Reduced Pain Responses Research Articles

Sertraline Alleviates Chronic Prostatitis by Regulating the TRPV1 Channel.

Although sertraline has been widely used for chronic prostatitis (CP), the mechanisms are unclear. Herein, we explored the mechanisms of sertraline in treating CP. Network pharmacology methods were used to explore the potential targets and molecular mechanisms. LPS was used to stimulate RWPE-1 cells to construct an in vitro model of CP. An experimental autoimmune prostatitis (EAP) mice model was built. CCK-8 assay, EdU assay, BrdU detection, and Tunel assay were performed to evaluate the proliferation and apoptosis process of cells or tissues, respectively. DCFH-DA and Fluo-4 fluorescence probes were used to detect intracellular ROS and calcium concentrations. Von Frey filaments and open-field tests were utilized to evaluate pain response and depressive-like behavior of mice. Histopathology was evaluated through hematoxylin and eosin staining. RT-qPCR, Western blot, immunofluorescence, and immunohistochemistry were utilized to evaluate the transcription, expression, and location of related proteins. Molecular dynamics (MD) simulation and surface plasmon resonance (SPR) assay were performed to measure the binding capacity of sertraline and related proteins. Through a network pharmacology analysis, 27 potential targets of sertraline for CP were obtained, and 5 key targets (CHRM1, ADRA1B, HTR2B, HTR2A, and TRPV1) were finally identified. Functional experiments suggested that TRPV1 was involved in the proliferation, apoptosis inhibition, and ROS production of LPS-induced RWPE-1 cells. In vitro experiments showed that sertraline significantly inhibited cell proliferation, ROS generation, and transcription of inflammation cytokines of LPS-induced RWPE-1 cells. Additionally, sertraline markedly promoted the apoptosis level of LPS-stimulated RWPE-1 cells and elevated the expression level of BAX while reducing the expression levels of Bcl2 and Caspase-3. MD simulation and SPR assay confirmed the direct binding of sertraline to TRPV1. Moreover, sertraline significantly down-regulated the expression level of TRPV1 and inhibited calcium influx of LPS-induced RWPE-1 cells. TRPV1 agonist (Capsaicin) significantly restored the effects on proliferation, apoptosis, ROS production, and calcium influx of sertraline on LPS-induced RWPE-1 cells. Mice experiments demonstrated that sertraline treatment could reduce pain response, improve depression-like symptoms, and relieve local prostate inflammation of EAP mice, as well as down-regulated the expression level of TRPV1, inhibit the proliferation, and promote apoptosis of prostate tissues in EAP mice. The results revealed the anti-inflammatory effect of sertraline for RWPE-1 cells and EAP mice, and the potential mechanism was regulating the TRPV1 channel. It indicated that sertraline might serve as a complementary anti-inflammatory agent for CP.

Modulation of endogenous opioid signaling by inhibitors of puromycin-sensitive aminopeptidase

The endogenous opioid system regulates pain through local release of neuropeptides and modulation of their action on opioid receptors. However, the effect of opioid peptides, the enkephalins, is short-lived due to their rapid hydrolysis by enkephalin-degrading enzymes. In turn, an innovative approach to the management of pain would be to increase the local concentration and prolong the stability of enkephalins by preventing their inactivation by neural enkephalinases such as puromycin-sensitive aminopeptidase (PSA). Our previous structure-activity relationship studies offered the S-diphenylmethyl cysteinyl derivative of puromycin (20) as a nanomolar inhibitor of PSA. This chemical class, however, suffered from undesirable metabolism to nephrotoxic puromycin aminonucleoside (PAN). To prevent such toxicity, we designed and synthesized 5′-chloro substituted derivatives. The compounds retained the PSA inhibitory potency of the corresponding 5′-hydroxy analogs and had improved selectivity toward PSA. In vivo treatment with the lead compound 19 caused significantly reduced pain response in antinociception assays, alone and in combination with Met-enkephalin. The analgesic effect was reversed by the opioid antagonist naloxone, suggesting the involvement of opioid receptors. Further, PSA inhibition by compound 19 in brain slices caused local increase in endogenous enkephalin levels, corroborating our rationale. Pharmacokinetic assessment of compound 19 showed desirable plasma stability and identified the cysteinyl sulfur as the principal site of metabolic liability. We gained additional insight into inhibitor-PSA interactions by molecular modeling, which underscored the importance of bulky aromatic amino acid in puromycin scaffold. The results of this study strongly support our rationale for the development of PSA inhibitors for effective pain management.

