Electrochemical evidence of nitrate release from the nitrooxy compound 4-((nitrooxy) methyl)-3-nitrobenzoic acid and its antinociceptive and anti-inflammatory activities in mice.

Considering the many biological activities of nitric oxide (NO), some lines of research focused on the modulation of these activities through the provision of this mediator by designing and synthesizing compounds coupled with an NO donor group. Thus, the objectives of the present study were to carry out an electrochemical investigation of the nitrooxy compound 4-((nitrooxy) methyl)-3-nitrobenzoic acid (1) and evaluate its activities and putative mechanisms in experimental models of pain and inflammation. Voltammetric studies performed in aprotic medium (mimetic of membranes) showed important electrochemical reduction mechanisms: nitroaromatic reduction, self-protonation, and finally reductive elimination, which leads to nitrate release. Systemic administration of the nitrooxy compound (1) inhibited the nociceptive response induced by heat and the tactile hypersensitivity and paw edema induced by carrageenan in mice. The activities in the models of inflammatory pain and edema were associated with reduced neutrophil recruitment and production of inflammatory cytokines, such as interleukin (IL)-1ß, IL-6, tumor necrosis factor-α and CXCL-1, and increased production of IL-10. Concluding, electrochemical analysis revealed unequivocally that electron transfer at the nitro group of the nitrooxy compound (1) results in the cleavage of the organic nitrate, potentially resulting in the generation of NO. This electrochemical mechanism may be compared to a biochemical electron-transfer mediated nitrate release that, by appropriate in vivo bioreduction (enzymatic or not) would lead to NO production. Compound (1) exhibits activities in models of inflammatory pain and edema that may be due to reduced recruitment of neutrophils and production of inflammatory cytokines and increased production of IL-10. These results reinforce the interest in the investigation of NO donor compounds as candidates for analgesic and anti-inflammatory drugs.

Antinociceptive activity of Schinus terebinthifolia leaf lectin (SteLL) in sarcoma 180-bearing mice.

ETHNOPHARMACOLOGY RELEVANCE: Schinus terebinthifolia Raddi leaves have been used in folk medicine due to several properties, including antitumor and analgesic effects. The variable efficacy and adverse effects of analgesic drugs have motivated the search for novel antinociceptive agents. It has been reported that the S. terebinthifolia leaf lectin (SteLL) has antitumor activity against sarcoma 180 in mice. AIM OF THE STUDY: This work aimed to evaluate whether SteLL would reduce cancer pain using an orthotopic tumor model. MATERIALS AND METHODS: A sarcoma 180 cell suspension was inoculated into the right hind paws of mice, and the treatments (150 mM NaCl, negative control; 10 mg/kg morphine, positive control; or SteLL at 1 and 2 mg/kg) were administered intraperitoneally 24 h after cell inoculation up to 14 days. Spontaneous nociception, mechanical hyperalgesia, and hot-plate tests were performed. Further, the volume and weight of the tumor-bearing paws were measured. RESULTS: SteLL (2 mg/kg) improved limb use during ambulation. The lectin (1 and 2 mg/kg) also inhibited mechanical hyperalgesia and increased the latency time during the hot-plate test. Naloxone was found to reverse this effect, indicating the involvement of opioid receptors. The tumor-bearing paws of mice treated with SteLL exhibited lower volume and weight. CONCLUSION: SteLL reduced hyperalgesia due to sarcoma 180 in the paws of mice, and this effect can be related to its antitumor action.

Postoperative pain pathophysiology and treatment strategies after CRS + HIPEC for peritoneal cancer.

BACKGROUND: Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is a treatment choice for peritoneal cancer. However, patients commonly suffer from severe postoperative pain. The pathophysiology of postoperative pain is considered to be from both nociceptive and neuropathic origins. MAIN BODY: The recent advances on the etiology of postoperative pain after CRS + HIPEC treatment were described, and the treatment strategy and outcomes were summarized. CONCLUSION: Conventional analgesics could provide short-term symptomatic relief. Thoracic epidural analgesia combined with opioids administration could be an effective treatment choice. In addition, a transversus abdominis plane block could also be an alternative option, although further studies should be performed.

Efficacy of multimodal analgesic treatment of severe traumatic acute pain in mice pretreated with chronic high dose of buprenorphine inducing mechanical allodynia.

