Antinociceptive Effect Research Articles

Anti-Inflammatory and Antinociceptive Properties of the Quercetin-3-Oleate AV2, a Novel FFAR1 Partial Agonist

Free fatty acid receptor 1 (FFAR1) has emerged as the most targeted isoform of the free fatty acid receptors because of its involvement in the modulation of energy balance and its potential role in the control of inflammatory and pain conditions. Quercetin-3-oleate (AV2), recognized as a new FFAR1 partial agonist, was investigated for its ability to modulate inflammation and nociception. Human immortal neuroblastoma SH and the murine macrophagic RAW 264.7 cells were used to evaluate cell viability, the potential cytoprotective activity, and the anti-inflammatory properties of AV2 in vitro. Paw edema, caused by zymosan-A, and the formalin test were used to assess the in vivo anti-inflammatory and antinociceptive effects in CD-1 mice. In vitro, AV2 was devoid of cytotoxicity, significantly reduced ROS in both cell types, and protected RAW 264.7 cells from lipopolysaccharide damage by reducing tumor necrosis factor-α production. Interestingly, AV2 induced a transient elevation of intracellular calcium that was reduced in cells, pre-incubated with the FFAR1 antagonist DC260126. In vivo, AV2 reduced formalin-induced nociception and zymosan A-induced paw edema, and both effects were reversed by the FFAR1 antagonist GW1100. In conclusion, these data strongly support the AV2-mediated antioxidant, anti-inflammatory, and antinociceptive activity. AV2 represents a promising molecule for the clinical management of inflammatory-related pain conditions.

Structure-Activity Relationship of 7-Chloro-4-(Phenylselanyl) Quinoline: Novel Antinociceptive and Anti-Inflammatory Effects in Mice.

The 7-chloro-4-(phenylselanyl)quinoline (4-PSQ) stands out for its potential antinociceptive and anti-inflammatory activities. Thus, in this study we investigated the structure-activity relationship of 4-PSQ and its analogues 7-chloro-4-[(4-fluorophenyl) selanyl]quinoline (a), 7-chloro-4-{[3-trifluoromethyl)phenyl] selanyl}quinoline (b), 4-((3,5-Bis(trifluoromethyl)phenyl)selanyl-7-chloroquinoline (c), 7-chloro-4-[(2,4,6-trimethyl)selanyl]quinolinic acid (d) and 7-chloroquinoline-4-selenium acid (e) in models of acute inflammation and chemical, thermal and mechanical nociception in mice, as well as by in silico methods. The compoundsa(-F),b(-CF3),c(-Bis-CF3),d(-CH3),e(-OOH) and 4-PSQ exert antinociceptive effects in chemical and thermal nociception models, except compoundsd(-CH3) ande(-OOH) that did not show antinociceptive effects in the hot plate test. In addition, treatments with all compounds did not cause locomotor changes in mice. In silico datathe compounds revealed that only compoundc(Bis-CF3) exhibited low gastrointestinal absorption and that compoundsc(Bis-CF3) ande(-OOH) do not have the ability to penetrate the blood-brain barrier, indicating that compounde(-OOH) did not produce a central antinociceptive effect. Furthermore, we found that this class of compounds has a higher affinity for COX-2 than for COX-1. In general, our data indicate that the insertion of substituents can alter the efficiency of 4-PSQ as an antinociceptive and anti-inflammatory agent.

The Development of a Novel Nanoherbal Passionfruit (Passiflora edulis) Leaves with Safety and Analgesic Effect