From Genotype to Phenotype of Polish Patients with Pitt-Hopkins Syndrome concerning the Quality of Life and Family Functioning.

Background: Pitt-Hopkins syndrome (PTHS) is a rare genetic disorder affecting psychomotor, social, and intellectual development, caused by a mutation in the TCF4 gene. The study aims to gather the phenotype and genotype data of PTHS patients from Poland and to assess the quality of life (QoL) and the impact of the disorders on the family. Methods: Eight families with PTHS participated in the study. To obtain data, the following standardized questionnaires were used: Questionnaire on Clinical Problems (QCP), the PedsQL™ Family Impact Module, and the QL-Disability Questionnaire. Additionally, a retrospective analysis of clinical examination, genetic consult, medical history, and genotype of each individual was performed. Results: All of the examined children exhibited a mutation in the TCF4 gene and typical features of PTHS. The most prevalent clinical symptoms in the study group included typical PTHS appearance, intellectual disability (n = 5; as the rest of the patients were too young to be assessed), abnormal speech development (n = 8), reduced pain response (n = 7), constipation (n = 7), drooling (n = 7), cold extremities (n = 7), and disturbances in sensory integration processes (n = 7). The QL-Disability Questionnaire revealed a total QoL score of 67.7/100 for children with PTHS, while the QoL for their families in the PedsQL Family Impact Module was 53.82/100. The highest-rated domain was cognitive functioning (Median (Me) = 67.50; Standard Deviation (SD) = 21.95), while the lowest was daily activities (Me = 25.00; SD = 29.86). Conclusions: The study allowed the collection of data on the phenotype and genotype of children with PTHS living in Poland. Overall, our study showed that the QoL of children with PTHS is impaired.

Effectiveness and safety of Buzzy device in needle-related procedures for children under twelve years of age: A systematic review and meta-analysis.

Pain transcends simple physiology, encompassing biological, emotional, psychological, and social facets. Children show pronounced immediate and enduring responses to pain-related procedures. The aim of this meta-analysis is to investigate the efficacy and safety of the Buzzy device for needle-related procedures in children aged twelve years or younger. PubMed, Web of Science, and Embase were searched from inception to July 2023. Only randomized controlled trials utilizing the Buzzy device for needle-related procedures in children under twelve years old were included. Two reviewers independently conducted study selection, data extraction, and risk of bias assessment. Random-effects models were utilized, and analyses were performed using mean differences or standardized mean differences as well as risk ratios. A total of 19 studies were included, involving 2846 participants (Buzzy = 1095, Control = 1751). Compared to no intervention, the Buzzy device significantly reduced pain response [self-report SMD = -1.90 (-2.45, -1.36), parental SMD = -3.04 (-4.09, -1.99), observer SMD = -2.88 (-3.75, -2.02)] and anxiety scores [self-report SMD = -1.97 (-3.05, -0.88), parental SMD = -2.01 (-2.93, -1.08), observer SMD = -1.92 (-2.64, -1.19)]. Compared to virtual reality (VR), the Buzzy device reduced self-reported anxiety levels SMD = -0.47 (-0.77, -0.17), and compared to distraction cards, the Buzzy device reduced parental and observer-reported pain [parental SMD = -0.85 (-1.22, -0.48), observer SMD = -0.70 (-1.00, -0.40)] and anxiety [parental SMD = -0.96 (-1.46, -0.47), observer SMD = -0.91 (-1.40, -0.42)]. Subgroup analysis results showed that procedure type, patient age, measurement scales used, and distance of operation were not the reason of heterogeneity. The summarized first puncture attempt success rate did not differ from other interventions. There were no significant adverse events in the included studies. The Buzzy device reduces pain and anxiety in children during needle procedures, ensuring success and safety. Additionally, the effectiveness of the Buzzy device in reducing pain during venipuncture is superior when compared to its effectiveness during intramuscular injections.