Managing severe acute nociceptive pain in buprenorphine-maintained individuals for opioid use disorder management is challenging owing to the high affinity and very slow dissociation of buprenorphine from µ-opioid receptors that hinders the use of full agonist opioid analgesics. In a translational approach, the aim of this study was to use an animal setting to investigate the effects of a chronic high dose of buprenorphine treatment on nociceptive thresholds before and after applying a severe acute nociceptive traumatic surgery stimulus and to screen postoperative pharmacological analgesic strategies. A chronic treatment of mice with a high dose of buprenorphine (BUP HD, 2 × 200 µg/kg/day; i.p.) revealed significant mechanical allodynia. One and two days after having discontinued buprenorphine administration and having induced a severe nociceptive acute pain by a closed tibial fracture, acute administration of morphine at a dose which has analgesic effects in absence of pretreatment (4.5 mg/kg; i.p.), was ineffective to reduce pain in the BUP HD group. However, mimicking multimodal analgesia strategy used in human postoperative context, the combination of morphine (administered at the same dose) with a NMDA receptor antagonist (ketamine) or an NSAID (ketoprofen) produced antinociceptive responses in these animals. The mouse model of closed tibial fracture could be useful to identify analgesic strategies of postoperative pain for patients with chronic exposure to opioids and suffering from hyperalgesia.

Chronic Pain in Breast Cancer Survivors: Nociceptive, Neuropathic, or Central Sensitization Pain?

INTRODUCTION: The differentiation between acute and chronic pain can be insufficient for appropriate pain management. The aim of this study was to evaluate the prevalence of the predominant pain type (nociceptive, neuropathic, or central sensitization [CS] pain) in breast cancer survivors (BCS) with chronic pain. The secondary aims were to examine (1) differences in health-related quality of life (HRQoL) between the different pain groups; and (2) the associations between patient-, disease-, and treatment-related factors and the different pain types. METHODS: To determine the prevalence of the predominant type of pain, a recently proposed classification system was used. BCS were asked to complete the VAS for pain, Douleur Neuropathique 4 Questionnaire, Margolis Pain Diagram, Central Sensitization Inventory, and Short Form 36 (SF-36). RESULTS: Ninety-one BCS participated, among whom 25.3% presented neuropathic pain, 18.7% nociceptive pain, and 15.4% CS pain. Mixed pain was found in 40.6%. A significant intergroup difference in HRQoL was found for SF-36 "general health" (P = 0.04). The odds for the presence of CS rather than nociceptive pain are 26 times higher in patients exposed to hormone therapy in comparison to the nonexposed (odds ratio 25.95, 95% confidence interval 1.33 to 504.37, P = 0.03). CONCLUSION: Neuropathic pain is most frequent in BCS. Strong associations were found between CS pain and hormone therapy.

Rapamycin alleviates proinflammatory cytokines and nociceptive behavior induced by chemotherapeutic paclitaxel.

Background/Aims: Paclitaxel is largely used as a chemotherapeutic agent for the treatment of several types of cancers. However, one of the significant limiting complications of paclitaxel is painful peripheral neuropathy during its therapy. The purposes of this study were to examine (1) the effects of blocking mammalian target of rapamycin (mTOR) on mechanical and thermal hypersensitivity evoked by paclitaxel; and (2) the underlying mechanisms responsible for the role of mTOR in regulating paclitaxel-induced neuropathic pain. Methods: Behavioral test was performed to determine mechanical and thermal sensitivity in rats. ELISA was used to examine the levels of proinflammatory cytokines (PICs including IL-1ß, IL-6, and TNF-α) and substance P and calcitonin gene-related peptide (CGRP) in the dorsal root ganglion (DGR); and Western blot analysis was used to examine expression of mTOR signal pathway. Results: Paclitaxel increased mechanical and thermal sensitivity as compared with vehicle control animals (P < 0.05 vs. controls). Paclitaxel also amplified the expression of p-mTOR, mTOR-mediated phosphorylation of p70 ribosomal S6 protein kinase 1 (p-S6K1), 4E-binding protein 1 (p-4E-BP1) in the DRG. Blocking mTOR using rapamycin attenuated peripheral painful neuropathy observed in paclitaxel rats (P < 0.05 vs. without rapamycin). This inhibitory effect was accompanied with decreases of IL-1ß, IL-6, and TNF-α as well as substance P and CGRP. In addition, inhibition of phosphatidylinositide 3-kinase (p-PI3K) attenuated expression of p-mTOR and PICs/substance P/CGRP in paclitaxel rats and this further attenuated mechanical and thermal hypersensitivity. Conclusions: The data revealed specific signaling pathways leading to paclitaxel-induced peripheral neuropathic pain, including the activation of PI3K-mTOR, PIC signal, and substance P and CGRP. Inhibition of these pathways alleviates neuropathic pain. Targeting one or more of these molecular mediators may present new opportunities for treatment and management of neuropathic pain observed during chemotherapeutic application of paclitaxel.

