Inflammatory Pain In Rats Research Articles

Peripheral NLR family pyrin domain-containing 3 protein pathway participates in the development of orofacial inflammatory pain in rats

Peripheral NLR family pyrin domain-containing 3 protein pathway participates in the development of orofacial inflammatory pain in rats

Trim14-IκBα Signaling Regulates Chronic Inflammatory Pain in Rats and Osteoarthritis Patients

Chronic inflammatory pain is the highest priority for people with osteoarthritis when seeking medical attention. Despite the availability of NSAIDs and glucocorticoids, central sensitization and peripheral sensitization make pain increasingly difficult to control. Previous studies have identified the ubiquitination system as an important role in the chronic inflammatory pain. Our study displayed that the E3 ubiquitin ligase tripartite motif-containing 14 (Trim14) was abnormally elevated in the serum of patients with osteoarthritis and pain, and the degree of pain was positively correlated with the degree of Trim14 elevation. Furthermore, CFA-induced inflammatory pain rat model showed that Trim14 was significantly increased in the L3-5 spinal dorsal horn (SDH) and dorsal root ganglion (DRG), and in turn the inhibitor of nuclear factor Kappa-B isoform α (IκBα) was decreased after Trim14 elevation. After intrathecal injection of Trim14 siRNA to inhibit Trim14 expression, IκBα expression was reversed and increased, and the pain behaviors and anxiety behaviors of rats were significantly relieved. Overall, these findings suggested that Trim14 may contribute to chronic inflammatory pain by degrading IκBα, and that Trim14 may become a novel therapeutic target for chronic inflammatory pain.

The Role of p38 Mitogen-Activated Protein Kinase-Mediated F-Actin in the Acupuncture-Induced Mitigation of Inflammatory Pain in Arthritic Rats.

The analgesic efficacy of acupuncture has been widely recognized. However, the mechanism by which manual acupuncture-generated mechanical stimuli translate into biological signals remains unclear. This study employed a CFA-induced inflammatory pain rat model. Acupuncture intervention was then performed following standardized procedures. Enzyme-linked immunosorbent assay (ELISA) assessed inflammatory cytokines levels, while immunofluorescence and qRT-PCR screened the level of p38 and F-actin expression in the ST36 acupoint area of rats. Results indicated increased inflammatory factors, including IL-1β and TNFα, with reduced paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) in CFA rats compared to unmodeled rats. After acupuncture intervention, the heightened expression level of F-actin and p38 mRNA and the phosphorylation of p38 in the acupoint area was observed alongside decreased inflammatory factors in diseased ankle joints. The application of lifting and thrusting manipulations further enhanced the effect of acupuncture, in which the molecular expression level of muscle and connective tissue increased most significantly, indicating that these two tissues play a major role in the transformation of acupuncture stimulation. Moreover, antagonizing p38 expression hindered acupuncture efficacy, supporting the hypothesis that p38 MAPK-mediated F-actin transduces mechanical signals generated by acupuncture and related manipulation into biological signals.

Adolescent morphine exposure changes the endogenous vlPAG opioid response to inflammatory pain in rats.

Adolescence is one of the most critical periods for brain development, and exposure to morphine during this period can have long-life effects on pain-related behaviors. The opioid system in the periaqueductal gray (PAG) is highly vulnerable to drug exposure. However, the impact of adolescent morphine exposure (AME) on the endogenous opioid system in the PAG is currently unknown. This study aims to investigate the long-lasting effects of AME on the endogenous opioid system and its involvement in altering nociceptive behaviors. Adolescent rats were given escalating doses of morphine (2.5-25mg/kg, subcutaneous) or an equal volume of saline twice daily for 10 consecutive days (PND 31-40). After a 30-day washout period, adult rats underwent formalin tests following microinjection of morphine, naloxone, or saline into the ventrolateral PAG (vlPAG) region. The results indicated that morphine microinjection into the vlPAG of the adolescent morphine-treated group significantly reduced the nociceptive score. However, the analgesic response to morphine in this group was significantly lower compared to the saline-treated group during adolescence. Additionally, the nociceptive score significantly increased following naloxone but not saline microinjection into the vlPAG of the saline-treated group during adolescence, rather than the morphine-treated one. These findings indicate that AME has long-lasting effects on the endogenous opioid system in the vlPAG, which can consequently alter behaviors related to inflammatory pain in adulthood.