Contribution of the intra-hippocampal orexin system in the regulation of restraint stress response to pain-related behaviors in the formalin test.

Stress-induced antinociception (SIA) is due to the activation of several neural pathways and neurotransmitters that often suppress pain perception. Studies have shown that the orexin neuropeptide system is essential in pain modulation. Therefore, this study aimed to investigate the role of orexinergic receptors in the hippocampal CA1 region in modulating SIA response during the formalin test as an animal model of inflammatory pain. The orexin-1 receptor (OX1r) antagonist, SB334867, at 1, 3, 10, and 30 nmol or TCS OX2 29 as an orexin-2 receptor (OX2r) antagonist at the same doses were microinjected into the CA1 region in rats. Five minutes later, rats were exposed to restraint stress (RS) for 3 h, and pain-related behaviors were monitored in 5-min blocks for the 60-min test period in the formalin test. Results showed that applying RS for 3 h reduced pain responses in the early and late phases of the formalin test. The main findings showed that intra-CA1 injection of orexin receptor antagonists reduced the antinociception caused by stress in both phases of the formalin test. In addition, the contribution of OX2r in mediating the antinociceptive effect of stress was more prominent than that of OX1r in the early phase of the formalin test. However, in the late phase, both receptors worked similarly. Accordingly, the orexin system and its two receptors in the CA1 region of the hippocampus regulate SIA response to this animal model of pain in formalin test.

PENGARUH TERAPI RELAKSASI AUTOGENIK TERHADAP PENURUNAN TINGKAT NYERI AKUT PADA PASIEN ABDOMINAL PAIN DI KABUPATEN BONE BOLANGO

Background: Abdominal pain is the main symptom of an acute abdomen that occurs suddenly and not specific. Pain is an unpleasant sensory experience, the main element that must be present to be called pain is unpleasant feeling. Previous studies reported that autogenic relaxation therapy effectively reduces pain in patients with abdominal pain. Aim: This study aimed to analyze the effect of autogenic relaxation therapy on reducing acute pain levels in abdominal pain patients at Toto Kabila Hospital, District Bone Bolango. Methods: The research design used in this study was a pre-experimental design with one group pretest posttest design without comparison group (control). The number of samples was 10 respondents of abdominal pain. The type of intervention used is autogenic relaxation therapy with an evaluation of pain intensity. Results: The results of this study found that autogenic relaxation therapy had an effect on reducing the level of acute pain in abdominal pain patients with a p value of 0.003 < α 0.05. Conclusion: Relaxation therapy is effective in reducing pain response, these studies were conducted on acute and chronic pain. Keywords: Abdominal Pain; Painful; Autogenic Relaxation Therapy

Widespread Hyperalgesia by Pancreatic Quantitative Sensory Testing Is Associated With Reduced Pain Response in Chronic Pancreatitis.

Widespread Hyperalgesia by Pancreatic Quantitative Sensory Testing Is Associated With Reduced Pain Response in Chronic Pancreatitis.

