Antinociceptive Activity Research Articles

A Novel Cortex Phellodendri Chinensis-Based Carbon Dots Platform for Remarkable Analgesia for Clinical Pain Management.

In this study, we explored the eco-friendly synthesis of photoluminescent CCDs employing a direct one-step pyrolysis process, utilizing natural Cortex Phellodendri Chinensis as the precursor material and studied their analgesic effect in mice. The synthesized carbon dots underwent comprehensive characterization through a range of spectroscopic and microscopic techniques. These included UV-Vis, FTIR, fluorescence spectroscopy and HR-TEM, DLS instruments. HR-TEM results exhibited the presence of homogenous spherical-shaped C-dots of about 3.3nm without aggregates. Furthermore, the prepared CCDs were studied for their in vivo analgesic effect in mice by performing tail-immersion, hot plate and acetic acid writhing tests. Also, an MTT assay was performed to assess the in vitro cytotoxicity of CCDs against L929 cells. In vitro cytotoxicity studies revealed that L929 cells exhibited higher cell viability when treated with prepared CCDs. The cellular uptake studies revealed the phase contrast images of MG-63 cells at wavelength 488nm clearly depicted the aggregation of green, fluorescent CCDs within the cells while leaving nuclei unobscured. In addition, to the best of our understanding, the results presented in this paper showed that CCDs exhibited an important analgesic effect and enhanced anti-nociceptive activity, which may be due to stimulation of the opioidergic system. Consequently, CCDs appear to be a viable analgesic alternative for traditional analgesic candidates in pain management.

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.

Chemodiversity and Antinociceptive Activity of Amorpha fruticosa L. Essential Oil.

An essential oil dominated by germacrene D (19.3% by GC) was isolated from the fresh fruit of Amorpha fruticosa L. (Fabaceae). Agglomerative clustering and k-means clustering were employed to compare the composition of the oil with the existing literature data, suggesting that the A. fruticosa used in this study represents a new chemotype. The essential oil was evaluated for its antinociceptive activity using the acetic acid-induced writhing test in rats at doses of 400, 200, and 100 mg/kg. All tested doses reduced the number of writhes induced by the intraperitoneal injection of acetic acid. The 400 mg/kg dose of the oil demonstrated a 54.4% inhibition, which was statistically different from the positive control, aspirin, which showed 90.2% inhibition at a dose of 200 mg/kg. Since the injection of acetic acid produces the release of prostaglandins, such as PGE2α and PGF2α, as well as sympathetic nervous system mediators in peritoneal fluids, the results suggest that the inhibition of prostaglandin release might represent one of the possible mechanisms of action exerted by the oil.

Pharmacological Effects of Paeonia lactiflora Focusing on Painful Diabetic Neuropathy

AbstractPainful diabetic neuropathy (PDN) is a highly prevalent complication in patients suffering from diabetes mellitus. Given the inadequate pain-relieving effect of current therapies for PDN, there is a high unmet medical need for specialized therapeutic options. In traditional Chinese medicine (TCM), various herbal formulations have been implemented for centuries to relieve pain, and one commonly used plant in this context is Paeonia lactiflora (P. lactiflora). Here, we summarize the chemical constituents of P. lactiflora including their pharmacological mechanisms-of-action and discuss potential benefits for the treatment of PDN. For this, in silico data, as well as preclinical and clinical studies, were critically reviewed and comprehensively compiled. Our findings reveal that P. lactiflora and its individual constituents exhibit a variety of pharmacological properties relevant for PDN, including antinociceptive, anti-inflammatory, antioxidant, and antiapoptotic activities. Through this multifaceted and complex combination of various pharmacological effects, relevant hallmarks of PDN are specifically addressed, suggesting that P. lactiflora may represent a promising source for novel therapeutic approaches for PDN.

In silico analysis of quercetin and its derivatives as potential TRPC6-targeted treatments for diabetic neuropathy

Background: Diabetic neuropathy is a condition that arises as a complication of diabetes mellitus and often causes pain in patient. Quercetin and its derivatives have antinociceptive activity, making them potential agents for relieving the pain associated with diabetic neuropathy. Objective: This study aims to analyze the interactions between quercetin and its eight derivatives with canonical transient receptor potential channels 6 (TRPC6) as protein target. Method: The TRPC6 structure (PDB ID: 6UZ8) was prepared and validated with redocked to native ligand R0D using Autodock 4.2.6, with the established grid box and grid center settings. The test compounds were then optimized and docked using the same grid box and grid center settings as in the validation process, followed by visualization and analysis of the docking results. Results: The compound with the best affinity for TRPC6 was tamarixetin, with a binding energy value of -3.27 kcal/mol, close to the binding energy value of the native ligand, which was -4.22 kcal/mol. The amino acid residues interacting with tamarixetin at the active site were 702-Asn, 705-Tyr, 706-Val, and 709-Gly. This indicates that tamarixetin and the native ligand bind to the same active site amino acids, resulting in a similar affinity to the native ligand in inhibiting TRPC6. Conclusion: A total of eight quercetin derivatives were predicted to have TRPC6 antagonistic activity against diabetic neuropathy, with tamarixetin exhibiting the highest affinity compared to the other quercetin derivatives.