Passionfruit (Passiflora edulis) leaves are proven to contain flavonoids especially quercetin and showed a significant antinociceptive effect at acetic acid-induced wriggling. Modification of passionfruit leaf extract into nanoparticles can provide therapeutic effects precisely, quickly, and optimally. This study aimed to provide the method of preparation, and characterization of nanoherbal passionfruit leaves (NPL) and evaluate its safety profiles and analgesic effect. NPL was synthesized using ionic gelation methods, with 3 formula variations. Passionfruit leaf extract was dissolved using mixed solvents. The passionfruit leaves extract solution was suspended in Chitosan and dripped with sodium tripolyphosphate solution until nanoparticle formation. The characterization of the NPL study was evaluated by measuring the particle size, polydispersity index (PI), zeta potential, entrapment efficiency (EE), drug release, and transmission electron microscope (TEM) images. The safety profiles of NPL were then assessed in mice by acute and subchronic toxicity using OECD methods. The effectiveness of NPL as an analgesic was tested using an acetic acid test (visceral pain) in mice. We found the particle size of the NPL’s best formula (F2-NPL) obtained was 187.6 nm with polydispersity index 0.626 and zeta potential +31.2 mV. The entrapment efficiency of flavonoid content in NPL was 50.9 % and the flavonoid release for 3 h with 3 replications were 22.91, 27.88 and 25.27 % respectively. The morphology of the particles by TEM showed that the nanoparticles were circular shape. Safety evaluation in mice resulted in the LD50 of NPL being greater than 5000 mg/kg in the acute toxicity study and had no adverse effects on blood, liver, and renal profiles in the subchronic toxicity study. The NPL-200 group had better effectiveness as an analgesic (84.87 %) compared to NPL-50 (37.80 %) and NPL-100 (69.15 %). This finding indicates that the NPL is a safe and effective formula for enhancing analgesic effects. Thus, enables its applications for the treatment of various diseases related to analgesics and inflammation such as osteoarthritis. HIGHLIGHTS The development of traditional medicine continues to be improved, to obtain the availability of safe, high quality, efficacious traditional medicines that are scientifically tested and can be widely utilized both for self-treatment by the community and in health services It is known that the most widely reported flavonoid derivative contained in edulis leaves is quercetin. Quercetin has poor bioavailability, solubility, and stability, reducing its therapeutic effect. By creating nanoparticles, adjustments can be made to natural products including quercetin in flavonoids in order to maximize their activity, boost their bioavailability, solubility, and capacity to be swiftly absorbed in the body to deliver the best possible therapeutic effects In developing nanoherbal passionfruit leaves using the ionic galation method, several solvents were used. It is known that no chemical substance can be said to be completely safe. It is important to study the toxicity profile further to obtain safe traditional medicines. Nanoparticle formulation of passion fruit leaf extract can provide better pain inhibition effectiveness in mice GRAPHICAL ABSTRACT

Anti-nociceptive effect of STW 5-II in rodent models of stress and post-inflammatory visceral hypersensitivity

AimsVisceral hypersensitivity is a therapy-resistant hallmark of irritable bowel syndrome (IBS). Many IBS patients’ symptoms develop following an acute colitis, and most report that stress worsens symptoms. STW 5-II, a combination of six herbal extracts, is a clinically proven treatment for IBS, but the mechanism is uncertain. Here, we employ two well-characterized rodent models to test the hypothesis that STW 5-II attenuates chronic colonic hypersensitivity. Main methodsSeparate cohorts of male rats were used for each model of colonic hypersensitivity. The first model used repeated water avoidance stress (1hr/day for 10 days), while the second model used intracolonic trinitrobenzene sulfonic acid to induce a short-lived colitis followed by post-inflammatory visceral hypersensitivity. Both models used sham treatment controls. Colonic sensitivity was quantified as the number of abdominal contractions to graded pressures (20–60 mmHg) of isobaric colorectal distension (CRD). Phosphorylation of extracellular signal-regulated kinase (pERK) was assessed via immunohistochemistry in the brain, spinal cord, and dorsal root ganglion (DRG). STW 5-II (10 ml/kg, p.o.) or vehicle (p.o.) was administered for 7 days, prior to CRD and pERK expression. Key findingsRats exposed to either model developed significant colonic hypersensitivity. Both models enhanced CRD-evoked pERK in DRGs, spinal cord, and brain. STW 5-II decreased colonic hypersensitivity and reduced CRD-evoked brain, spinal, and DRG pERK. SignificanceBoth models induced colonic hypersensitivity and enhanced pERK expression. STW 5-II inhibited colonic hypersensitivity and decreased noxious neuronal activation in both models, which could explain its clinically proven efficacy in relieving visceral hypersensitivity-related symptoms in IBS.

Targeted non-invasive Metformin-Curcumin co-loaded nanohyaluosomes halt osteoarthritis progression and improve articular cartilage structure: A preclinical study