MiR‑3120/Hsc70 participates in forced swim stress‑induced mechanical hyperalgesia in rats in an inflammatory state.

The heat shock cognate 71kDa protein (Hsc70) is a stress‑inducible ATPase that can protect cells against harmful stimuli. Transient receptor potential vanilloid 1 (TRPV1) is a well‑documented nociceptor. Notably, Hsc70 can inhibit TRPV1 expression and function, suggesting that Hsc70 may have pain regulation potential. However, the role of Hsc70 in stress‑induced hyperalgesia remains unclear. In the present study, the participation of Hsc70 and its regulator microRNA (miR)‑3120 were investigated in forced swim (FS) stress‑induced mechanical hyperalgesia in rats in an inflammatory state. Complete Freund's adjuvant (CFA) hind paw injection was performed to induce inflammatory pain in rats (CFA rats). Furthermore, in FS+CFA rats, FS stress was performed for 3days before CFA injection. The levels of Hsc70, miR‑3120 and their downstream molecule TRPV1 were measured in the dorsal root ganglion (DRG) with western blotting, immunofluorescence, reverse transcription‑quantitative polymerase chain reaction and fluorescence insitu hybridization. The results revealed that FS stress significantly exacerbated CFA‑induced mechanical pain. Furthermore, CFA upregulated Hsc70 and TRPV1 expression, which was partially inhibited or further enhanced by FS stress, respectively. In FS+CFA rats, intrathecal injection of a lentiviral vector overexpressing Hsc70 (LV‑Hsc70) could decrease TRPV1 expression and improve the mechanical pain. Additionally, the expression levels of miR‑3120, a regulator of Hsc70, were markedly upregulated on day3 following FS stress. Finally, miR‑3120 was identified to be colocalized with Hsc70 and expressed in all sizes of DRG neurons. In CFA rats, DRG injection of miR‑3120 agomir to induce overexpression of miR‑3120 resulted in similar TRPV1 expression and behavioral changes as those caused by FS stress, which were abolished in the presence of LV‑Hsc70. These findings suggested that miR‑3120/Hsc70 may participate in FS stress‑induced mechanical hyperalgesia in rats in an inflammatory state, possibly via disinhibiting TRPV1 expression in the DRG neurons.

Synthesis, characterization and evaluation of anti-hyperalgesia, anticonvulsant and antioxidant activity of novel VV-hemorphin-5 analogs.

Two series of new VV-hemorphin-5 analogs with structures Val-Val-Tyr-Xxx-Trp-Thr-Gln-NH2 and Adam-Val-Val-Tyr-Xxx-Trp-Thr-Gln-NH2 , where Xxx is Ac5c (1-aminocyclopentane-1-carboxylic acid), Ac6c (1-aminocyclohexane-1-carboxylic acid), Ac7c (1-aminocycloheptane-1-carboxylic acid), and Adam is the low-molecular-weight lipophilic adamantyl building block, were synthesized, characterized electrochemically and evaluated for antioxidant, anti-hyperalgesia, and anticonvulsant activity. The design of the compounds followed the strategy to improve the propensity for aqueous solubility and/or to increase their affinity for the target receptor or enzyme. The partition coefficient value shows that the peptide scaffold goes from hydrophilic to lipophilic with the increasing size of the cycloalkane ring and even more with the introduction of the adamantane. The peptides C5-V and C7-V were the only analogs that provoked an immediate antinociceptive effect changing the mechanical pain threshold. The six new peptide analogs produced a significant and long-lasting carrageenan model of inflammatory pain in rats. While the adamantane hemorphin analog Ad7-V was the only compound with the potency to suppress psychomotor seizures in the 6-Hz test, the C6-V and Ad6-V exhibited protective activity against the seizure spread in the maximal electroshock seizure test in mice. The active analogs did not show neurotoxicity or sedative effects. Our results revealed a structure-related specific activity of a newly designed hemorphin analog that could be used as a template for future modification and preparation of compounds with potential analgesic and anticonvulsant activity.