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.

Exploring the potential therapeutic benefits of 7-methoxy coumarin for neuropathy pain: an in vivo, in vitro, and in silico approach.

7-Methoxycoumarin (7-MC) is well recognized for its anti-inflammatory and anti-nociceptive actions. Its capacity to lessen neuropathic pain hasn't been documented yet. Hence the impact of 7-MC on vincristine-induced peripheral neuropathic pain in rodents was investigated. The investigation also looked at the impact of 7-MC in reducing neuropathic pain via voltage-gated calcium channels and phospholipase enzyme inhibition using pertinent in vitro and in silico methods. Vincristine (0.1mg/kg, i.p., daily) was administered continuously for 7 days to induce peripheral neuropathic pain in mice, with cold allodynia and thermal hyperalgesia and evaluated on the 8th day using the acetone bubble test and hot water tail immersion test. In order to derive the mechanistic approach for ameliorating neuropathic pain, the role of 7-MC in the inhibition of the phospholipase enzyme, gene expression studies on voltage-gated calcium channels using mouse BV2 microglial cells and in silico studies for its calcium channel binding affinity were also performed. The test compounds reduced vincristine-induced cold allodynia and thermal hyperalgesia in mice in a dose-dependent experiments. In vitrostudies on phospholipase inhibition by 7-MC showed an IC50 of 27.08µg/ml and down-regulated the gene expression of calcium channels in the BV2 microglial cell line. In silico docking scores for 7-MCwere higher than the standard drug gabapentin. The compound 7-MC has shown promise in alleviating vincristine-induced peripheral neuropathicin mice. Studies conducted in parallel, both in silico and in vitro have demonstrated that 7-MC effectively reduces neuropathic pain. This pain reduction is achieved through two mechanisms: inhibiting the phospholipase enzyme and blocking voltage-gated calcium channels.

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.

Synthesis and biological activity of substituted 5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxamides

A four-component solvent-free reaction of acetoacetic acid amide with dimedone, aromatic aldehydes and ammonium acetate leads to new substituted 5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxamides. The structures of the products were proved using IR, 1H and 13C NMR spectroscopy, mass spectrometry and X-ray diffraction analysis. The synthesized compounds were tested for antimicrobial and antinociceptive activities.

Discovery of Antinociceptive α9α10 Nicotinic Acetylcholine Receptor Antagonists by Stable Receptor Expression.

Chronic neuropathic pain is an increasingly prevalent societal issue that responds poorly to existing therapeutic strategies. The α9α10 nicotinic acetylcholine receptor (nAChR) has emerged as a potential target to treat neuropathic pain. However, challenges in expressing functional α9α10 nAChRs in mammalian cell lines have slowed the discovery of α9α10 ligands and studies into the relationship between α9α10 nAChRs and neuropathic pain. Here, we develop a cell line in the HEK293 background that stably expresses functional α9α10 nAChRs. By also developing cell lines expressing only α9 and α10 subunits, we identify distinct receptor pharmacology between homomeric α9 or α10 and heteromeric α9α10 nAChRs. Moreover, we demonstrate that incubation with nAChR ligands differentially regulates the expression of α9- or α10-containing nAChRs, suggesting a possible mechanism by which ligands may modify receptor composition and trafficking in α9- and α10-expressing cells. We then apply our α9α10 cell line in a screen of FDA-approved and investigational drugs to identify α9α10 ligands that provide new tools to probe α9α10 nAChR function. We demonstrate that one compound from this screen, diphenidol, possesses antinociceptive activity in a murine model of neuropathic pain. These results expand our understanding of α9α10 receptor pharmacology and provide new starting points for developing efficacious neuropathic pain treatments.

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.

