Inflammatory Pain Conditions Research Articles

Topical treatment with a mu opioid receptor agonist alleviates corneal allodynia and corneal nerve sensitization in mice

Corneal pain is considered to be a core symptom of ocular surface disruption and inflammation. The management of this debilitating condition is still a therapeutic challenge. Recent evidence supports a role of the opioid system in the management of corneal nociception. However, the functional involvement of the mu opioid receptor (MOR) underlying this analgesic effect is not known. We first investigated the expression of the MOR in corneal nerve fibers and trigeminal ganglion (TG) neurons in control mice and a mouse model of corneal inflammatory pain. We then evaluated the anti-nociceptive and electrophysiological effects of DAMGO ([D-Ala2,N-Me-Phe4,Gly5-ol] enkephalin), a MOR-selective ligand. MOR immunoreactivity was detected in corneal nerve fibers and primary afferent neurons of the ophthalmic branch of the TG of naive mice. MOR expression was significantly higher in both structures under conditions of inflammatory corneal pain. Topical ocular administration of DAMGO strongly reduced both the mechanical (von Frey) and chemical (capsaicin) corneal hypersensitivity associated with inflammatory ocular pain. Repeated instillations of DAMGO also markedly reversed the elevated spontaneous activity of the ciliary nerve and responsiveness of corneal polymodal nociceptors that were observed in mice with corneal pain. Finally, these DAMGO-induced behavioral and electrophysiological responses were totally blunted by the topical application of naloxone methiodide, an opioid receptor antagonist. Overall, these results provide evidence that topical pharmacological MOR activation may constitute a therapeutic target for the treatment of corneal pain and improve corneal nerve function to alleviate chronic pain.

Understanding Cannabis-Based Therapeutics in Sports Medicine.

With increased use of cannabis-based products by the public for both recreational and medical use, sports medicine clinicians should be informed of historical context, current legal considerations, and existing evidence with regard to efficacy, safety, and risks in the athletic community. A review of ClinicalTrials.gov, MEDLINE, and CINAHL from 2015 to present was conducted with emphasis on the most recent literature using search terms, cannabis, nabiximols, cannabinoids, pain management, THC, CBD, and marijuana. Bibliographies based on original search were utilized to pursue further literature search. Clinical review. Level 3. At present, limited high-quality studies exist for use of cannabinoids for acute pain, chronic pain, or concussion. None of the trials involving cannabinoids included the athletic population. Thus, results from this clinical review are extrapolated to conditions of the sports medicine population. For acute pain, 2 small-randomized double-blinded crossover trials concluded no immediate effect of cannabinoid therapy. More robust evidence exists for treatment of chronic pain conditions through meta-analysis and systemic reviews. Cannabinoid therapy exhibits moderate efficacy as a treatment for some chronic pain conditions. Investigations included a broad spectrum of chronic pain conditions, including neuropathic, musculoskeletal, inflammatory, and central pain conditions, and reveal reduction in pain and improvement of quality of life with limited adverse effects. For concussion, evidence is based on preclinical in vitro and animal models revealing possible neuroprotective effects as well as 2 clinical studies involving the presence of cannabinoids for concussion (some sports-related), but there are no high-quality trials evaluating efficacy for treatment with cannabinoids at this time. Although various biochemical explanations exist on the use of cannabinoid therapy through modulation of the endocannabinoid system for several medical issues affecting athletes, recommendations from clinicians must be extrapolated from a majority of research done in the nonathletic population. Lack of strong-quality clinical evidence, coupled with inconsistent federal and state law as well as purity issues with cannabis-based products, make it difficult for the sports medicine clinician to widely recommend cannabinoid therapeutics at present. Future larger, higher quality clinical research studies with standardized pure extracts will better guide appropriate medical use going forward. At present, evidence for a multitude of therapeutic applications is emerging for cannabinoid treatment approaches. With emphasis placed on patient-centered clinical decisions, cannabinoids hold promise of treatment for athletes with chronic pain conditions. Clinicians who treat the athletic community must consider legal and ethical issues when discussing and recommending the use of cannabinoids, with acknowledgment of inconsistencies in purity of various formulations and concerns of drug testing.