Opioid responsiveness of nociceptive versus mixed pain in clinical cancer patients.

OBJECTIVE: To investigate whether clinical cancer patients with mixed nociceptive-neuropathic pain are less responsive to opioids than patients with nociceptive pain. BACKGROUND: Pain is common in advanced cancer patients. Pain driven by neuropathic mechanisms is considered to be resistant to opioids. This hypothesis is mainly based on animal studies and single-dose opioid studies in humans but has not been confirmed in clinical practice. METHODS: Data were prospectively collected from 240 clinical cancer pain patients using opioids. Multiple linear regression was used for assessing the associations between the logarithm of the morphine equivalent dose (MED) at three days after admission (T = 3d) relative to admission (T = 0d) (logRMED) and type of pain (nociceptive versus mixed pain), corrected for gender, age, primary cancer site and use of non-opioid and adjuvant analgesics. As secondary outcome measures, associations between logMED and logPFent (fentanyl plasma level) at T = 3d and type of pain were assessed. RESULTS: Pain intensity between T = 0d and T = 3d was significantly and evenly reduced in patients with nociceptive pain (n = 173) and mixed pain (n = 67). Median (interquartile range) MED was 20 (10-52) and 20 (20-80) mg (T = 0d), 40 (10-67) and 40 (20-100) mg (T = 3d), median PFent (T = 3d) was 1.59 (0.58-3.19) and 1.38 (0.54-4.39) ng/ml, none of them significantly different, in patients with nociceptive and mixed pain, respectively. Neither logRMED, logMED (T = 3d), or logPFent (T = 3d) was significantly associated with type of pain, after correction for confounding factors. CONCLUSIONS: We conclude that, at least in clinical cancer patients, mixed pain is as responsive to opioids as nociceptive pain.

Methadone versus Fentanyl in Patients with Radiation-Induced Nociceptive Pain with Head and Neck Cancer: A Randomized Controlled Noninferiority Trial.

BACKGROUND: Pain is still a burden for many patients with cancer. A recent trial showed the superiority of methadone over fentanyl in neuropathic pain, and we expect that this finding could influence the number of patients treated with methadone. METHODS: We performed a randomized controlled noninferiority trial in patients with nociceptive pain. Eighty-two strong-opioid-naïve patients with head and neck cancer with substantial pain (pain numeric rating scale [NRS] score ≥ 4) due to radiation therapy were included. Forty-two patients were treated with methadone, and 40 with fentanyl. Patients were evaluated at 1, 3, and 5 weeks. The primary outcomes were reduction in average pain and clinical success (50% pain decrease). We set the predefined noninferiority margin at 1 on the NRS and 10% clinical success. Secondary outcomes were pain interference, global perceived effect (GPE), side effects, and opioid escalation index. RESULTS: Noninferiority was shown for decrease in NRS for maximum and mean pain scores at 1 and 3 weeks. Noninferiority was shown for clinical success at 1 week only. The opioid escalation index was lower in the methadone group at 3 and 5 weeks as compared to fentanyl (1.44 vs. 1.99, P = 0.004; and 1.50 vs. 2.32, P = 0.013). The pain interference in the methadone group was significantly decreased at 3 weeks only. GPE and side effects were not different. CONCLUSION: This is the first study to show noninferiority of methadone compared to fentanyl at 1 and 3 weeks in the treatment of radiation-induced nociceptive pain in patients with head and neck cancer.