The ethanol extract of Scutellaria baicalensis Georgi attenuates complete Freund's adjuvant (CFA)-induced inflammatory pain by suppression of P2X3 receptor

Ethnopharmacological relevanceScutellaria baicalensis Georgi (SBG) is a perennial herb with anti-inflammatory, antibacterial, and antioxidant activities, which is traditionally used to treat inflammation of respiratory tract and gastrointestinal tract, abdominal cramps, bacterial and viral infections. Clinically, it is often used to treat inflammatory-related diseases. Research has shown that the ethanol extract of Scutellaria baicalensis Georgi (SGE) has anti-inflammatory effect, and its main components baicalin and baicalein have analgesic effects. However, the mechanism of SGE in relieving inflammatory pain has not been deeply studied. Aim of the studyThis study aimed to evaluate the analgesic effect of SGE on complete Freund's adjuvant (CFA)-induced inflammatory pain rats, and to investigate whether its effect on relieving inflammatory pain is associated with regulation of P2X3 receptor. Materials and methodsThe analgesic effects of SGE on CFA-induced inflammatory pain rats were evaluated by measuring mechanical pain threshold, thermal pain threshold, and motor coordination ability. The mechanisms of SGE in relieving inflammatory pain were explored by detecting inflammatory factors levels, NF-κB, COX-2 and P2X3 expression, and were further verified by addition of P2X3 receptor agonist (α, β me-ATP). ResultsOur results revealed that SGE can notably increase the mechanical pain threshold and thermal pain threshold of CFA-induced inflammatory pain rats, and markedly alleviate the pathological damage in DRG. SGE could suppress the release of inflammatory factors including IL-1β, IL-6, TNF-α and restrain the expression of NF-κB, COX-2 and P2X3. Moreover, α, β me-ATP further exacerbated the inflammatory pain of CFA-induced rats, while SGE could markedly raise the pain thresholds and relieve inflammatory pain. SGE could attenuate the pathological damage, inhibit P2X3 expression, inhibit the elevation of inflammatory factors caused by α, β me-ATP. SGE can also inhibit NF-κB and ERK1/2 activation caused by α, β me-ATP, and inhibit the mRNA expression of P2X3, COX-2, NF-κB, IL-1β, IL-6 and TNF-α in DRG of rats induced by CFA coupled with α, β me-ATP. ConclusionsIn summary, our research indicated that SGE could alleviate CFA-induced inflammatory pain by suppression of P2X3 receptor.

Ketoprofen, lysine and gabapentin co-crystal magnifies synergistic efficacy and tolerability of the constituent drugs: Pre-clinical evidences towards an innovative therapeutic approach for neuroinflammatory pain

Chronic pain is an enormous public health concern, and its treatment is still an unmet medical need. Starting from data highlighting the promising effects of some nonsteroidal anti-inflammatory drugs in combination with gabapentin in pain treatment, we sought to combine ketoprofen lysine salt (KLS) and gabapentin to obtain an effective multimodal therapeutic approach for chronic pain. Using relevant in vitro models, we first demonstrated that KLS and gabapentin have supra-additive effects in modulating key pathways in neuropathic pain and gastric mucosal damage. To leverage these supra-additive effects, we then chemically combined the two drugs via co-crystallization to yield a new compound, a ternary drug-drug co-crystal of ketoprofen, lysine and gabapentin (KLS-GABA co-crystal). Physicochemical, biodistribution and pharmacokinetic studies showed that within the co-crystal, ketoprofen reaches an increased gastrointestinal solubility and permeability, as well as a higher systemic exposure in vivo compared to KLS alone or in combination with gabapentin, while both the constituent drugs have increased central nervous system permeation. These unique characteristics led to striking, synergistic anti-nociceptive and anti-inflammatory effects of KLS-GABA co-crystal, as well as significantly reduced spinal neuroinflammation, in translational inflammatory and neuropathic pain rat models, suggesting that the synergistic therapeutic effects of the constituent drugs are further boosted by the co-crystallization. Notably, while strengthening the therapeutic effects of ketoprofen, KLS-GABA co-crystal showed remarkable gastrointestinal tolerability in both inflammatory and chronic neuropathic pain rat models. In conclusion, these results allow us to propose KLS-GABA co-crystal as a new drug candidate with high potential clinical benefit–to–risk ratio for chronic pain treatment.