Synthesis and Biological Evaluation of Gastroprotective Polymer Conjugates of Aceclofenac

: Nonsteroidal anti-inflammatory drugs account for a sizeable fraction of the drugs prescribed worldwide. If consumed for a long time, they can cause ulcers and lifethreatening side effects. Since the acidic group present in NSAIDs is mainly responsible for these side effects, the scientists try to synthesize polymer drug conjugates that avoid these side effects but still retain the potency of the parent drug. Macromolecular drug conjugates of aceclofenac were prepared by employing pectin, β cyclodextrin, deacetylated chitin (chitosan) and albumin (egg and bovine serum). The prepared conjugates were characterized and tested for their anti-inflammatory, antinociceptive and antiulcerogenic activity. Further experimentation was undertaken to analyze the behavior of compounds and their stability in hydrolytic conditions. Test compound A1, a pectin conjugate of aceclofenac, exhibited significant antinociceptive and anti-inflammatory activity with a significant decrease in ulcer index (4.45±0.24) as against aceclofenac (8.61±0.40) or vehicle (12.39±0.44) treated group. A novel and safer polymer drug conjugate of aceclofenac has been synthesized and evaluated.

Cannabigerol Reduces Acute and Chronic Hypernociception in Animals Exposed to Prenatal Hypoxia-Ischemia

Cannabigerol (CBG), a phytocannabinoid, has shown promise in pain management. Previous studies by our research group identified an increase in pain sensitivity as a consequence of prenatal hypoxia-ischemia (HI) in an animal model. This study aimed to investigate the efficacy of CBG in acute and chronic hyperalgesia induced by prenatal HI. A pharmacological screening was first conducted using hot plate and open-field tests to evaluate the antinociceptive and locomotor activities of animals administered with a 50 mg/kg oral dose of cannabis extract with a high CBG content. Prenatal HI was induced in pregnant rats, and the offspring were used to evaluate the acute antinociceptive effect of CBG in the formalin-induced peripheral pain model, while chronic antinociceptive effects were observed through spinal nerve ligation (SNL) surgery, a model used to induce neuropathic pain. Our results show that CBG exhibited an antinociceptive effect in the hot plate test without affecting the animals’ motor function in the open-field test. CBG significantly reduced formalin-induced reactivity in HI offspring during both the neurogenic and inflammatory phases. CBG treatment alleviated thermal and mechanical hypernociception induced by SNL. Biomolecular analysis revealed CBG’s ability to modulate expression, particularly reducing TNFα and Nav1.7 in HI male and female rats, respectively. These results highlight CBG as a potential antinociceptive agent in acute and chronic pain models, suggesting it as a promising therapeutic option without inducing motor impairment. Further research is needed to fully elucidate its mechanisms and clinical applications in pain management.

Novel efficacy of pregnane and flavonoid glycosides from Desmidorchis flava in in vivo nociceptive and inflammatory paradigms and their target prediction by cheminformatics approach

Inflammation is associated with multiple life-threatening conditions. Desmidorchis flava is an edible plant and traditionally used for managing various diseases. Three novel molecules, namely desmiflavaside-C (1), nizwaside (2), and desmiflanoside (3) were isolated from Desmidorchis flava, and their structures were confirmed by mass spectrometry and through reported literature. These compounds were in vivo examined for antinociceptive (tonic visceral nociception) and anti-inflammatory (carrageenan induced paw edema) activities. Significant antinociceptive potential was demonstrated by compound 1 at 0.5 and 1 mg/kg doses followed by compounds 2 and 3. At similar doses, significant anti-inflammatory activity was noted for all the tested compounds. Their antinociceptive and anti-inflammatory activities were comparable to the reference standards. In silico predicted binding modes suggests that these compounds may target allosteric sites of COX-1 and COX-2 enzymes to elicit their anti-inflammatory activities. These isolated natural products may have therapeutic potential in conditions afflicted with pain and inflammation.

Phytochemical composition, hypnotic activity, and antinociceptive properties of cumin essential oil collected from various geographical regions

AbstractThe quantity and quality of the active components of plants are strongly influenced by environmental factors. In this regard, dried cumin seeds were collected from four different locations (SaadatShahr (P1) and Sarvestan (P2) from Fars Province and Kashmar (P3) and Sabzevar (P4) from Khorasan), and their essential oils were isolated by Clevenger apparatus and evaluated using GC and GC–MS. In addition, the hypnotic and antinociceptive activities of the cumin EO sample, which had the highest yield and quality, respectively, were assessed via the pentobarbital‐induced loss of righting test and acetic acid‐induced writhing test. Our results showed that the highest amount of EO was present in sample P4 (3.63%), followed by P3 (2.92%), P2 (2.69%), and P1 (2.31%). GC–MS analysis revealed cuminaldehyde (21.31–33.60%), γ‐terpinene (13.68–23.29%), p‐mentha‐1,4‐dien‐7‐al (14.44–20.84%), p‐mentha‐1,3‐dien‐7‐al (10.06–14.02%), β‐pinene (9.32–11.46%), and p‐cymene (3.16–7.89%) were the major constituents in all the populations. Generally, the results showed that the seeds harvested from areas with hotter and drier climates (P3 and P4) had higher EO yields and cuminaldehyde concentrations but had moderate amounts of γ‐terpinene, β‐pinene, and p‐cymene. In addition, the hypnotic (100 and 200 mg/kg) and antinociceptive (25, 50, and 100 mg/kg) effects of cumin EO were proven in animal models.