Short stem total hip arthroplasty: Potential explanations for persistent post-surgical thigh pain.

Short stem uncemented femoral implants were developed with the aim of preserving proximal bone stock for future revisions, improving biomechanical reconstruction, aiding insertion through smaller incisions and potentially decreasing or limiting the incidence of thigh pain. Despite all the advantages of short stem designs, it remains unclear whether they are able to limit post-surgical thigh pain. In patients with short stem hip arthroplasty and persistent thigh pain, it is of the utmost importance to understand the potential etiologies of this chronic pain for selecting the appropriate treatment strategy. Therefore, this manuscript explores the hypothetical etiologies of persistent thigh pain in short stem total hip arthroplasty, including both peripheral factors (structural or biomechanical causes) and central factors (involvement of the central nervous system). First, intrinsic causes (e.g. aseptic femoral loosening and prosthetic joint infection) and extrinsic sources (e.g. muscle pathology or spinal pathology) of persistent thigh pain related to hip arthroplasty are explained. In addition, other specific peripheral causes for thigh pain related to the short stem prosthetic reconstruction (e.g. stem malalignment and micro-motion) are unraveled. Second, the etiology of persistent thigh pain after short stem hip arthroplasty is interpreted in a broader concept than the biomechanical approach where peripheral structural injury is believed to be the sole driver of persistent thigh pain. Over the past decades evidence has emerged of the involvement of sensitization of central nervous system nociceptive pathways (i.e. central sensitization) in several chronic pain disorders. In this manuscript it is explained that there might be a relevant role for altered central nociceptive processing in patients with persistent pain after joint arthroplasty or revision surgery. Recognition of a potential role for centrally-mediated changes in pain processing in total hip replacement surgery has important implications for treatment. Comprehensive treatment addressing peripheral factors as well as neurophysiological changes occurring in the nervous system may help to improve outcomes in patients with short stem hip arthroplasty and chronic thigh pain. Working within a biopsychosocial approach in orthopaedic surgery, specifically in relation to total hip arthroplasty, could be very important and may lead to more satisfaction. Further research is warranted.

The MNK-eIF4E Signaling Axis Contributes to Injury-Induced Nociceptive Plasticity and the Development of Chronic Pain.

Injury-induced sensitization of nociceptors contributes to pain states and the development of chronic pain. Inhibiting activity-dependent mRNA translation through mechanistic target of rapamycin and mitogen-activated protein kinase (MAPK) pathways blocks the development of nociceptor sensitization. These pathways convergently signal to the eukaryotic translation initiation factor (eIF) 4F complex to regulate the sensitization of nociceptors, but the details of this process are ill defined. Here we investigated the hypothesis that phosphorylation of the 5' cap-binding protein eIF4E by its specific kinase MAPK interacting kinases (MNKs) 1/2 is a key factor in nociceptor sensitization and the development of chronic pain. Phosphorylation of ser209 on eIF4E regulates the translation of a subset of mRNAs. We show that pronociceptive and inflammatory factors, such as nerve growth factor (NGF), interleukin-6 (IL-6), and carrageenan, produce decreased mechanical and thermal hypersensitivity, decreased affective pain behaviors, and strongly reduced hyperalgesic priming in mice lacking eIF4E phosphorylation (eIF4ES209A ). Tests were done in both sexes, and no sex differences were found. Moreover, in patch-clamp electrophysiology and Ca2+ imaging experiments on dorsal root ganglion neurons, NGF- and IL-6-induced increases in excitability were attenuated in neurons from eIF4ES209A mice. These effects were recapitulated in Mnk1/2-/- mice and with the MNK1/2 inhibitor cercosporamide. We also find that cold hypersensitivity induced by peripheral nerve injury is reduced in eIF4ES209A and Mnk1/2-/- mice and following cercosporamide treatment. Our findings demonstrate that the MNK1/2-eIF4E signaling axis is an important contributing factor to mechanisms of nociceptor plasticity and the development of chronic pain.SIGNIFICANCE STATEMENT Chronic pain is a debilitating disease affecting approximately one in three Americans. Chronic pain is thought to be driven by changes in the excitability of peripheral nociceptive neurons, but the precise mechanisms controlling these changes are not elucidated. Emerging evidence demonstrates that mRNA translation regulation pathways are key factors in changes in nociceptor excitability. Our work demonstrates that a single phosphorylation site on the 5' cap-binding protein eIF4E is a critical mechanism for changes in nociceptor excitability that drive the development of chronic pain. We reveal a new mechanistic target for the development of a chronic pain state and propose that targeting the upstream kinase, MAPK interacting kinase 1/2, could be used as a therapeutic approach for chronic pain.