Retraction statement: Li B and Zheng J (2018) MicroR-9-5p suppresses EV71 replication through targeting NFκB of the RIG-I-mediated innate immune response. FEBS Open Bio 8, 1457-1470.

FEBS Open BioVolume 13, Issue 4 p. 795-795 Retraction NoticeOpen Access Retraction statement: Li B and Zheng J (2018) MicroR-9-5p suppresses EV71 replication through targeting NFκB of the RIG-I-mediated innate immune response. FEBS Open Bio 8, 1457–1470. This article retracts the following: Retraction statement: Li B and Zheng J (2018) MicroR-9-5p suppresses EV71 replication through targeting NFκB of the RIG-I-mediated innate immune response. FEBS Open Bio 8, 1457–1470. Volume 13Issue 4FEBS Open Bio pages: 795-795 First Published online: March 17, 2023 Retraction(s) for this article Retraction statement: Li B and Zheng J (2018) MicroR-9-5p suppresses EV71 replication through targeting NFκB of the RIG-I-mediated innate immune response. FEBS Open Bio 8, 1457–1470. Volume 13Issue 4FEBS Open Bio pages: 795-795 First Published online: March 17, 2023 First published: 17 March 2023 https://doi.org/10.1002/2211-5463.13583AboutSectionsPDF ToolsExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL https://doi.org/10.1002/2211-5463.12490. The above article, published online on 14 July 2018 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the Editor-in-Chief, FEBS Press, and John Wiley and Sons Ltd. The retraction has been agreed following an investigation into concerns raised by a third party, which revealed inappropriate duplications between this and other published articles [[1-4]]. Thus, the editors consider the conclusions of this manuscript substantially compromised. References 1Lv G, Zhu G, Xu M, Gao X and Xiao Q (2020) Inhibition of carrageenan-induced dental inflammatory responses owing to decreased TRPV1 activity by dexmedetomidine. J Inflamm 17, 18. 2Bai Z, Zhao X, Li C, Sheng C and Li H (2020) EV71 virus reduces Nrf2 activation to promote production of reactive oxygen species in infected cells. Gut Pathog 12, 22. 3Huang L, Jian Z, Gao Y, Zhou P, Zhang G, Jiang B and Lv Y (2019) RPN2 promotes metastasis of hepatocellular carcinoma cell and inhibits autophagy via STAT3 and NF-κB pathways. Aging 11, 6674– 6690. 4Lan J, Zheng J, Feng J and Peng W (2020) Nrf2 mediates the antinociceptive activity of dexmedetomidine in an acute inflammatory visceral pain rat model by activating the NF-κB sensor. Cell Biochem Funct 38, 97– 105. Volume13, Issue4April 2023Pages 795-795 ReferencesRelatedInformation

The volatile oil from Acori Graminei Rhizoma downregulates NMDARs-ERK1/2-CREB signaling pathway to alleviate pain related emotions induced by inflammatory pain in rats

ObjectiveTo investigate whether Acori Graminei Rhizoma (AGR) volatile oil can reduce inflammatory pain-induced pain-related mood in rats by downregulating NMDARs-ERK 1/2-CREB signaling pathway. MethodsThirty-six male SD rats were randomly divided into six groups: control group, sham group, complete Freund's adjuvant (CFA) group, CFA + 0.1 mL/10 g volatile oil group, CFA + 0.2 mL/10 g volatile oil group, and CFA + 0.4 mL/10 g volatile oil group. Six rats in each group were gavaged for 21 days and tested for mechanical pain hypersensitivity and positional avoidance (PEAP) before and after drug treatment. In addition, another batch of thirty-six male SD rats were randomly divided into six groups, including control, sham, CFA, CFA + saline, CFA + 0.1 mg/kg NMDA, and CFA + 0.1 mg/kg Ifenprodil groups. The control group did not receive any treatment, and the sham group received the same volume of sterile saline at the same site. Animals in each group were tested for mechanical pain hypersensitivity and positional avoidance before and after drug treatment. The expression levels of NMDAR1, NMDAR2A, NMDAR2A2B, mGlur1, ERK 1/2, CREB, and c-Fos in the basolateral amygdala (BLA) were determined by immunofluorescent staining and Western blot methods. ResultsAGR essential oil could reduce mechanical hyperalgesia and position avoidance in animals caused by CFA, and down-regulate NMDARs, mGlur1/5, ERK 1/2 and CREB expression. While up-regulation of c-Fos expression by NMDAR inhibitor Ifenprodil, reversed the above phenomena. ConclusionAGR essential oil alleviates inflammatory pain-induced pain-related mood in rats through downregulation of the NMDARs-ERK1/2-CREB signaling pathway.