Effect of Moringa oleifera Extract on Inflammatory Status in Cancer Patients with Aromatase-Induced Arthralgia

BACKGROUND: Aromatase inhibitor therapy is commonly used for breast cancer patients with characteristics of positive estrogen and progesterone receptors test without metastases. Thus, this kind of therapy generally gives side effects of aromatase-induced arthralgia (AIA). Moringa oleifera has a strong anti-inflammatory substance that has the potential to reduce inflammation and pain in a patient with AIA. AIM: This study aims to assess the effect of M. oleifera extract administration on pain response and inflammatory status in breast cancer with aromatase inhibitor-induced arthralgia patients. METHODS: Forty-two patients breast cancer patients with estrogen and progesterone receptor-positive in Dr. Kariadi General Hospital were assessed for pain response and inflammatory status before and after the treatment with M. oleifera leaf extract for one month. Assessment of pain response is using the Australian Canadian osteoarthritis hand index (AUSCAN) questionnaire and inflammation is measured by ANA serum level. This study is experimental with two parallel pre-test and post-test group. RESULTS: In the treatment group, there was a significant decrease of the AUSCAN score 13.5 ± 5.11 (p ≤ 0.001), while in the control group, there was an increase in the AUSCAN score 2.7 ± 4.96 (p = 0.022). In the measurement of ANA serum level, a significant decrease of the treatment group found 0.3 ± 0.40 (p ≤ 0.001). CONCLUSIONS: Moringa oleifera extract can help reduce pain response and inflammatory status of patients with chronic inflammation as an additional therapy.

Dermal macrophages set pain sensitivity by modulating the amount of tissue NGF through an SNX25–Nrf2 pathway

Cross-talk between peripheral neurons and immune cells is important in pain sensation. We identified Snx25 as a pain-modulating gene in a transgenic mouse line with reduced pain sensitivity. Conditional deletion of Snx25 in monocytes and macrophages, but not in peripheral sensory neurons, in mice (Snx25cKO mice) reduced pain responses in both normal and neuropathic conditions. Bone marrow transplantation using Snx25cKO and wild-type mice indicated that macrophages modulated pain sensitivity. Expression of sorting nexin (SNX)25 in dermal macrophages enhanced expression of the neurotrophic factor NGF through the inhibition of ubiquitin-mediated degradation of Nrf2, a transcription factor that activates transcription of Ngf. As such, dermal macrophages set the threshold for pain sensitivity through the production and secretion of NGF into the dermis, and they may cooperate with dorsal root ganglion macrophages in pain perception.

Evaluation of the anti-arthritic activity of Rhuflex-F - A proprietary Ayurvedic herbomineral formulation in albino rats.

Rhuflex-F is a proprietary Ayurvedic herbo-mineral formulation clinically used to combat and relieve stiffness in joints and muscles, reduce edema, restore mobility, and also effective in relieving the symptoms of other autoimmune illnesses that lead to rheumatism. The aim and objective of the research study is to evaluate the efficacy of Rhuflex-F against in vitro protein denaturation and in vivo Freund's adjuvant-induced arthritis in albino rats. In vitro inhibition of protein denaturation activity was carried out using bovine serum albumin. For in vivo activity, arthritis was induced by complete Freund's adjuvant in albino rats. Rhuflex-F (135-270 mg/kg, po) was administered for 30th days in arthritic rats, and effects were assessed on primary and secondary paw edema, on pain response, hematological, serum biochemical parameters (serum transaminases, alkaline phosphatase, urea, uric acid, and orosomucoid), and serum anti-oxidant parameters and adrenal ascorbic acid. Aqueous extract of Rhuflex-F showed in vitro protein denaturation inhibitory activity in a dose-dependent manner. Rhuflex-F showed nonsignificant decrease in primary and secondary paw edema with reduced pain response, some reversal effects on hematological parameters such as white blood cell and red blood cell related parameters and serum orosomucoid and adrenal ascorbic acid in comparison to Fruend's adjuvant control group. Further, Rhuflex-F reversed Freund's adjuvant-induced adverse effects on oxidant status in the serum of albino rats. Result of the present study suggested that Rhuflex-F formulation has anti-inflammatory activity, may be due to the inhibition of protein denaturation in vitro and in vivo anti-arthritic activity against complete Freund's adjuvant-induced arthritis in albino rats.