Anti-inflammatory and antinociceptive activity of Siparuna guianensis Aublet, an amazonian plant traditionally used by indigenous communities

Ethnopharmacological relevanceSiparuna guianensis Aublet leaves, known as negramina, are used by indigenous and local communities in Brazil and other countries in the Americas to treat pain and inflammatory diseases. Aim of the studyTo characterize the chemical constituents and to evaluate the antioxidant, anti-inflammatory, antinociceptive and locomotor activities of the dichloromethane fraction (DF) of S. guianensis leaves. Also, an acute oral toxicity test was accomplished. Material and methodsThe chemical characterization of DF was performed by ultra-high pressure liquid chromatography (UHPLC) analyses coupled with a high-resolution mass spectrometer. The antioxidant potential of DF was investigated using nitric oxide (NO) and hydroxyl radical (OH) scavenging test. The evaluation study of the anti-inflammatory activity was carried out in vitro by NO measurement in stimulated macrophages and, in vivo, by croton oil-induced ear edema, LPS-induced peritonitis, and zymosan-induced arthritis in mice. Different mechanisms of central and peripheral nociception were stimulated by acetic acid-induced writhing, formalin, and tail-flick tests. Besides that, the open field assay was performed. ResultsUHPLC analyses of DF showed the presence of a mixture of glycosylated and methoxylated flavonoids. DF was able to scavenge NO and OH radicals in vitro and showed anti-inflammatory activity by inhibiting NO production in LPS-stimulated murine macrophages. Oral administration of DF considerably inhibited the ear edema after croton oil application and reduced the leukocyte infiltrated in LPS-induced peritonitis. In the inflammatory intra-articular zymosan-induced process, DF showed a significant reduction in the inflammatory area and of the cells in the synovial and connective tissues adjacent to the joint. Also, DF was able to reduce the intra-articular edema. In nociception models, the oral administration of DF considerably inhibited the acetic acid-induced writhings. The formalin test showed that DF attenuated the licking time in both phases, which suggested that DF reduce the nociception by central and peripheral mechanisms. In the tail-flick test, DF showed no activity. Besides that, DF did not affect the animal locomotion, and no acute toxicity was observed. ConclusionsFor the first time, the anti-inflammatory and antinociceptive activities of S. guianensis were reported, supporting its ethnopharmacological uses for some inflammatory diseases and painful conditions.

The NLRP3 Inflammasome: Role and Therapeutic Potential in Pain Treatment.

Pain is a fundamental feature of inflammation. The immune system plays a critical role in the activation of sensory neurons and there is increasing evidence of neuro-inflammatory mechanisms contributing to painful pathologies. The inflammasomes are signaling multiprotein complexes that are key components of the innate immune system. They are intimately involved in inflammatory responses and their activation leads to production of inflammatory cytokines that in turn can affect sensory neuron function. Accordingly, the contribution of inflammasome activation to pain signaling has attracted considerable attention in recent years. NLRP3 is the best characterized inflammasome and there is emerging evidence of its role in a variety of inflammatory pain conditions. In vitro and in vivo studies have reported the activation and upregulation of NLRP3 in painful conditions including gout and rheumatoid arthritis, while inhibition of NLRP3 function or expression can mediate analgesia. In this review, we discuss painful conditions in which NLRP3 inflammasome signaling has been pathophysiologically implicated, as well as NLRP3 inflammasome-mediated mechanisms and signaling pathways that may lead to the activation of sensory neurons.

Anti-inflammatory and cytotoxic evaluation of extracts from the flowering stage of Celosia argentea

BackgroundThis study was aimed at investigating the possible anti-inflammatory and cytotoxic effects of extracts from the flowering stage of C. argentea. This growth stage was chosen because of its high polyphenolic content and high antioxidant capacity.MethodsAnti-inflammatory potential of the aqueous, acetone and methanol extracts of C. argentea was evaluated through the inhibition of nitric oxide production (LPS-induced) on stimulated macrophages (RAW 264.7), while MTT assay was used to assess cell viability with Silymarin as standard. Cytotoxicity of the plant extracts was evaluated on murine preadipocyte cell line (3 T3-L1) using the image-based method of two DNA-binding dyes; Hoechst 33342 and propidium iodide (PI) with melphalan as standard.ResultsAcetone extract exhibited moderate, dose-dependent anti-inflammatory activity with no significant toxicity to activated macrophages, however the aqueous and methanol extracts were unable to inhibit nitric oxide production at both trials. MTT assay and the toxicity assay revealed that the flowering stage extracts of C. argentea were not toxic to the RAW 264.7 macrophages and 3 T3-L1 cells at all the tested concentrations (0, 2, 50, 100 and 200 μg/mL).ConclusionsThese findings corroborate the traditional use of C. argentea for painful inflammatory conditions and encourage its possible use as lead for the development of novel, non-toxic, anti-inflammatory agents.