Transcriptional profiles of TGF-β superfamily members in the lumbar DRGs and the effects of activins A and C on inflammatory pain in rats.

Signaling by the transforming growth factor (TGF)-β superfamily is necessary for proper neural development and is involved in pain processing under both physiological and pathological conditions. Sensory neurons that reside in the dorsal root ganglia (DRGs) initially begin to perceive noxious signaling from their innervating peripheral target tissues and further convey pain signaling to the central nervous system. However, the transcriptional profile of the TGF-β superfamily members in DRGs during chronic inflammatory pain remains elusive. We developed a custom microarray to screen for transcriptional changes in members of the TGF-β superfamily in lumbar DRGs of rats with chronic inflammatory pain and found that the transcription of the TGF-β superfamily members tends to be downregulated. Among them, signaling of the activin/inhibin and bone morphogenetic protein/growth and differentiation factor (BMP/GDF) families dramatically decreased. In addition, peripherally pre-local administration of activins A and C worsened formalin-induced acute inflammatory pain, whereas activin C, but not activin A, improved formalin-induced persistent inflammatory pain by inhibiting the activation of astrocytes. This is the first report of the TGF-β superfamily transcriptional profiles in lumbar DRGs under chronic inflammatory pain conditions, in which transcriptional changes in cytokines or pathway components were found to contribute to, or be involved in, inflammatory pain processing. Our data will provide more targets for pain research.

Modulation of inflammatory mediators involved in the antinociceptive and anti-inflammatory effects of a new thioamide derivative: thiocyanoacetamide.

Inflammatory pain is part of the body's defense mechanism and plays an important role in the healing process. Although some drugs are efficient and intensively used for their potent anti-inflammatory properties, they present problematic side effects. The aim of this study was to evaluate the anti-nociceptive effect of the thiocyanoacetamide (Thm) compared to paracetamol (Para), dexamethasone (Dex) and morphine (Morph) and to study inflammatory mediators on models of acute inflammatory pain in rats using the formalin injection test in the hind paw of rats as chemical stimulus. The obtained results showed significant modulation of pain by Thm pretreatment with a maximum at an effective dose (10mg/kg) proved by the absence of lickingand biting of the affected paw during the early and late phases of inflammation. This effect was comparable to Dex at 10mg/kg, Para at 400mg/kg and less than Morph at 5mg/kg pretreatment doses. The study of anti-inflammatory targets showed that Thm pretreatment maintained plasma serotonin release at normal level compared to the negative control group (T-) and corrected the decrease in the plasma level of prostaglandins after inflammatory induction with no variation in the level of histamine in different groups. The evaluation of inflammation mediators demonstrated that the pretreatment with Thm induced the decrease in the amount of both IL-1 Beta and TNF alpha in plasma and the increase in their amount in the tissue of the injection site. The Thm has been promoted as an anti-nociceptive drug that induces modulation of inflammatory mediators.

Xueliankoufuye Suppresses Microglial Activation with Inflammatory Pain by Blocking NF-κB Signaling Pathway.

