is associated with decreased maternal care for the baby,longer hospitalization,and higher risk of developing postpartum depression.Esketamine is a more potent S-enantiomer of ketamine which has shown promising analgesic and antidepressant properties for managing post-cesarean pain and depression in clinical studies.However,due to its potential adverse effects on the neurological and hemodynamic status of patients,it is recommended that its usage in low doses should be limited to cesarean candidates experiencing unbearable pain.Before any recommendation for routine perioperative use of esketamine,more standardized clinical trials are needed to strengthen our existing knowledge of its effectiveness in reducing postpartum pain and depression.