ЛЕЧЕНИЕ ДЛИТЕЛЬНО НЕЗАЖИВАЮЩИХ РАН С ПРИМЕНЕНИЕМ МЕТИЛУРАЦИЛА: СЛУЧАЙ ИЗ ПРАКТИКИ

The ointment Stizamet® contains methyluracil as an active ingredient, which stimulates the activity of cells in the basal and suprabasal layers of the skin, promoting their rejuvenation. The ointment also stimulates regeneration processes, accelerating wound healing, has an anti-inflammatory effect, reduces pain response, improves metabolic processes, reduces microcirculation disorders and swelling at the site of inflammation.

The Impact of Breast Milk Taste and Smell in Reducing Pain in Infants Undergoing Blood Drawing Procedure: A Randomized Controlled Study.

Background: Infants hospitalized in neonatal intensive care units (NICUs) are exposed to numerous procedures that cause pain. In the literature, pain management methods in infants are evaluated by using breast milk in various ways. However, no study was found on whether the smell of breast milk, its taste, or both are more effective in pain management. Aim: The purpose of this study is to comparatively investigate the efficacy of breast milk taste and/or smell in reducing pain responses in infants undergoing a blood drawing procedure. Methods: The population of this study, which has a randomized controlled prospective design, consisted of infants who were treated in a NICU and met the inclusion criteria. The heart rate (HR), oxygen saturation (SpO2), and pain of the infants were evaluated before, during, and after the blood drawing procedure in all groups. Results: During and after the procedure, there were significant differences in terms of pain levels, SpO2 levels, and HR between the groups (p = 0.000). The lowest pain score during the procedure was found in the infants to whom breast milk taste and smell were administered together. The group with the second-lowest pain score was exposed to the taste of breast milk. The group with the highest pain score was the control group. Conclusion: Breast milk smell and taste are recommended for use as a nursing intervention to reduce pain, decrease the HR, and increase SpO2 in the NICU during painful procedures. Future research needs to explore different interventional practices.

A36 NON-PSYCHOTROPIC PHYTOCANNABINOIDS ATTENUATE VISCERAL HYPERSENSITIVITY IN DEXTRAN SULFATE SODIUM (DSS)-INDUCED COLITIS

BackgroundThe inflammatory bowel diseases (IBD), Crohn’s disease and ulcerative colitis, are complex chronic diseases that affect an increasing proportion of the population. Abdominal pain is a major clinical symptom, but current treatments are limited and a source of frustration for patients, many of whom seek alternatives such as cannabis. Cannabis contains many compounds with therapeutic potential that do not have the prohibitive psychotropic effects of tetrahydrocannabinol. These non-psychotropic cannabinoids (npCBs) have a variety of effects including analgesia and anti-inflammatory actions and show potentiating effects when administered in combination. The range of actions of these compounds potentially allows for their development as novel therapeutics for treatment of pain in IBD.AimsTo investigate the analgesic effects of cannabichromene (CBC), cannabidiol (CBD), cannabidivarin (CBDV), and cannabigerol (CBG), individually and in combination, in the treatment of colitis-evoked visceral hypersensitivity.MethodsThe analgesic effects of the npCBs were investigated in an acute dextran sodium sulfate model of colitis. Abdominal pain was quantified by electromyographic recordings of the reflexive contraction of the external oblique muscles in response to colorectal distension. Activation of the spinal cord was assessed using immunohistochemistry for the neuronal activity marker c-Fos in neurons of the spinal dorsal horn.ResultsCBD reduced pain responses in the functional assay and spinal cord c-Fos activity in a dose-dependent manner. A single intraperitoneal injection of 10 mg/kg, 30 minutes prior to application of the noxious stimulus, reduced pain responses to the level of non-DSS treated control animals. CBDV, and CBG were found to be ineffective in either assay at doses of 1, 5, and 10 mg/kg.ConclusionsThese results suggest CBD may be a promising therapeutic agent in the treatment of colitis–induced visceral hypersensitivity with rapid translational value due to the legalization of cannabis and rapidly growing cannabis industry in Canada. Additionally, CBDV, CBC, and CBG will be further investigated for their analgesic effects and any potentiating effects from administration of multiple npCBs examined.Funding AgenciesAlberta Innovates