Xuelian, as a traditional Chinese ethnodrug, plays an important role in anti-inflammation, immunoregulation, promoting blood circulation, and other physiological functions. It has been prepared into different traditional Chinese medicine preparations for clinical use, with xuelian koufuye (XL) being widely used to treat rheumatoid arthritis. However, whether XL can relieve inflammatory pain and its analgesic molecular mechanism are still unknown. The present study explored the palliative effect of XL on inflammatory pain and its analgesic molecular mechanism. In complete Freund's adjuvant (CFA)-induced inflammatory joint pain, oral XL dose-dependently improved the mechanical withdrawal threshold of inflammatory pain from an average value of 17.8 g to 26.6 g (P < 0.05) and high doses of XL significantly reduced inflammation-induced ankle swelling from an average value of 3.1 cm to 2.3 cm compared to the model group (P < 0.05). In addition, in carrageenan-induced inflammatory muscle pain rat models, oral XL dose-dependently improved the mechanical withdrawal threshold of inflammatory pain from an average value of 34.3 g to 40.8 g (P < 0.05). The phosphorylated p65 was inhibited in LPS-induced BV-2 microglia and spinal cord of mice in CFA-induced inflammatory joint pain within a value of 75% (P < 0.001) and 52% reduction (P < 0.05) on average, respectively. In addition, the results showed that XL could effectively inhibit the expression and secretion of IL-6 from an average value of 2.5 ng/ml to 0.5 ng/ml (P < 0.001) and TNF-α from 3.6 mg/ml to 1.8 ng/ml with IC50 value of 20.15 μg/mL and 112 μg/mL respectively, by activating the NF-κB signaling pathway in BV-2 microglia (P < 0.001). The above-given results provide a clear understanding of the analgesic activity and mechanism of action not found in XL. Considering the significant effects of XL, it can be evaluated as a novel drug candidate for inflammatory pain, which establishes a new experimental basis for expanding the indications of XL in clinical treatment and suggests a feasible strategy to develop natural analgesic drugs.

Dexamethasone-Loaded biodegradable magnetic microparticles for treatment of CFA-induced chronic pain in rats

ABSTRACT Traditional drug solutions or suspensions, have been shown to treat pain in complete Freund’s adjuvant (CFA)-induced chronic inflammatory pain in rats, with or without combination with magnetic therapy. In this study, we aimed to prepare, characterize, and evaluate the therapeutic effects of microparticles containing dexamethasone for local administration and treatment of chronic inflammatory pain. The results showed the following; a) Preparation and characterization: two ratios of poly(lactic-co-glycolic acid) (PLGA)/poly(lactic acid) (PLA) were used. The prepared batches were similar in size and magnetic responsiveness. The microparticle size distribution assessed via electron microscopy suggested a homogeneous distribution and absence of aggregates. Dexamethasone release profiles (microparticles synthesized with a feed ratio of 1:4) showed a sustained release in vitro and good biocompatibility with tissues. b) Therapeutic effect: the treatment effect of dexamethasone-PLGA magnetic microspheres + magnetic therapy was substantially better than that observed for other groups on day 4, as monitored by appearance, mechanical pain threshold, and histological analysis. This type of carrier could be a suitable magnetically retainable local drug delivery system for treating chronic pain.

TRPV1 and GABAB1 in the Cerebrospinal Fluid-Contacting Nucleus are Jointly Involved in Chronic Inflammatory Pain in Rats.

To assess the receptors of TRPV1 and GABAB1 receptors that were colocalized in cerebrospinal fluid contacting nucleus (CSF-contact nucleus) of chronic inflammatory pain (CIP) rats bringing inspiration for reducing chronic pain. A rat model of CIP was constructed by plantar injection of complete Freund's adjuvant (CFA), and the paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) were measured 1, 3, 5, 7, 10, and 14 days after plantar injection. In the first part of the experiment, rats with CIP were divided into the immunofluorescence group and the coimmunoprecipitation (Co-IP) group (n = 6). Rats in the immunofluorescence group were injected with the retrograde tracer CB conjugated with Alexa Fluor 594 into the lateral ventricle two days before the injection of CFA into the plantar surface of the left paw. Three days later, rats that exhibited hyperalgesia were perfused, and their brains were extracted and used for double immunofluorescence staining of the CSF-contacting nucleus. Rats in the Co-IP group were anesthetized and dissected 3 days after CFA injection, and fresh brain segments containing the CSF-contacting nucleus were collected for Co-IP to assess the colocalization of TRPV1 and GABAB1 in the CSF-contacting nucleus (n = 6). In the second part of the experiment, SD rats were divided into the normal saline group (control group) and the CFA group. Fresh CSF-contacting nucleus-containing tissues were collected for Western blot analysis 3 days after plantar injection to observe the changes in TRPV1 and GABAB1 expression in the CSF-contacting nucleus. TRPV1 and GABAB1 were co-expressed in the CSF-contacting nucleus in rats with CIP, and their expression was upregulated. TRPV1 and GABAB1 in the CSF-contacting nucleus are jointly involved in CIP in rats, and there is a direct or indirect link between TRPV1 and GABAB1.