Chronic stress-induced mechanical hyperalgesia is controlled by capsaicin-sensitive neurones in the mouse.

BACKGROUND: Clinical studies demonstrated peripheral nociceptor deficit in stress-related chronic pain states, such as fibromyalgia. The interactions of stress and nociceptive systems have special relevance in chronic pain, but the underlying mechanisms including the role of specific nociceptor populations remain unknown. We investigated the role of capsaicin-sensitive neurones in chronic stress-related nociceptive changes. METHOD: Capsaicin-sensitive neurones were desensitized by the capsaicin analogue resiniferatoxin (RTX) in CD1 mice. The effects of desensitization on chronic restraint stress (CRS)-induced responses were analysed using behavioural tests, chronic neuronal activity assessment in the central nervous system with FosB immunohistochemistry and peripheral cytokine concentration measurements. RESULTS: Chronic restraint stress induced mechanical and cold hypersensitivity and increased light preference in the light-dark box test. Open-field and tail suspension test activities were not altered. Adrenal weight increased, whereas thymus and body weights decreased in response to CRS. FosB immunopositivity increased in the insular cortex, dorsomedial hypothalamic and dorsal raphe nuclei, but not in the spinal cord dorsal horn after the CRS. CRS did not affect the cytokine concentrations of hindpaw tissues. Surprisingly, RTX pretreatment augmented stress-induced mechanical hyperalgesia, abolished light preference and selectively decreased the CRS-induced neuronal activation in the insular cortex. RTX pretreatment alone increased the basal noxious heat threshold without influencing the CRS-evoked cold hyperalgesia and augmented neuronal activation in the somatosensory cortex and interleukin-1α and RANTES production. CONCLUSIONS: Chronic restraint stress induces hyperalgesia without major anxiety, depression-like behaviour or peripheral inflammatory changes. Increased stress-induced mechanical hypersensitivity in RTX-pretreated mice is presumably mediated by central mechanisms including cortical plastic changes. SIGNIFICANCE: These are the first data demonstrating the complex interactions between capsaicin-sensitive neurones and chronic stress and their impact on nociception. Capsaicin-sensitive neurones are protective against stress-induced mechanical hyperalgesia by influencing neuronal plasticity in the brain.

Current Status of Malignant Neuropathic Pain in Chinese Patients with Cancer: Report of a Hospital-based Investigation of Prevalence, Etiology, Assessment, and Treatment.

OBJECTIVES: This study investigated the prevalence, etiology, assessment, treatment of pain in patients with cancer as well as their quality of life (QOL). METHODS: Patients at the West China Hospital Cancer Center were invited to complete a questionnaire under the guidance of pain specialists. The questionnaire included general information, cancer pain status, its assessment, use of analgesics, and the effects of pain on QOL. RESULTS: In total, 1,050 patients were enrolled in the study. Of these, valid data were collected from 919 patients, among whom 454 (49.4%) suffered from pain, including 333 (36.2%) patients who had neuropathic pain symptoms. On average, the visual analog scale (VAS) score of patients with cancer pain was 3.30 ± 1.68. Significant differences in the VAS score and pain frequency between patients with nociceptive and neuropathic pain were observed (both P < 0.05). Dull pain ranked first (64, 52.9%) among the patients with nociceptive pain, whereas pins and needles pain (97, 64.7%) was the most common type of pain in patients with neuropathic pain. There was a significant difference in QOL between the nociceptive and neuropathic pain groups (P < 0.05). Only 183 of 454 patients with cancer pain used analgesics. Compared with the patients with pain not using any analgesics, those receiving analgesics had a significantly lower average pain relief rate (P = 0.027). Adjuvant analgesics were inadequately used (9.3%) in patients with neuropathic cancer pain. CONCLUSION: This study revealed the prevalence of neuropathic cancer pain in Chinese patients with cancer. Malignant neuropathic pain significantly impaired the patients' QOL. Insufficient assessment and inadequate analgesia still exist. These require more awareness and attention from both doctors and patients.