The multidirectional effects of some comorbid disorders on the malignant process and tumor-bearing organism in the experiment.

e15616 Background: The question of the effects of comorbid diseases on oncogenesis has been little studied else. The increase in the frequency of dorsopathies and arthritis with age determines the important of the question about their influence on malignant process. The aim of the research was to study the features of the tumor growth and animal's condition under chronic neurogenic and inflammatory pain. Methods: In experiments on 54 white unbred male rats of 280-390 g, with transplantable Guerin's carcinoma (сG), two experimental models of chronic pain were used - unilateral sciatic nerve ligation (SNL) according to G.J. Bennet (neurogenic pain) and injections of formalin (Fm) into the ankle joint of the back paw (inflammatory pain). Formalin injection is known to be used to form both acute and chronic pain. The dynamics of tumors size, level of motor activity (MAL) in open field test, hematological parameters (by the blood analyzer «Exigo EOS vet», Sweden), adaptation status (AS) by Selye-Garkavi-Kvakina and also the lifespan of the animals (LS) were evaluated. Results: Unlike the unidirectional negative influence of chronic pain known in tumor-bearing animals in the cases of bilateral SNL, two opposite effects were observed with unilateral SNL and the formalin injection. Along with accelerated tumor growth in some animals (up to 62%), increase of LS of more than a third of the rats of the main groups by 3-30% in comparative with maximal LS in the control group was noted. In these cases, often the death of animals occurred with the larger tumors than in the control groups. In the cases of unilateral SNL, a relation between changes in the characteristics of the AS and the LS was noted. In the cases of Fm injections, animals with diverse LS differed in the features of the inflammatory reaction and the dynamics of the MAL. The prognostic value of shifts of the MAL in chronic inflammatory pain and tumor growth is assumed. Conclusions: A nonlinear relationship between the processes caused by chronic pain, oncogenesis, and individual characteristics of systemic regulation was shown. The question about the mechanisms of adaptation to the malignant process, promoting the body's viability in large tumors in conditions of chronic neurogenic and inflammatory pain is of interest.

Type I Interferons Act Directly on Nociceptors to Produce Pain Sensitization: Implications for Viral Infection-Induced Pain.

One of the first signs of viral infection is body-wide aches and pain. Although this type of pain usually subsides, at the extreme, viral infections can induce painful neuropathies that can last for decades. Neither of these types of pain sensitization is well understood. A key part of the response to viral infection is production of interferons (IFNs), which then activate their specific receptors (IFNRs) resulting in downstream activation of cellular signaling and a variety of physiological responses. We sought to understand how type I IFNs (IFN-α and IFN-β) might act directly on nociceptors in the dorsal root ganglion (DRG) to cause pain sensitization. We demonstrate that type I IFNRs are expressed in small/medium DRG neurons and that their activation produces neuronal hyper-excitability and mechanical pain in mice. Type I IFNs stimulate JAK/STAT signaling in DRG neurons but this does not apparently result in PKR-eIF2α activation that normally induces an anti-viral response by limiting mRNA translation. Rather, type I IFNs stimulate MNK-mediated eIF4E phosphorylation in DRG neurons to promote pain hypersensitivity. Endogenous release of type I IFNs with the double-stranded RNA mimetic poly(I:C) likewise produces pain hypersensitivity that is blunted in mice lacking MNK-eIF4E signaling. Our findings reveal mechanisms through which type I IFNs cause nociceptor sensitization with implications for understanding how viral infections promote pain and can lead to neuropathies.SIGNIFICANCE STATEMENT It is increasingly understood that pathogens interact with nociceptors to alert organisms to infection as well as to mount early host defenses. Although specific mechanisms have been discovered for diverse bacterial and fungal pathogens, mechanisms engaged by viruses have remained elusive. Here we show that type I interferons, one of the first mediators produced by viral infection, act directly on nociceptors to produce pain sensitization. Type I interferons act via a specific signaling pathway (MNK-eIF4E signaling), which is known to produce nociceptor sensitization in inflammatory and neuropathic pain conditions. Our work reveals a mechanism through which viral infections cause heightened pain sensitivity.