Preclinical comparison of antinociceptive effects between ibuprofen, diclofenac, naproxen, and acetaminophen on acid-stimulated body stretching and acid-depressed feeding behaviors in rats.

Pain is a major problem that burdens the health and economy of societies worldwide. Nonsteroidal anti-inflammatory drugs (NSAIDs) are over-the-counter medications that are widely indicated for mild to moderate pain conditions. Clinically, the selection of a medication among this class is mainly based according to both patient's and doctor's previous experiences. Herein, we studied differences in therapeutic efficacies among the most commonly prescribed NSAIDs and acetaminophen in inflammatory pain rat model. Body stretching and food consumption behaviors were assessed after intraperitoneal administration of lactic acid. Initially, different concentrations of lactic acid were evaluated in adult male rats in both behavioral models. Acid concentrations of 1.8 and 3.2% were selected to assess the effects of ibuprofen, diclofenac, naproxen, and acetaminophen in body stretching and feeding behaviors, respectively. In the feeding study, food restriction for 1-24 h prior to feeding studies was assessed at first, and 24 h was selected for further tests. Acetaminophen (100 mg/kg), diclofenac (10 mg/kg), ibuprofen (10-32 mg/kg), and naproxen (3.2-10 mg/kg) significantly decreased acid-stimulated body stretching. Likewise, acetaminophen (100 mg/kg), diclofenac (10 mg/kg), and ibuprofen (32 mg/kg) increased food consumption significantly after 3.2% lactic acid. There were no significant differences between different test drugs efficacies in both stretching and feeding behaviors. In conclusion, feeding behavior provides a good appraisal for pain and analgesic drugs in preclinical studies. There were comparable efficacies between all tested medications in both lactic acid-stimulated body stretching and -depressed feeding behaviors.

Investigation of the Antinociceptive Activity of the Hydroethanolic Extract of Junglas nigra Leaf by the Tail-Immersion and Formalin Pain Tests in Rats

BackgroundJuglans (J.) nigra leaf is obtained from a plant that is used in traditional medicine in some countries to alleviate inflammatory diseases.AimThe aim of this study was to compare the effects of J. nigra extract on acute nociceptive and inflammatory pain in rats.MethodsAntinociceptive activity was examined in Wistar rats by the tail-immersion and formalin tests. Motor function was assessed using the rotarod test. Plant extract was administered intraperitoneally.ResultsIn the tail-immersion test, the maximal antinociceptive effect of the plant extract (100–330 mg/kg) was about 24–30% and is the result of the effect of a high concentration of ethanol. In the formalin test, the plant extract (41.3–330 mg/kg) significantly and dose-dependently inhibited nociception in both phases of the test with similar maximal effects of about 76% and 85%. Only the plant extract at the dose of 330 mg/kg caused a significant time-dependent reduction in time spent on the rotarod.ConclusionsIn rats, the preventive systemic administration of the hydroethanolic extract of J. nigra leaf reduced chemically but not thermally induced pain. Higher efficacy was obtained in pain associated with inflammation and tissue injury. The antinociceptive effect is dose-dependent and may be limited by motor impairment.

Synergistic Antinociceptive Effects of Indomethacin-Pregabalin and Meloxicam-Pregabalin in Paclitaxel-Induced Neuropathic Pain.