Essential Oil from the Stem Bark of Casuarina equisetifolia Exerts Anti-inflammatory and Anti-nociceptive Activities in Rats

Herein the chemical constituents and the anti-pain properties of the essential oil from the stem bark of Casuarina equisetifolia L. (Casuarinaceae) grown in Nigeria were evaluated. The essential oil was obtained by hydrodistillation method in an all glass Clevenger-type apparatus, and characterized by gas chromatography (GC-FID) and gas chromatography-mass spectrometry (GC-MS). The hot plate method was used to determine the anti-nociceptive property whereas the anti-inflammatory activity was evaluated by carrageenan-induced and formalin experimental models. The pale-yellow essential oil was obtained in yield of 0.21% (v/w), calculated on a dry weight basis. The main constituents of the essential oil were methyl salicylate (30.4%), a-zingiberene (15.5%), (E)-anethole (9.5%), b-bisabolene (8.6%), b- sesquiphellandrene (6.9%), and ar-curcumene (6.2%). In the anti-nociceptive study, the rate of inhibition increases as the doses of essential oil increases with optimum activity at the 30th and 60th min for all tested doses. The essential oil displayed anti-nociceptive activity independently of reaction time at the highest tested dose (200 mg/kg). The essential oil of C. equisetifolia moderately reduced pain responses in early and late phases of the formalin test. The oil inhibited the paw licking in the neurogenic phase (60-63%) compared to the late phase of the formalin test. The carrageenan- induced oedema model revealed the suppression of inflammatory mediators within the 1st - 3rd h. Thus, C. equisetifolia essential oil displayed both anti-nociceptive and anti-inflammatory activities independent of the dose tested. The anti-inflammatory and anti-nociceptive activities of C. equisetifolia essential oil are herein reported for the first time.

Potential of nafimidone derivatives against co-morbidities of epilepsy: In vitro, in vivo, and in silico investigations.

Nafimidone is known for its clinical antiepileptic effects and alcohol derivatives of nafimidone were reported be potent anticonvulsants. These compounds are structurally similar to miconazole, which is known to inhibit cholinesterases, protect neurons, and ameliorate cognitive decline. Herein, we aimed to reveal the potential of three nafimidone alcohol esters (5g, 5i, and 5k), which were previously reported for their anticonvulsant effects, against co-morbidities of epilepsy such as inflammatory and neuropathic pain, cognitive and behavioral deficits, and neuron death, and understand their roles in related pathways such as γ-butyric acid type A (GABAA ) receptor and cholinesterases using in vitro, in vivo and in silico methods. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test was used for cytotoxicity evaluation, hippocampal slice culture assay for neuroprotection, formalin test for acute and inflammatory pain, sciatic ligation for neuropathic pain, Morris water maze and open field locomotor tasks for cognitive and behavioral deficits, radioligand binding for GABAA receptor affinity, spectrophotometric methods for cholinesterase inhibition in vitro, and molecular docking in silico. The compounds were non-toxic to fibroblast cells. 5 k was neuroprotective against kainic acid-induced neuron death. 5i reduced pain response of mice in both the acute and the inflammatory phases. 5i improved survival upon status epilepticus. The compounds showed no affinity to GABAA receptor but inhibited acetylcholinesterase, 5k also inhibited butyrylcholinesterase. The compounds were predicted to interact mainly with the peripheric anionic site of cholinesterase enzymes. The title compounds showed neuroprotective, analgesic, and cholinesterase inhibitory effects, thus they bear promise against certain co-morbidities of epilepsy with neurological insults.

Efficacy of EMLA™ cream for reducing pain associated with venepuncture in felines

PICO question
 In adult cats undergoing a venepuncture procedure, does the application of a topical lidocaine based anaesthetic to the skin at the venepuncture site reduce the severity of signs associated with pain when compared to no topical anaesthetic?
 