Approaches to Targeting Adenylyl Cyclase 1 for Novel Pain Therapeutics

Adenylyl cyclases (AC) catalyze the formation of cyclic AMP (cAMP) from ATP and are involved in a number of disease states, making them attractive potential drug targets. Recent preclinical studies have identified neuronal adenylyl cyclase type 1 (AC1) as a novel target for treating chronic pain. AC1 is highly expressed in neuronal tissues associated with pain processing and neuronal plasticity, and studies using AC1 knockout mice provide direct evidence linking AC1 to chronic inflammatory pain conditions. Furthermore, AC1 inhibitors would lack the side effects associated with other agents (e.g. opioids) used to treat chronic inflammatory pain. We have designed our studies to target NOT the conserved P‐site or forskolin‐binding site, but rather a novel approach, targeting the unique protein‐protein interaction of AC1 and calmodulin (CaM). AC1 and AC8 are both activated by CaM; however, the CaM binding domains are unique in structure and location providing an unprecedented opportunity to achieve AC1 selectivity. We hypothesize that developing a small molecule inhibitor of AC1 will allow us to mimic the AC1 knockout phenotype and provide a new avenue for the treatment of chronic inflammatory pain. Through the development and implementation of a novel biochemical high‐throughput screening paradigm we will interrogate a library of 100,000 compounds to identify inhibitors of the AC1/CaM protein‐protein interaction. Hit compounds will be validated and chemically optimized to lead molecules using cellular assays focused on selectivity and potency to guide medicinal chemistry efforts. To date, we have screened 14,080 compounds and identified 18 compounds capable of disrupting the AC1/CaM protein‐protein interaction, a hit rate of 0.13%. We anticipate the identification of selective AC1 inhibitors that will ultimately be improved and applied in models of chronic inflammatory pain.Support or Funding InformationThis work was supported by The National Institutes of Health (1R61NS111070 DLR & VJW), The University of Iowa Center for Biocatalysis and Bioprocessing and the NIH‐sponsored Predoctoral Training Program in Biotechnology (5T32GM008365 JBO).

Diclofenac Mouthwash as a potential therapy for reducing pain and discomfort in chemo-radiotherapy-induced oral mucositis.

Oral and/or oropharyngeal acute mucositis during and after chemo-radiotherapy (chemo-RT) for head and neck squamous cell carcinoma (HNSCC) can be extremely painful, sometimes requiring nasogastric feeding to enable adequate nutrition. The MASCC/ISOO evidence-based guidelines recommend benzydamine mouthwash for mucositis prevention in RT (recently updated to include chemo-RT), and a Cochrane systematic review found other agents to be effective in prophylaxis. Diclofenac mouthwash is licensed for painful oral mucosal inflammatory conditions but to our knowledge has not been assessed in chemo-RT-associated oral mucositis. A clinical observation and service evaluation study in 10 patients undergoing chemo-RT for HNSCC to assess the potential value of diclofenac mouthwash (0.74mg/mL) in reducing symptoms. Patients used 20ml of mouthwash up to 4 times a day starting in week 3 (of a 6-week course of treatment), recording pain and discomfort scores using a visual analogue scale on days 0, 1,7 and 14 (until the end of week 4). As per our current clinical practice, oral mucositis was not clinically scored as an outcome. Statistical analysis was performed using a one-way ANOVA. Using diclofenac mouthwash, 9/10 patients experienced pain score reduction from day 0 (mean score 6.75±SD 1.83) to day 2 (5.05±SD 1.62) and day 14 (4.09±SD 1.96). Diclofenac mouthwash may be beneficial for managing chemo-RT-induced oral mucositis. While a prospective randomised clinical trial is needed, it can be prescribed for this condition within its current licence.