Osteoarthritis (OA) is a degenerative disease that affects the quality of life in elderly and young populations. Current therapies using corticosteroids and non-steroidal anti-inflammatory drugs via parenteral or oral routes show limited ability to retard progression of the disease and achieve long term effectiveness and safety. Herein, the potential of MT-Cur combinatorial nano-formulations in OA management was explored for the first time. MT-Cur loaded nanohyaluosomes (MT-Cur-HL1) were designed for topical administration of the combined therapy in OA. The optimized MT-Cur-HL1 showed particle size 247.7 ± 3.7 nm, zeta potential −37.3 ± 0.4 mV; and entrapment efficiency (%EE) 70.22 %±0.303 and 76.7 %±0.077 for MT and Cur, respectively. MT-Cur-HL1 exhibited sustained drug release over 24 h and were stable over 3 months at 4 °C in terms of P.S., ZP and %EE. A detailed preclinical study, using MIA-induced osteoarthritis rat model, revealed the most significant anti-arthritic effect and halted OA progression of MT-Cur-HL1. This was proved to be mainly through the potentiation of p-AMPK signaling that ultimately led to suppression of its downstream TLR4/ NF-κB signaling pathway with subsequent reduction in MMP13 and ADAMTS5 induced chondrocytes degeneration. This study proved that this trajectory effectively promotes a significant improvement in the articular cartilage structure and reinforcement of joint mobility with an efficient antinociceptive effect. In conclusion, the novel MT-Cur coloaded nanohyaluosomes offer a promising non-invasive approach for the local management of OA.

The Role of the Insular Cortex and Serotonergic System in the Modulation of Long-Lasting Nociception.

The insular cortex (IC) is a brain region that both receives relevant sensory information and is responsible for emotional and cognitive processes, allowing the perception of sensory information. The IC has connections with multiple sites of the pain matrix, including cortico-cortical interactions with the anterior cingulate cortex (ACC) and top-down connections with sites of descending pain inhibition. We explored the changes in the extracellular release of serotonin (5HT) and its major metabolite, 5-hydroxyindoleacetic acid (5HIAA), after inflammation was induced by carrageenan injection. Additionally, we explored the role of 5HT receptors (the 5HT1A, 5HT2A, and 5HT3 receptors) in the IC after inflammatory insult. The results showed an increase in the extracellular levels of 5HT and 5-HIAA during the inflammatory process compared to physiological levels. Additionally, the 5HT1A receptor was overexpressed. Finally, the 5HT1A, 5HT2A, and 5HT3 receptor blockade in the IC had antinociceptive effects. Our results highlight the role of serotonergic neurotransmission in long-lasting inflammatory nociception within the IC.

Exploration of neuroprotective and cognition boosting effects of Mazus pumilus in Alzheimer's disease model.

Mazus pumilus (MP) an Asian flowering plant, known for various reported pharmacological activities including antioxidant, anti-nociceptive, anti-inflammatory, anticancer, antibacterial, antifungal, and hepatoprotective effects. This study focused on further exploring Mazus pumilus's methanol leaf extract (MPM) for bioactive principles and investigating its neuroprotective and cognition-enhancing potential in Alzheimer's disease models. For the phytochemical screening and identification, TLC, HPLC, and Fourier transform infrared (FTIR) were employed. In-vitro antioxidant potential was assayed by DPPH Free Radical Scavenging method, followed by in-vivo neuroprotective effect of MPM (100, 200, 300 mg/kg) using Wistar-albino rats, sodium azide for induction of AD and rivastigmine as standard. Over 21days, we observed neurobehavioral changes and performed biochemical (GSH, CAT, SOD, and AchE activity) and histopathological evaluations. Results revealed the presence of alkaloids, flavonoids, amino acids, terpenoids, glycosides, sterols, and saponins. HPLC analysis confirmed the presence of gallic acids, sinapic acid, and caffeic acid. DPPH confirmed the antioxidant effect of MPM, which served as a base for its potential neuroprotective activity. Biochemically, oxidative stress markers improved significantly post-treatment, with decreased GSH, SOD, CAT levels, and increased AchE activity, indicating a reversal of AD-induced changes. Behavioral assessments showed improvements in locomotion, memory, spatial learning, and cognition. Histologically, there was a dose-dependent reduction in neurodegenerative features like neurofibrillary tangles and amyloid beta plaques. Hence, this study concluded MPM is a promising candidate for prophylaxis and treatment of behavioral deficits and cognitive dysfunction in Alzheimer's disease.

Cyperus articulatus: Anti-inflammatory and antinociceptive activity of a medicinal plant from the Amazon