 Clinical bottom line
 Category of research question
 Treatment
 The number and type of study designs reviewed
 Four papers were critically reviewed. Three were prospective, double-blind, randomised, controlled clinical trials, and one was a prospective, double-blind, controlled experimental trial
 Strength of evidence
 Moderate
 Outcomes reported
 The application of Eutectic Mixture of Local Anaesthetics (EMLA™) cream to clipped skin over the procedure site, a minimum of 30 minutes prior to the venepuncture procedure, significantly reduced the severity of pain-associated behaviours during jugular phlebotomy in healthy, conscious feline patients when compared to a placebo1,2. In felines sedated with dexmedetomidine and either methadone or nalbuphine, the administration of EMLA™ cream to clipped skin for 20 minutes significantly decreased the severity of pain responses during intravenous (IV) cephalic vein catheterisation when compared to no treatment3. In clinically unwell feline patients, the use of EMLA™ cream on clipped skin at the site of jugular catheterisation 60 minutes prior demonstrated reduced pain responses compared to a placebo, but further investigation with a larger sample size is required to verify statistical significance4
 Conclusion
 The available evidence moderately supports the hypothesis that EMLA™ cream is an effective and noninvasive treatment for providing enhanced pain-relief during jugular and cephalic vein phlebotomy for the purposes of blood collection and catheterisation, respectively. The areas for treatment should be clipped free of hair, and the cream applied for a minimum of 30 minutes in non-sedated cats and 20 minutes in cats sedated with dexmedetomidine and either methadone or nalbuphine. Moreover, when applied to normal, intact skin and covered by an occlusive bandage to avoid ingestion, it is well supported by supplementary evidence that EMLA™ cream has a wide safety margin for topical use in cats4,5
 
 How to apply this evidence in practice
 The application of evidence into practice should take into account multiple factors, not limited to: individual clinical expertise, patient’s circumstances and owners’ values, country, location or clinic where you work, the individual case in front of you, the availability of therapies and resources.
 Knowledge Summaries are a resource to help reinforce or inform decision making. They do not override the responsibility or judgement of the practitioner to do what is best for the animal in their care.
 

A novel placental tissue biologic, PTP-001, inhibits inflammatory and catabolic responses in vitro and prevents pain and cartilage degeneration in a rat model of osteoarthritis

Characterization of a novel human placental tissue-derived biologic, PTP-001, which is in development as a candidate therapeutic for the treatment of osteoarthritis symptoms and pathophysiology. Human placental tissues from healthy donors were prepared as a particulate formulation, PTP-001. PTP-001 extracts were assayed for the presence of disease-relevant biofactors which could have beneficial effects in treating osteoarthritis. PTP-001 eluates were tested in human chondrocyte cultures to determine effects on the production of a key collagen-degrading matrix metalloproteinase, MMP-13. PTP-001 eluates were also assessed for anti-inflammatory potential in human monocyte/macrophage cultures, as well as for growth-stimulating anabolic effects in human synoviocytes. The in vivo effects of PTP-001 on joint pain and histopathology were evaluated in a rat model of osteoarthritis induced surgically by destabilization of the medial meniscus. PTP-001 was found to contain an array of beneficial growth factors, cytokines and anti-inflammatory molecules. PTP-001 eluates dose-dependently inhibited the production of chondrocyte MMP-13, and the secretion of proinflammatory cytokines from monocyte/macrophage cultures. PTP-001 eluates also promoted proliferation of cultured synovial cells. In a rat osteoarthritis model, PTP-001 significantly reduced pain responses throughout 6 weeks post-dosing. The magnitude and duration of pain reduction following a single intraarticular treatment with PTP-001 was comparable to that observed for animals treated with a corticosteroid (active control). For rats dosed twice with PTP-001, significant reductions in cartilage histopathology scores were observed. PTP-001 represents a promising biologic treatment for osteoarthritis, with a multi-modal mechanism of action that may contribute to symptom management and disease modification.

Effects of GABAA receptors in nucleus cuneiformis on the cannabinoid antinociception using the formalin test.