Lavandula angustifolia essential oil inhalation reduces mechanical hyperalgesia in a model of inflammatory and neuropathic pain: The involvement of opioid and cannabinoid receptors

Lavandula angustifolia (LaEO) essential oil has been widely used by aromatherapy in the treatment of various clinical conditions, with evidence of its analgesic and anti-inflammatory potential. Our results demonstrate that sixty-five substances were identified in LaEO. Among the compounds found, the major ones were linalool (30.61%) and linalyl acetate (20.36%). We found that LaEO inhalation reduces mechanical hyperalgesia in conditions of chronic inflammatory and neuropathic pain. Furthermore, this effect seems to be mediated by peripheral and central opioid and cannabinoid 2 receptors. The findings of the present study suggests that the LaEO inhalation is effective on the chronic pain treatment.

Group II metabotropic glutamate receptor expressing neurons in anterior cingulate cortex become sensitized after inflammatory and neuropathic pain.

The anterior cingulate cortex is a limbic region associated with the emotional processing of pain. How neuropathic and inflammatory pain models alter the neurophysiology of specific subsets of neurons in the anterior cingulate cortex remains incompletely understood. Here, we used a GRM2Cre:tdtomato reporter mouse line to identify a population of pyramidal neurons selectively localized to layer II/III of the murine anterior cingulate cortex. GRM2encodes the group II metabotropic glutamate receptor subtype 2 which possesses analgesic properties in mouse and human models, although its function in the anterior cingulate cortex is not known. The majority of GRM2-tdtomato anterior cingulate cortex neurons expressed GRM2gene product in situ but did not overlap with cortical markers of local inhibitory interneurons, parvalbumin or somatostatin. Physiological properties of GRM2-tdtomato anterior cingulate cortex neurons were investigated using whole-cell patch clamp techniques in slice from animals with neuropathic or inflammatory pain, and controls. After hind-paw injection of Complete Freund’s Adjuvant or chronic constriction injury, GRM2-tdtomato anterior cingulate cortex neurons exhibited enhanced excitability as measured by an increase in the number of evoked action potentials and a decreased rheobase. This hyperexcitability was reversed pharmacologically by bath application of the metabotropic glutamate receptor subtype 2 agonist (2R, 4R)-4-Aminopyrrolidine-2,4-dicarboxylate APDC (1 µM) in both inflammatory and neuropathic models. We conclude that layer II/III pyramidal GRM2-tdtomato anterior cingulate cortex neurons express functional group II metabotropic glutamate receptors and undergo changes to membrane biophysical properties under conditions of inflammatory and neuropathic pain.

Breast Pathologies and Inadequate Breastfeeding Practices: A Survey Among a Group of Newly Delivered Women in Yaoundé, Cameroon

Breastfeeding women may develop a number of breast disorders during the postpartum period. Such disorders could involve masses of varying sizes, breastmilk secretion anomalies and painful-inflammatory or infectious conditions. Though very few of these conditions may be absolute contraindications to breastfeeding, they are however a significant source of worry for newly delivered women and may disrupt the breastfeeding process. This survey aimed to investigate breast anomalies in women with inadequate breastfeeding practices. We conducted a cross-sectional study from December 2018 to May 2019 at the Yaoundé Gynaeco-Obtetric and Paediatric Hospital. Mothers with livebirth neonate infants weighing > 2000g and with no initial contraindication to breastfeeding were included. A total of 250 mothers were enrolled in the survey. Delivery was eutocic in 230 (92%) women and 199 (79.6%) had the intension to exclusively breastfeed their babies. The state of the neonates was satisfactory in 204 (96%) deliveries. However, inadequate breastfeeding was noted in 153 mothers (61.2%), with breast pathologies occurring in 85 women (55.5%), among which 24 (28.2%) had secretion anomalies predominated by quantitative disorders. Painful inflammatory and/or infectious conditions occurred in 58 women (69.4%) including nipple crevices, breast engorgement, inverted nipples, mastitis and abscess. All women with obvious or supposed breast disorders had inadequate breastfeeding practices. Therefore, painful breast pathologies and secretion disorders should firstly be investigated in women with eutocic delivery, who are willing to breastfeed, but unable to do so adequately. More so, these pathologies are essentially benign and may be prevented by good hygiene, adequate breastfeeding techniques such as proper nipple and areolar positioning into the baby’s mouth.