Ethnopharmacological relevanceCyperus articulatus L., popularly known as priprioca, is a plant used in the Amazon for perfumed baths and homemade perfumes. In traditional medicine, its rhizomes are used to treat diseases related to inflammatory processes. Aim of the studyDue to its promising bioactive properties, this study sought to investigate its phytochemistry and the anti-inflammatory and antinociceptive activity of the essential oil obtained from C. articulatus (CAEO) in in vitro and in vivo tests. Material and methodsThe essential oil was obtained from the rhizomes of C. articulatus and extraction was carried out via hydrodistillation. Then, the oil was analyzed by GC-MS analyses. Initially, culture of RAW 264.7 macrophages stimulated by lipopolysaccharide (LPS) was used to evaluate cytotoxicity and interference in the production of mediators of the inflammatory process (nitrite, IL-1β, TNF-α and PGE2) after exposure to CAEO. The acute toxicity of CAEO was evaluated and the results were used to define doses of 10, 100 and 400 mg kg−1 for evaluation of CAEO in in vivo tests using mice. The carrageenan-induced air pouch models and the Evans test were used to evaluate the anti-inflammatory activity by measuring the number of total leukocytes and vascular permeability. Antinociceptive activity was evaluated via tests of contortions induced by acetic acid, hot plate, and formalin. ResultsTreatment with CAEO reduced the levels of nitrite IL-1β, TNF-α and PGE2 in the macrophage culture, revealing its anti-inflammatory potential. CAEO decreased carrageenan-induced leukocyte migration and vascular permeability, which are important events related to the acute inflammatory response. Nociceptive activity was significantly inhibited by CAEO in the acetic acid-induced contortions model, hot plate, and in both phases of the formalin test. The treatment with naloxane reversed the antinociceptive effect observed in the formalin test, suggesting the participation of opioid receptors in the mechanism of action of CAEO. ConclusionThe observed results reveal the anti-inflammatory and antinocipeptive activity of C. articulatus essential oil in vivo and support the traditional use of this plant in the treatment of different diseases involving inflammation and pain.

Ethnomedicinal and Phytopharmacological Aspects of Vernonia amygdalina (Bitter Leaf) Utilized as a Traditional Medicinal Herb

Vernonia amygdalina Delile, commonly known as “bitter leaf,” is a shrub in the Asteraceae family, widely seen in tropical regions of Africa. Vernonia amygdalina is found to be traditionally used in African medicine. Various parts of this plant, especially the leaves, are utilized to treat ailments such as fever, diabetes, and gastrointestinal issues. Research from multiple researchers has shown a wide range of phytochemical and bioactive compounds present in Vernonia amygdalina; examples are terpenoids, tannins, alkaloids, saponins, flavonoids, steroids, glycosides, etc., which have contributed to the medicinal properties of Vernonia amygdalina. Vernonia amygdalina has shown its therapeutic and remedial potentials due to the presence of phytochemicals which exhibit effects such as anti-microbial, anti-inflammatory, anti-cancer, anti-oxidant, anti-diabetic, anti-hyperglycemic, anti-diarrheal, anti-helminthic, anti-pyretic, and anti-nociceptive effects. In this article, the authors highlight recent progress in using Vernonia amygdalina and its therapeutic effects. Research, review, and case study articles were used to write this review. The articles were obtained from academic websites such as Research Gate, Google Scholar, the National Library of Medicine, African journals online, and Semantic journals, and some articles were obtained through a simple Google search. Articles that discussed the medicinal, ethanopharmacological, and therapeutic properties of Vernonia amygdalina were selected for the review. Search terms such as “Vernonia amygdalina,” “bitter leaf,” “phytochemical properties,” and “therapeutic effects” were used to search for relevant articles on the academic databases. Boolean operators such as “AND” and “OR” were used to refine the search further and ensure a comprehensive selection of articles.

Antinociceptive and antineuropathic effects of Trifolium resupinatum L. on formalin-induced nociception and cervical spinal cord hemi-contusion: Underlying Mechanisms

Ethnopharmacological relevanceTrifolium resupinatum L. (Fabaceae), known as Persian clover, ethnomedicinally used in Persian folk medicine to treat peritoneal inflammation, rheumatism, and back pain. Aim of the studyTo investigate the antineuropathic and antinociceptive activities of Trifolium resupinatum leaves essential oil (TREO) in male Wistar rats, as well as to explore the potential mechanisms of action. Materials and methodsThe antinociceptive activity of TREO and its main constituents, quercetin (Qc) was assessed using the formalin-induced paw licking test. Moreover, the potential mechanisms of antinociception were evaluated through various competitive and non-competitive antagonisms. Additionally, the antineuropathic potential was investigated using the cervical spinal cord hemi-contusion (CCS) model, and the role of phosphorylated Stat-3 was analyzed using Western blotting. ResultsTREO exerted significant antinociceptive activity (P < 0.01) in both phases of the formalin-induced test; however, its effects were more pronounced in the second phase. Modulators of the NO-cGMP-K+ channel pathway significantly reversed the antinociceptive activity of TREO (P < 0.05). Additionally, antagonists of TRPV1 and TRPV2, as well as CB1 and GABAA receptors, significantly reversed the antinociceptive effects of TREO (P < 0.05). In another study, both TREO and Qc significantly attenuated hyperalgesia and mechanical allodynia (P < 0.01) when evaluated using the CCS-induced nociception model. Notably, TREO also reduced the expression levels of interleukin-1 beta, interleukin-2, and tumor necrosis factor alpha in CCS-induced rats (P < 0.05). ConclusionTREO and Qc exhibit both antinociceptive and anti-neuropathic activities. The antinociceptive effects are partially mediated through the NO-cGMP-K+ channel pathways, along with the activation of TRPV, GABA, and cannabinoid receptors. Furthermore, the anti-neuropathic activity of TREO may be partially regulated through the inhibition of cytokines.