Nucleus cuneiformis (NC), a reticular nucleus of the midbrain, is a part of the descending pain modulatory system and therefore has an important role in pain perception. Considering the abundance of GABAA and cannabinoid receptors in the NC and also the bidirectional roles for GABA in controlling nociception, the present study examined the effects of bilateral intra-NC microinjection of different doses of the GABAA receptor agonist, muscimol, and the GABAA receptor antagonist, bicuculline, on pain modulation using formalin test. We also assessed interaction between canabinergic and GABAergic systems in the NC during this test. Rats were exposed to intra-NC microinjection of bicuculline (50,100, and 200 ng/side) or muscimol (60, 120, and 240 ng/side) and then subjected to the formalin test. In another set of experiments, the effects of muscimol (60 ng/side) or bicuculline (50 ng/side) administration 5 min before a cannabinoid receptor agonist WIN 55,212-2 (5, 10, and 20 μg/side) microinjection into NC on the formalin test were evaluated. Microinjection of bicuculline and muscimol into the NC decreased and increased pain responses, respectively, in a dose-dependent manner during both phases of the test. Microinjection of WIN 55,212-2 into the NC significantly reduced pain responses in a dose-dependent manner. Microinjection of bicuculline or muscimol in combination with WIN 55,212-2 into the NC respectively potentiated and attenuated WIN 55,212-2-induced antinociception in the formalin test. This study shows that GABA in the NC is involved in pain modulation and suggests the existence of a GABAA-mediated inhibitory system in the NC on pain control. Furthermore, it seems that the antinociceptive effect of WIN 55,212-2 in the formalin test is mediated partly by the activity of local GABAA receptors in the NC.

Deletion of MyD88 adaptor in nociceptor alleviates low-dose formalin-induced acute pain and persistent pain in mice.

The myeloid differentiation factor 88 (MyD88) adaptor mediates signaling by Toll-like receptors and some interleukins (ILs) in neural and non-neuronal cells. Recently, MyD88 protein was found to express in primary sensory neurons and be involved in the maintenance of persistent pain induced by complete Freund's adjuvant, chronic constriction injury and chemotherapy treatment in rodents. However, whether MyD88 in nociceptive neurons contributes to persistent pain induced by intraplantar injection of formalin remains elusive. Here, using conditional knockout (CKO) mice, we found that selective deletion of Myd88 in Nav1.8-expressing primary nociceptive neurons led to reduced pain response in the recovery phase of 1% formalin-induced mechanical pain and impaired the persistent thermal pain. Moreover, CKO mice exhibited reduced phase II pain response in 1%, but not 5%, formalin-induced acute inflammatory pain. Finally, nociceptor MyD88 deletion resulted in less neuronal c-Fos activation in spinal dorsal horns following 1% formalin stimulation. These data suggest that MyD88 in nociceptive neurons is not only involved in persistent mechanical pain but also promotes the transition from acute inflammatory pain to persistent thermal hyperalgesia induced by low-dose formalin stimulation.

Interplay between Heat Shock Proteins, Inflammation and Pain: A Promising Therapeutic Approach.

Heat Shock Proteins (HSPs) are important molecular chaperones that facilitate many functions of the cells. They also play a pivotal role in cell survival, especially in the presence of stressors, including nutritional deprivation, lack of oxygen, fever, alcohol, inflammation, oxidative stress, heavy metals, as well as conditions that cause injury and necrosis. In the face of a painful stimulus encounter, many factors could be associated with pain that may include nitric oxide, excitatory amino acids, reactive oxygen species (ROS) formation, prostaglandins, and inflammatory cytokines. One influential factor affecting pain reduction is the expression of HSPs that act as a ROS scavenger, regulate the inflammatory cytokines, and reduce pain responses subsequently. Hence, we assembled information on the painkilling attributes of HSPs. In this field of research, new painkillers could be developed by targetting HSPs to alleviate pain and widen our grasp of pain in pathological conditions and neurological diseases.