Neuropathic pain is often closely associated with nerve injury or inflammation, and the role of traditional nonsteroidal anti-inflammatory drugs as adjuvants for treating chemotherapy-induced peripheral neuropathic pain remains unclear. In this study, the potential synergistic antinociceptive effects of indomethacin–pregabalin and meloxicam–pregabalin were evaluated in paclitaxel-induced neuropathic pain and carrageenan-induced inflammatory pain in rodents. Although indomethacin and meloxicam alone only slightly relieved mechanical allodynia in the above two models, isobolographic analysis showed that the combination of indomethacin or meloxicam with pregabalin produced significant synergistic antinociceptive effects for paclitaxel-induced neuropathic pain (IN-PGB, experimental ED25 = [4.41 (3.13–5.82)] mg/kg, theoretical ED25 = [8.50 (6.62–10.32)] mg/kg; MEL-PGB, experimental ED25 = [3.96 (2.62–5.46)] mg/kg, theoretical ED25 = [7.52 (5.73–9.39)] mg/kg). In addition, MEL-PGB dosed via intraplantar injection into the left paw, intragastric injection, or intraperitoneal injection reversed paclitaxel-induced allodynia, indicating that they may act at multiple sites in the neuroaxis and periphery. However, indomethacin–pregabalin and meloxicam–pregabalin exerted antagonistic antiallodynic interactions in carrageenan-induced inflammatory pain in rats. Taken together, coadministration of indomethacin or meloxicam with pregabalin may possess potential therapeutic advantages for treating chemotherapy-induced neuropathic pain.

LncRNA MEG3-TRPV1 signaling regulates chronic inflammatory pain in rats.

Osteoarthritis (OA) is a common osteoarthropathy with chronic inflammatory pain as the core symptom in middle-aged and elderly people. LncRNA MEG3 (Maternally expressed gene 3) is involved in the development of OA via regulation of angiogenesis, which causes the activation and overexpression of transient receptor potential vanilloid type-1 (TRPV1). In this study, we investigated the mechanism of MEG3-TRPV1 signaling in chronic inflammatory pain (CIP) of rat model. Chronic inflammatory pain was modeled using subcutaneous microinjection of complete Freund's adjuvant (CFA) into the left hind paw of rats. We showed that TRPV1 mRNA and protein were significantly increased, while MEG3 mRNA was significantly decreased, in the DRG and SDH of CFA-induced rats. In addition, intrathecal injection of MEG3-overexpressing lentivirus significantly downregulated TRPV1 expression and alleviated chronic inflammatory pain in CFA-induced rats. Treatment with a TRPV1 antagonist also significantly relieved chronic inflammatory pain in CFA-induced rats. In general, our results reveal that MEG3 alleviates chronic inflammatory pain by downregulating TRPV1 expression. These findings may provide new therapeutic targets in the treatment of patients with OA.

Nalbuphine alleviates inflammation by down-regulating NF-κB in an acute inflammatory visceral pain rat model

IntroductionNalbuphine can relieve patients’ inflammation response after surgery compared to other opioid drugs. However, its molecular mechanism has not been clear. Activation of NF-κB signaling pathway under oxidative stress and inflammation can maintain pain escalation.MethodsWe firstly investigated the effect of nalbuphine on writhing test and mechanical allodynia using a rat model of inflammatory visceral pain (acetic acid (AA) administrated). Cytokines (including tumor necrosis factor (TNF)-α, Interleukin (IL)-1β, IL-2, and IL-6 in plasma were tested with ELISA technology. Expression levels of TNF-α, IκBα and p-NF-κB p65 at the spinal cord (L3–5) were measured by western blot or RT-qPCR.ResultsWe found that the paw withdrawal threshold (PWT) values of rats were reduced in the model group, while the numbers of writhing, levels of IL-1β, IL-2, IL-6, and TNF-α in plasma, and p-NF-κB protein and its gene expressions in the lumbar spinal cord were up-regulated. Subcutaneously injection of nalbuphine (10 μg/kg) or PDTC (NF-κB inhibitor) attenuated acetic acid-induced inflammatory pain, and this was associated with reversal of up-regulated IL-1β, IL-2, IL-6, and TNF-α in both plasma and spinal cord. Furthermore, acetic acid increased p-NF-κB and TNF-α protein levels in the white matter of the spinal cord, which was attenuated by nalbuphine. These results suggested that nalbuphine can significantly ameliorate inflammatory pain via modulating the expression of NF-κB p65 as well as inflammation factors level in the spinal cord.ConclusionIn conclusion, nalbuphine inhibits inflammation through down-regulating NF-κB pathway at the spinal cord in a rat model of inflammatory visceral pain.