Assessment of the antinociceptive effect of a single fentanyl bolus dose in children: A pharmacokinetic and pharmacodynamic analysis based on the nociception level index during sevoflurane general anesthesia.

The Nociception Level Index has shown benefits in estimating the nociception/antinociception balance in adults, but there is limited evidence in the pediatric population. Evaluating the index performance in children might provide valuable insights to guide opioid administration. To evaluate the Nociception Level Index ability to identify a standardized nociceptive stimulus and the analgesic effect of a fentanyl bolus. Additionally, to characterize the pharmacokinetic/pharmacodynamic relationship of fentanyl with the Nociception Level Index response during sevoflurane anesthesia. Nineteen children, 5.3 (4.1-6.7) years, scheduled for lower abdominal or urological surgery, were studied. After sevoflurane anesthesia and caudal block, a tetanic stimulus (50 Hz, 60 mA, 5 s) was performed in the forearm. Following the administration of fentanyl 2 μg/kg intravenous bolus, three similar consecutive tetanic stimuli were performed at 5-, 15-, and 30-min post-fentanyl administration. Changes in the Nociception Level Index, heart rate, mean arterial pressure, and bispectral index were compared in response to the tetanic stimuli. Fentanyl plasma concentrations and the Nociception Level Index data were used to elaborate a pharmacokinetic/pharmacodynamic model using a sequential modeling approach in NONMEM®. After the first tetanic stimulus, both the Nociception Level Index and the heart rate increased compared to baseline (8 ± 7 vs. 19 ± 10; mean difference (CI95) -12(-18--6) and 100 ± 10 vs. 102 ± 10; -2(-4--0.1)) and decrease following fentanyl administration (19 ± 10 vs. 8 ± 8; 12 (5-18) and 102 ± 10 vs. 91 ± 11; 11 (7-16)). In subsequent tetanic stimuli, heart rate remained unchanged, while the Nociception Level Index progressively increased within 15 min to values similar to those before fentanyl. An allometric weight-scaled, 3-compartment model best characterized the pharmacokinetic profile of fentanyl. The pharmacokinetic/pharmacodynamic modeling analysis revealed hysteresis between fentanyl plasma concentrations and the Nociception Level Index response, characterized by plasma effect-site equilibration half-time of 1.69 (0.4-2.9) min. The estimated fentanyl C50 was 1.93 (0.73-4.2) ng/mL. The Nociception Level Index showed superior capability compared to traditional hemodynamic variables in discriminating different nociception-antinociception levels during varying fentanyl concentrations in children under sevoflurane anesthesia.

N-Terminal Capping of the αO-Conotoxin Analogue GeX-2 Improves the Serum Stability and Selectivity toward the Human α9α10 Nicotinic Acetylcholine Receptor.

α9α10 nicotinic acetylcholine receptors (nAChRs) are a promising nonopioid analgesic target, with α9α10 nAChR antagonists showing efficacy against chemotherapy-induced hyperalgesia and allodynia. GeX-2, a potent analgesic conotoxin antagonist of α9α10 nAChRs, has limited serum stability. This study improved GeX-2 stability by capping its N-terminal with fatty acids or polyethylene glycol chains, which enhanced its serum stability but eliminated activity at G protein-coupled γ-aminobutyric acid type B (GABAB) receptor-coupled CaV2.2 channels while preserving activity at α9α10 nAChRs. In vivo, α9α10 nAChRs antagonism alone did not alleviate neuropathic pain, highlighting the importance of GABAB receptor-coupled CaV2.2 channels in GeX-2's antinociceptive effects in the chronic constriction injury rat model. The GeX-2 analogue, with an N-terminal methyl group, showed improved activity and selectivity for α9α10 nAChRs, increased serum half-life, and strong analgesic effects in oxaliplatin-induced cold allodynia models. AlphaFold3 and molecular dynamics simulations provided insights into the binding modes and the effects of N-terminal capping, which informed future peptide therapeutic developments.