High prevalence of neuropathic pain in the hand of patients with traumatic brachial plexus injury: a cross-sectional study / Alta prevalência de dor neuropática em sujeitos com lesão traumática do plexo braquial: um estudo de corte transversal

ABSTRACT Objective To describe the pain profile of patients with traumatic brachial plexus injury. Methods We enrolled 65 patients with traumatic brachial plexus injury. The Douleur Neuropathique 4 questionnaire was used to classify pain and the SF-36 was used to evaluate quality of life. Results The patients with traumatic brachial plexus injury were predominantly young male victims of motorcycle accidents. Pain was present in 75.4% of the individuals and 79% presented with neuropathic pain, mostly located in the hands (30.41%). The use of auxiliary devices (p = 0.05) and marital status (p = 0.03) were both independent predictors of pain. Pain also impacted negatively on the quality of life (p = 0.001). Conclusions Pain is frequent in patients with traumatic brachial plexus injury. Despite the peripheral nervous system injury, nociceptive pain is not unusual. Pain evaluation, including validated instruments, is essential to guide optimal clinical management of patients with the condition.

RESUMO Objetivo Descrever o perfil de dor de sujeitos com lesão traumática do plexo braquial. Métodos Nós incluímos 65 indivíduos com lesão traumática do plexo braquial. O Douleur Neuropathique 4 foi usado para classificar a dor e o SF-36 foi usado para avaliar a qualidade de vida. Resultados Sujeitos com lesão traumática do plexo braquial eram em sua maioria homens jovens, vítimas de acidentes motociclísticos. A dor esteve presete em 75.4% dos indivíduos e 79% deles apresentaram dor neuropática, mais frequentemente localizada nas mãos (30.41%). O uso de dispositivos auxiliares (p = 0.05) e o estado civil foram, ambos, preditores independentes de dor. A dor ainda impactou negativamente da qualidade de vida (p = 0.001). Conclusões A dor é frequente em sujeitos com lesão traumática do plexo braquial. Apesar de envolver uma lesão do sistema nervoso a dor nociceptiva não é infrequente. A avaliação da dor, incluindo instrumentos validados, é essencial para direcionar as condutas clínicas de sujeitos com esta condição.

Persistent Postoperative Pain: Pathophysiology, Risk Factors, and Prevention.

OBJECTIVE: Persistent postoperative pain (PPOP) is the second most common reason for a patient to seek care at a chronic pain center. Many of the patients seen with prolapse or incontinence are at risk for developing PPOP as a result of the surgeries done for these problems. The pathophysiology of this disabling pain disorder is well understood, and the risk factors are easy to identify. Once identified, perioperative interventions can be offered to attempt to prevent PPOP. METHODS AND RESULTS: Evaluation of articles obtained using a MEDLINE search involving chronic pain and PPOP, including prevalence, pathophysiology, and prevention was reviewed. The concept of central censitization and the key role it plays in chronic pain disorders were also reviewed. A history of chronic pain (anywhere) as well as findings of levator myalgia, allodynia, and hypertonic pelvic floor disorders is critical in identifying patients at risk for PPOP. CONCLUSIONS: Identification of patients at risk allows the clinician to educate the patient about the risk of PPOP and the various perioperative interventions that can be used to prevent its development. Further studies will be required to determine how effective these interventions are in patients undergoing surgery for incontinence and/or pelvic organ prolapse.

Pain following cancer treatment: Guidelines for the clinical classification of predominant neuropathic, nociceptive and central sensitization pain.