The redox-sensitive APE1 is a master cellular regulator for inflammatory pain condition

The redox-sensitive APE1 is a master cellular regulator for inflammatory pain condition

Ethosuximide improves chronic pain-induced anxiety- and depression-like behaviors

Chronic pain is a heavy burden disease. Current treatments are generally weakly effective or associated with adverse effects. New therapeutic approaches are therefore needed. Recent studies have suggested T-type calcium channels as an attractive target for the treatment of chronic pain. In this perspective, it was decided to perform a preclinical evaluation of the efficacy of ethosuximide, a T-type channel blocker used clinically as an antiepileptic, as a novel pharmacological treatment for chronic pain. Assessment of the effect of ethosuximide was thus made in both nociception and pain-related comorbidities as anxiety and depression are frequently encountered in chronic pain patients. Our results show that such symptoms occurred in three animal models of chronic pain designed to reflect traumatic neuropathic, chemotherapy-induced neuropathic and inflammatory pain conditions. Administration of ethosuximide reduced both chronic pain and comorbidities with a marked intensity ranging from partial reduction to a complete suppression of symptoms. These results make ethosuximide, and more broadly the inhibition of T-type calcium channels, a new strategy for the management of uncontrolled chronic pain, likely to improve not only pain but also the accompanying anxiety and depression.

The analgesic effect of refeeding on acute and chronic inflammatory pain

Pain is susceptible to various cognitive factors. Suppression of pain by hunger is well known, but the effect of food intake after fasting (i.e. refeeding) on pain remains unknown. In the present study, we examined whether inflammatory pain behavior is affected by 24 h fasting and 2 h refeeding. In formalin-induced acute inflammatory pain model, fasting suppressed pain behavior only in the second phase and the analgesic effect was also observed after refeeding. Furthermore, in Complete Freund’s adjuvant-induced chronic inflammatory pain model, both fasting and refeeding reduced spontaneous pain response. Refeeding with non-calorie agar produced an analgesic effect. Besides, intraperitoneal (i.p.) administration of glucose after fasting, which mimics calorie recovery following refeeding, induced analgesic effect. Administration of opioid receptor antagonist (naloxone, i.p.) and cannabinoid receptor antagonist (SR 141716, i.p.) reversed fasting-induced analgesia, but did not affect refeeding-induced analgesia in acute inflammatory pain model. Taken together, our results show that refeeding produce analgesia in inflammatory pain condition, which is associated with eating behavior and calorie recovery effect.

RETRACTED ARTICLE: Anti-hyperalgesic properties of a flavanone derivative Poncirin in acute and chronic inflammatory pain models in mice

BackgroundPoncirin is flavanone derivative (isolated from Poncirus trifoliata) with known pharmacological activities such as anti-tumor, anti-osteoporotic, anti-inflammatory and anti-colitic. The present study aimed to explore the anti-allodynic and anti-hyperalgesic potentials of poncirin in murine models of inflammatory pain.MethodsThe analgesic potential of poncirin was evaluated in formalin-, acetic acid-, carrageenan- and Complete Freund’s Adjuvant (CFA)-induced inflammatory pain models in mice. Anti-allodynic and anti-hyperalgesic activities were measured using Von Frey filaments, Randall Selitto, hotplate and cold acetone tests. The serum nitrite levels were determined using Griess reagent. The Quantitative Real-time PCR (qRT-PCR) was performed to assess the effect of poncirin on mRNA expression levels of inflammatory cytokines and anti-oxidant enzymes.ResultsIntraperitoneal administration of poncirin (30 mg/kg) markedly reduced the pain behavior in both acetic acid-induced visceral pain and formalin-induced tonic pain models used as preliminary screening tools. The poncirin (30 mg/kg) treatment considerably inhibited the mechanical hyperalgesia and allodynia as well as thermal hyperalgesia and cold allodynia. The qRT-PCR analysis showed noticeable inhibition of pro-inflammatory cytokines (mRNA expression levels of TNF-α, IL-1β and IL-6) (p < 0.05) in poncirin treated group. Similarly, poncirin treatment also enhanced the mRNA expressions levels of anti-oxidant enzymes such as transcription factor such as nuclear factor (erythroid-derived 2)-like 2 (Nrf2) (p < 0.05), heme oxygenase (HO-1) (p < 0.05) and superoxide dismutase (SOD2) (p < 0.05). Chronic treatment of poncirin for 6 days did not confer any significant hepatic and renal toxicity. Furthermore, poncirin treatment did not altered the motor coordination and muscle strength in CFA-induced chronic inflammatory pain model.ConclusionThe present study demonstrated that poncirin treatment significantly reduced pain behaviors in all experimental models of inflammatory pain, suggesting the promising analgesic potential of poncirin in inflammatory pain conditions.