Differential chemoproteomic analysis of RRS-1 candidate molecule and molecules of several nonsteroidal anti-inflammatory drugs

Background. To plan effective and safe pharmacotherapy for inflammation and pain, it is important to evaluate the mechanisms and spectrum of action of nonsteroidal anti-inflammatory drugs (NSAIDs), including their effects on human proteome.Objective: to identify and evaluate the most significant specific differences of candidate molecule RRS-1 (N-{(Z)-2-(1-methyl-1H-indol-3-yl)-1-[(propylamino)carbonyl]vinyl}benzamide) from other NSAIDs through differential chemoreactome analysis.Materials and methods. Chemoproteomic modeling of pharmacological effects of RRS-1 molecule and a number of well-known NSAIDs (diclofenac, nimesulide, ketorolac) on human proteome was carried out on the basis of numerical prediction algorithms over the space of heterogeneous feature descriptions, developed in the topological approach to recognition by Yu.I. Zhuravlev and K.V. Rudakov scientific school.Results. Significant differences in the effects of the studied molecules were found for 1232 proteins of human proteome. The features of assessing interactions of the studied molecules with 47 target proteins, which most distinguished the effects of RRS-1 molecule from all others were identified. RRS-1 could activate adenosine and dopamine receptors, cannabinoid receptor 2 and GABAA receptor to a greater extent than other molecules. Activation of these receptors corresponded to anti-inflammatory, anti-nociceptive and neuroprotective effects. RRS-1 could preferably inhibit a number of pro-inflammatory proteins, receptor bradykinin 1, metabotropic glutamate receptor 5, matrix metalloproteinases 8, 9, 12, and blood coagulation factor X. Additionally, RRS-1 molecule showed preferable inhibition of a number of kinases targeted in antitumor and anti-inflammatory therapy. RRS-1, less than other studied molecules, interacted with the receptors of vitamin D3, thyroid hormone, acetylcholine, cannabinoids and opioids, orexin, and various metabolic enzymes, which is important in assessment of the safety of using drugs based on this molecule. RRS-1 characteristically exhibited a moderate profile of antivitamin action: the total score of vitamin and mineral loss (7.4±3.7) was significantly less in comparison to diclofenac (11.7±4.5) and was actually on the same level as nimesulide (6.9±3.7) and ketorolac (6.7±3.6).Conclusion. Chemoreactomic and chemoproteomic profiling of RRS-1 candidate molecule provided pre-experimental assessments of its efficacy and safety through modeling interactions with the human proteome.

Sex differences in the orofacial antinociceptive effect of metformin and the role of transient receptor potential channels.

Metformin is classified as a biguanide and is used in the treatment of type 2 diabetes. It is used worldwide and has been investigated in drug repositioning. The present study aims to investigate whether there is sexual dimorphism in the orofacial antinociceptive effect of metformin and the participation of TRP channels. Acute nociceptive behavior was induced by administering cinnamaldehyde or capsaicin to the upper lip. Nociceptive behavior was assessed through orofacial rubbing, and the effects of pre-treatment with metformin (125 or 250mg/Kg) or vehicle (control) were tested on the behavior. Nociceptive behavior was also induced by formalin injected into the temporomandibular joint. The chronic pain model involved infraorbital nerve transection (IONX) was evaluated using Von Frey electronic filaments. Trpv1 gene expression was analyzed in the nerve ganglion. Docking experiments were performed. Metformin, but not the vehicle, produced antinociception (p < 0.0001) in all acute nociceptive behaviors in both sexes, and these effects were attenuated by the TRPV1 antagonist capsazepine and the TRPA1 antagonist HC-030031. In IONX with better (**p < 0.01, ****p < 0.0001 vs. control) results in females. TRPV1 gene expression was observed in the metformin treated group (*p < 0.05 vs. control). Docking experiments revealed that metformin may interact with TRPV1 and TRPA1 channels. Metformin promotes orofacial antinociception in both sexes in acute pain and is more effective in chronic pain in females than in males, through the modulation of TRPV1 and TRPA1 channels. These preclinical findings suggest a potential repositioning of metformin as an analgesic agent in acute and chronic orofacial pain states.