BACKGROUND: In addition to fatigue, pain is the most frequent persistent symptom in cancer survivors. Clear guidelines for both the diagnosis and treatment of pain in cancer survivors are lacking. Classification of pain is important as it may facilitate more specific targeting of treatment. In this paper we present an overview of nociceptive, neuropathic and central sensitization pain following cancer treatment, as well as the rationale, criteria and process for stratifying pain classification. MATERIAL AND METHODS: Recently, a clinical method for classifying any pain as either predominant central sensitization pain, neuropathic or nociceptive pain was developed, based on a large body of research evidence and international expert opinion. We, a team of 15 authors from 13 different centers, four countries and two continents have applied this classification algorithm to the cancer survivor population. RESULTS: The classification of pain following cancer treatment entails two steps: (1) examining the presence of neuropathic pain; and (2) using an algorithm for differentiating predominant nociceptive and central sensitization pain. Step 1 builds on the established criteria for neuropathic pain diagnosis, while Step 2 applies a recently developed clinical method for classifying any pain as either predominant central sensitization pain, neuropathic or nociceptive pain to the cancer survivor population. CONCLUSION: The classification criteria allow identifying central sensitization pain following cancer treatment. The recognition of central sensitization pain in practice is an important development in the integration of pain neuroscience into the clinic, and one that is relevant for people undergoing and following cancer treatment.

Assessment of anti-inflammatory, antinociceptive, immunomodulatory, and antioxidant activities of Cajanus cajan L. seeds cultivated in Egypt and its phytochemical composition.

CONTEXT: Cajanus cajan L. (Fabaceae), a food crop, is widely used in traditional medicine. OBJECTIVES: The phytochemical composition of C. cajan seeds and evaluation of the anti-inflammatory, immunomodulatory, antinociceptive, and antioxidant activities were studied. MATERIALS AND METHODS: Unsaponifiable matter and fatty acids were analyzed by GC and GC/MS. The n-butanol fraction was chromatographed on polyamide column. The anti-inflammatory activity of hexane extract (200 and 400 mg/kg, p.o.) was evaluated using the carrageenan-induced rat paw edema at 1, 2, and 3 h. The serum tumor necrosis factor-α, interleukin-6, and immunoglobulin G levels were detected by ELISA. The hexane extract antinociceptive activity was determined by adopting the writhing test in mice. DPPH radical scavenging, total reduction capability, and inhibition of lipid peroxidation of butanol fraction were evaluated. RESULTS AND CONCLUSION: Twenty-one unsaponifiable compounds (mainly phytol, 2,6-di-(t-butyl)-4-hydroxy-4-methyl-2,5-cyclohexadiene-1-one, ß-sitosterol, stigmasterol, and campesterol), as well as 12 fatty acids (primarily 9,12-octadecadienoic and palmitic acids) were identified in hexane extract of C. cajan seeds. n-BuOH fraction contains quercetin-3-O-ß-d-glucopyranoside, orientin, vitexin, quercetin, luteolin, apigenin, and isorhamnetin. For the first time, quercetin-3-O-ß-d-glucopyranoside is isolated from C. cajan plant. The hexane extract (200 and 400 mg/kg) inhibited carrageenan-induced inflammation by 85 and 95%, respectively, 3 h post-carrageenan challenge. This was accompanied by an 11 and 20%, 8 and 13%, respectively, decrease of TNF-α and IL-6, as well as significant decrease in IgG serum levels. Moreover, hexane extract (200 and 400 mg/kg) decreased the number of writhings by 61 and 83%, respectively. The butanol fraction showed DPPH radical scavenging (inhibitory concentration (IC50) value: 9.07 µg/ml).

Nocifensive behavior-related laser heat-evoked component in the rostral agranular insular cortex revealed using morphine analgesia.

The rostral agranular insular cortex (RAIC), an opioid-responsive site, is essential for modulating nociception in rats. Our previous studies have shown that morphine suppressed long latency laser heat-evoked nociceptive responses in the primary somatosensory cortex (SmI). By contrast, morphine significantly attenuated both short and long latency responses in the anterior cingulate cortex (ACC). The present study assessed the effect of morphine on laser heat-evoked responses in the RAIC. Laser heat irradiation applied to the rat forepaws at graded levels was used as a specific noxious stimulus. In the RAIC, the first part of the long latency component (140-250ms) of the laser heat-evoked response was enhanced by intraperitoneal morphine (5mg/kg). When the laser heat-evoked cortical responses were examined for trials showing strong nocifensive movement (paw licking), moderate nocifensive movement (paw lifting), and no nocifensive movement, a 140-250ms period enhancement was observed in the RAIC only for the paw lifting movement. This enhancement was absent in the SmI. Thus, our data suggest that the RAIC has a pain-related behavior-dependent neuronal component. Furthermore, the RAIC, ACC, and SmI are differentially modulated by morphine analgesia.