Tumor necrosis factor α induces α1B-adrenergic receptor expression in keratinocytes

Keratinocytes produce cytokines and nerve growth factor (NGF) as part of a repair response to injury, disease or stress, and express alpha1-adrenoceptors (α1-AR). The expression of these receptors is elevated in some inflammatory diseases and chronic pain conditions. In this study, we investigated whether inflammatory signalling affects α1-AR expression in keratinocytes in vitro. Tumor necrosis factor α (TNFα) was administered to human keratinocytes, after which the levels of other key pro-inflammatory cytokines and NGF were measured. The production of these cytokines and NGF increased in cells treated with TNFα compared to untreated cells. Furthermore, exposure to TNFα increased gene expression of the α1-AR subtype B in keratinocytes. Our results suggest that inflammatory cytokines released during injury stimulate α1-AR expression in keratinocytes. The up-regulation of α1-AR may amplify the adrenergic sensitivity of these cells to catecholamines released during sympathetic nervous system activation after injury which, in turn, could heighten the inflammatory response.

Modulation of nociception by social bonds in the monogamous rodent: c-Fos expression in the brain “pain matrix” under conditions of inflammatory pain

Modulation of nociception by social bonds in the monogamous rodent: c-Fos expression in the brain “pain matrix” under conditions of inflammatory pain

Improved efficacy of naproxen-loaded NLC for temporomandibular joint administration

Inflammatory conditions of the temporomandibular joint (TMJ) and peripheral tissues affect many people around the world and are commonly treated with non-steroidal anti-inflammatory drugs (NSAIDs). However, in order to get desirable results, treatments with NSAIDs may take weeks, causing undesirable side effects and requiring repeated administration. In this sense, this work describes the development of an optimized nanostructured lipid carrier (NLC) formulation for intra-articular administration of naproxen (NPX). An experimental design (23) selected the best formulation in terms of its physicochemical and structural properties, elucidated by different methods (DLS, NTA, TEM, DSC, and ATR-FTIR). The chosen formulation (NLC-NPX) was tested on acute inflammatory TMJ nociception, in a rat model. The optimized excipients composition provided higher NPX encapsulation efficiency (99.8%) and the nanoparticles were found stable during 1 year of storage at 25 °C. In vivo results demonstrated that the sustained delivery of NPX directly in the TMJ significantly reduced leukocytes migration and levels of pro-inflammatory cytokines (IL-1β and TNF-α), for more than a week. These results point out the NLC-NPX formulation as a promising candidate for the safe treatment of inflammatory pain conditions of TMJ or other joints.

Effects of childhood psychological trauma on rheumatic diseases.

The etiology of rheumatic diseases is unclear, but it is thought that environmental factors added to immunogenetic mechanisms in chronic inflammatory diseases play a role. Many inflammatory disorders, autoimmune diseases, and painful conditions have been shown to be associated with the psychological trauma of childhood. The aim of the present study was to investigate childhood psychological trauma that is considered to be one of the environmental factors that initiate inflammation on patients with rheumatic diseases. In our study, a total of 440 patients (220 patients who have rheumatic diseases as the case group and 220 patients who have no rheumatic disease as the control group) were examined. The Childhood Trauma Questionnaire-28 (CTQ-28) was administered and was completed by the patients. This was a cross-sectional study design. No statistically significant differences were found between the case and control groups with respect to age, gender, marital status, and educational level. The CTQ-28 scale was found to be significantly higher in patients with rheumatic diseases (ankylosing spondylitis, rheumatoid arthritis, and connective tissue disease) in our study. We think that childhood psychiatric traumas are effective in the etiopathogenesis of rheumatic diseases. To make this relationship more understandable, multidisciplinary research and long-term follow-up studies are needed to examine neuroendocrine, genetic, and epidemiological factors.