The Effect of Metoclopramide on the Antinociceptive, Locomotor and Neurobehavioral Effects of Metamizole in Mice

Abstract Combining analgesic medications with distinct pharmacodynamics may result in effective analgesia and reduced adverse effects by lowering dosages of one or both medications. The objective was to investigate the nature of interactions of metoclopramide and metamizole by measuring the antinociceptive and neurobehavioral effects in mice. The drugs were administered intraperitoneally (ip) in mice. The antinociceptive effect was determined by the up-and-down method. Isobolographic analysis was performed by simultaneous injection of the two drugs at ED50 ratios of 1:1 and 0.5:0.5. The treated mice were also subjected to an open-field behavioral test as well as dorsal immobility and negative geotaxis behavioral paradigms. The ED50 of metoclopramide and metamizole were 33.71 and 43 mg/kg ip, respectively. Lower ED50 was established for metoclopramide and metamizole by 48.44% and 47.49%, respectively when given at a ratio of 0.5:0.5, and by 35.81% and 29.88%, respectively at a ratio of 1:1. The combined dose of metoclopramide and metamizole (8 and 10 mg/kg, ip, respectively) significantly decreased the open field-activity test in mice. This was observed by lower number of squares crossing compared to the control. Additionally, the drug combination resulted in a substantial increase in the duration of dorsal immobility response and delayed the negative geotaxis task when compared with the control group. The results indicated that the interaction between metoclopramide and metamizole in lower dose ratio with ED50 50:50, was synergistic in producing analgesia in mice with reduced risk for adverse reaction but with decreased behavioral and motor neuronal activity.

Anti-nociceptive effects of non-antibiotic derivatives of demeclocycline and doxycycline against formalin-induced pain stimulation

In previous studies, some tetracycline (TC) antibiotics showed potential as analgesic. We investigated here the analgesic activity of new non-antibiotic TC derivatives using the formalin-induced nociceptive pain model in adult C57BL/6 mice. Specifically, we tested the effects of i.p. injections of DDMC (5, 10, 20 mg.kg-1) and DDOX (10, 20, 40 mg.kg-1), which are non-antibiotic derivatives of demeclocycline and doxycycline, respectively. Repeated treatments with DDMC remarkably reduced nociceptive pain in both phases of the test, at 10 mg.kg-1 its efficacy was comparable to that of 10 mg.kg-1 of morphine. DDOX was also effective in this paradigm but intrinsically less potent than DDMC, exerting analgesic effects between 20 and 40 mg.kg-1. Interestingly, a single injection of DDMC (10 mg.kg-1) was sufficient to produce a robust anti-nociceptive effect similar to that of morphine. A single injection of DDOX (40 mg.kg-1) also produced anti-nociceptive effects but only in the second phase of the test. Noticeably, male mice exhibited a better analgesic response to DDMC (10 mg.kg-1) than females. A single injection of DDMC (10 mg.kg-1) and morphine but not of DDOX (40mg.kg-1), powerfully inhibited formalin-induced spinal cord c-Fos expression whereas both TC derivatives restrained the activation of Iba-1-immunoreactive cells, indicating a potential indirect effect on inflamed microglial cells. In summary, the non-antibiotic TCs, DDMC and DDOX, demonstrated notable analgesic efficacy against formalin-induced pain, suggesting their potential as alternatives for analgesic treatment.

Benzylpiperidine derivatives as new dual μ-opioid and σ1 receptor ligands with potent antinociceptive effects

Dual-acting μ-opioid receptor (MOR)/sigma-1 receptor (σ1R) ligands have displayed promise in exerting robust antinociceptive effects while reducing opioid-related side effects. To discover safer and more effective analgesics, we designed, prepared, and evaluated 30 benzylpiperidine derivatives as dual MOR and σ1R ligands. The obtained benzylpiperidine analogs were tested for MOR and σ1R binding affinity in vitro. The best compound 52 showed high affinity for both MOR [Ki (MOR) = 56.4 nM] and σ1R [Ki (σ1R) = 11.0 nM] and produced potent antinociceptive effects in the abdominal contraction test (ED50 = 4.04 mg/kg in mice), carrageenan-induced inflammatory pain model (ED50 = 6.88 mg/kg in mice), formalin test (ED50 = 13.98 mg/kg in rats) and complete Freund’s adjuvant (CFA)-induced chronic pain model (ED50 = 7.62 mg/kg in mice). Moreover, 52 had less MOR-related adverse effects than oxycodone, including constipation, acute hyperlocomotion and physical dependence. The above results suggested that 52 may be a promising candidate for the development of safer analgesics.

Study on peripheral antinociception induced by hydrogen peroxide (H2O2): characterization and mechanisms.