Mice undergoing neuropathic pain induce anxiogenic-like effects and hypernociception in cagemates.

Rodents can recognize pain-related responses in conspecifics. Therefore, cohabitation with a conspecific animal with chronic pain can potentially promote a stressful situation, which can trigger behavioral changes such as anxiety and depression and alter nociceptive responses. In this study we investigated the effect of cohabitation with a mouse undergoing sciatic nerve constriction (neuropathic pain model). The cagemates were evaluated for nociception (writhing test), anxiety (elevated plus-maze and open field tests), depression (forced swim, tail suspension, and sucrose preference tests), and corticosterone levels. Male Swiss mice were housed in pairs for 14 days, and then divided into three groups: cagemate nerve constriction, in which one animal of each pair was subjected to constriction of the sciatic nerve; cagemate sham, in which one animal from each pair was subjected to the same surgery but without constriction; and control, in which animals were not subjected to any surgical procedure. After 14 days, the cagemates were evaluated using behavioral tests. Social interaction with a conspecific undergoing constriction of the sciatic nerve induced hypernociception and increased anxiety-related responses, whereas in depression tests inconclusive responses and no changes in corticosterone levels were found. In conclusion, cohabitation with suffering conspecifics induces changes in nociceptive responses, as well as in affective responses including anxiety.

Involvement of nuclear factor kappa B in the maintenance of persistent inflammatory hypernociception.

The pathophysiology of chronic inflammatory pain remains poorly understood. In this context, we developed an experimental model in which successive daily injection of prostaglandin E2 (PGE2) for 14days into rat hind paws produces a persistent state of hypernociception (i.e. decrease in mechanical nociceptive threshold). This state persists for more than 30days after discontinuing PGE2 injection. In the present study, we investigated the participation of nuclear factor kappa B (NF-κB), in the maintenance of this process. Mechanical hypernociception was evaluated using the electronic von Frey test. Activation of NF-κB signaling was measured through the determination of NF-κB p65 subunit translocation to the nucleus of dorsal root ganglion neurons (DRG) by immunofluorescence and western blotting. Herein, we detected an increase in NF-κB p65 subunit translocation to the nucleus of DRG neurons along with persistent inflammatory hypernociception compared with controls. Intrathecal treatment with either dexamethasone or PDTC (NF-κB activation inhibitor) after ending of the induction phase of the persistent inflammatory hypernociception, curtailed the hypernociception period as well as reducing NF-κB p65 subunit translocation. Treatment with antisense oligonucleotides against the NF-κB p65 subunit for 5 consecutive days also reduced persistent inflammatory hypernociception. Inhibition of PKA and PKCε reduced persistent inflammatory hypernociception, which was associated with inhibition of NF-κB p65 subunit translocation. Together these results suggest that peripheral activation of NF-κB by PKA and PKC in primary sensory neurons plays an important role in maintaining persistent inflammatory pain.

Visceral and somatic hypersensitivity, autonomic cardiovascular dysfunction and low-grade inflammation in a subset of irritable bowel syndrome patients.

The pathophysiology of irritable bowel syndrome (IBS) is complex and not fully understood, so the aim of this study was to evaluate whether visceral and somatic hypersensitivity, autonomic cardiovascular dysfunction, and low-grade inflammation of the gut wall are associated with diarrhea-predominant IBS (D-IBS). Sixty-two patients with D-IBS and 20 control subjects participated in the study. Using the ascending method of limits (AML) protocol, we demonstrated that D-IBS patients had significantly lower sensory thresholds compared with healthy controls (P<0.001). Using diverse methods, especially the ischemic sensitivity test, for the first time in China, we confirmed that D-IBS patients have somatic hypersensitivity. They had a significantly higher systolic blood pressure and heart rate after a cold stimulus, indicative of autonomic cardiovascular dysfunction. Compared with the control group, D-IBS patients had a significantly higher level of calprotectin (P<0.001). We also found significant correlations between visceral and somatic hypersensitivity, visceral hypersensitivity and autonomic cardiovascular dysfunction, and somatic hypersensitivity and autonomic cardiovascular dysfunction. Our findings may provide valuable suggestions for the treatment of D-IBS.