The present study aimed to evaluate the possible peripheral H2O2-induced antinociception and determine the involvement of opioidergic, cannabinoidergic and nitrergic systems, besides potassium channels in its antinociceptive effect. Prostaglandin E2 was used to induce hyperalgesia in male Swiss mice using the mechanical paw pressure test. H2O2 (0.1, 0.2, 0.3 µg/paw) promoted a dose-dependent antinociceptive effect that was not observed in contralateral paw. Female mice also showed antinociception in the model. The partial H2O2-induced antinociception was potentiated by the inhibitor of catalase enzyme, aminotriazole (40, 60, 80 µg/paw). The antinociception was not reversed by opioid and cannabinoid receptor antagonists naloxone, AM 251 and AM 630. The involvement of nitric oxide (NO) was observed by the reversal of H2O2-induced antinociception using the non-selective inhibitor of nitric oxide synthases L-NOarg and by inhibition of iNOS (L-NIL), eNOS (L-NIO) and nNOS (L-NPA). ODQ, a cGMP-forming enzyme selective inhibitor, also reversed the antinociception. The blockers of potassium channels voltage-gated (TEA), ATP-sensitive (glibenclamide), large (paxillin) and small (dequalinium) conductance calcium-activated were able to revert H2O2 antinociception. Our data suggest that H2O2 induced a peripheral antinociception in mice and the NO pathway and potassium channels (voltage-gated, ATP-sensitive, calcium-activated) are involved in this mechanism. However, the role of the opioid and cannabinoid systems was not evidenced.

Biological activity and characterization of leaf and seed lectins from Terminalia brownii: Insights into their analgesic and antiulcer properties

Terminalia brownii Fresen, an African medicinal plant, is known for its analgesic, antiulcer, and antimicrobial properties, with its leaves, bark, and fruits deeply ingrained in indigenous healing practices. Two lectins, TerBLL (from leaves) and TerBSL (from seeds) of Terminalia brownii Fresen, were purified using salting-out and affinity chromatography on a fetuin-agarose column. The purified lectins were then assessed for protein yield, hemagglutination activity, and physicochemical properties. Both TerBLL and TerBSL have subunits with molecular weights of 57.3 and 65.7 kDa, respectively. TerBLL remains stable at 60–80 °C and is activated by Mn+2, while TerBSL is activated by Zn+2. These lectins maintain consistent activity under acidic conditions, with TerBLL demonstrating heightened activity at extreme alkaline pH. TerBLL retained 50 % of its activity in 2–8M urea, in contrast to the 13 % of TerBSL. Investigation of the properties of TerBLL revealed that it had antinociceptive effects, reducing abdominal pain and prolonging latency time in the hotplate assay, potentially through μ-opioid receptor blockade akin to that of morphine. TerBLL exhibits antiulcer activity at doses of 0.25 and 1 mg/kg, reducing ulcer formation by up to 33 %, comparable to that of pantoprazole (80 mg/kg). The physiochemical attributes of TerBLL, in addition to its pain-relieving and gastroprotective effects, underscore its therapeutic promise, which is consistent with its traditional use.

Anti-inflammatory and antinociceptive effects of Aloysia gratissima leaves essential oil: An in vivo study

Background and aimAloysia gratissima is used in popular medicine as an analgesic and sedative. However, studies on its biological activities are still scarce. Therefore, this work aimed to evaluate the antinociceptive and anti-inflammatory effect of A. gratissima leaves essential oil (OAG) in mice. Experimental procedureThe OAG was obtained by hydrodistillation and its composition was determined by gas chromatography-mass spectrometry. The sesquiterpenes pinocamphone, β-pinene, and guaiol were the major constituents of OAG. The effect of OAG (1, 10, and 30 mg/kg, p.o.) was assessed by pre-treating male mice 1h before the formalin assay, carrageenan-induced peritonitis test, or the paw edema induced by arachidonic acid (AA). The acute toxicity of OAG (2000 mg/kg, p.o.) was also investigated. Results and conclusionThe minimum effective dose of OAG in the formalin test was 1 mg/kg. This dose did not affect the locomotor activity of mice. The OAG decreased the number of leukocytes/mm³ in the peritoneal exudate of mice and reduced paw edema 45 min after the arachidonic acid injection. OAG treatment elicited a reduction in NPSH levels in the paw tissue and increased NPSH levels in mice blood plasma and did not cause mice mortality. The OAG is devoid of acute toxicity and shows anti-inflammatory activity, which can be related to the presence of pinocamphone, guaiol, and β-pinene and is mediated, at least in part, by mechanisms that involve the participation of NPSH.