A Patent-Pending Ointment Containing Extracts of Five Different Plants Showed Antinociceptive and Anti-Inflammatory Mechanisms in Preclinical Studies.

Background/Objectives: The antinociceptive and anti-inflammatory effects of a patent-pending ointment containing plant extracts from Eucalyptus globulus, Curcuma longa, Hamamelis virginiana, Echinacea purpurea, and Zingiber officinale were evaluated. Methods: Plant extracts were chemically characterized by gas chromatography-mass spectroscopy. The antinociceptive activity of the ointment was assessed using the hot plate, tail flick, and formalin tests, whereas the anti-inflammatory activity was measured using the acute and chronic TPA-induced ear edema tests. Mechanisms of action were evaluated using inhibitors from signaling pathways related to pain response and by using histological analysis and assessing the expression and activity of pro-inflammatory mediators. Results: The ointment showed antinociceptive and anti-inflammatory effects like those observed with diclofenac gel (1.16% v/v) and ketoprofen gel (2.5% v/v). The antinociceptive actions of the ointment are mediated by the possible participation of the opiodergic system and the nitric oxide pathway. The anti-inflammatory response was characterized by a decrease in myeloperoxidase (MPO) activity and by a reduction in ear swelling and monocyte infiltration in the acute inflammation model. In the chronic model, the mechanism of action relied on a decrease in pro-inflammatory mediators such as COX-2, IL-1β, TNF-α, and MPO. An in-silico study with myristic acid, one of the compounds identified in the ointment's plant mixture, corroborated the in vivo results. Conclusions: The ointment showed antinociceptive activities mediated by the decrease in COX-2 and NO levels, and anti-inflammatory activity due to the reduction in IL-1β and TNFα levels, a reduction in MPO activity, and a decrease in NF-κB and COX-2 expression.

Antinociceptive activity of transdermal nanostructured surfactant-based systems containing duloxetine hydrochloride

Duloxetine hydrochloride (DLX) is a serotonin and norepinephrine reuptake inhibitor that is effective in the treatment of chronic pain. However, the drug has several adverse reactions and extensive hepatic first-pass effect. This study aimed at developing surfactant-based formulations such as liquid crystals (LCs) and evaluating the influence of the formulations on DLX skin permeation and in vivo antinociceptive activity. Thereafter, the formulations were obtained using PEG-40 Hydrogenated Castor Oil, Tween 80, licuri oil and water. The systems selected showed isotropy, high viscosity and rheology suggestive of LCs. The systems presented ability to permeate DLX through the skin. ATR-FTIR demonstrated that formulations promoted lipid disorganization and modification of protein conformation, facilitating the drug diffusion through the stratum corneum. Moreover, the formulation loaded with DLX showed high antinociceptive activity in mice (tests of acetic acid-induced abdominal writhing, formalin and tail immersion) via the transdermal route. The antinociceptive activity was close to that of morphine (i.p.). In conclusion, the LC obtained proved to be a promising system for transdermal delivery of DLX and pain management.

Antinociceptive in vivo activity and chemical profiling by UHPLC-MS/MS of stem bark and leaves extracts of Ficus maxima Mill. (Moraceae)

Ethnopharmacological relevanceFicus maxima is a medicinal plant extensively used in traditional medicine by Indigenous peoples across Central and South America. It is a member of the family Moraceae, subgenus Pharmacosycea, employed in treating various conditions, including intestinal parasites, gingivitis, internal inflammations, and snake bites. Despite its significant pharmacological potential, the species remains underrepresented in scientific literature. Aim of the studyThis study aimed to evaluate the in vivo antinociceptive properties of leaf (ELFM) and stem bark (EBFM) extracts from Ficus maxima. Additionally, the chemical composition of these extracts was determined using ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Materials and methodsPlant material was collected in Abaetetuba, Pará, Brazil, in October 2013 and subjected to static maceration to obtain crude ELFM and EBFM. Bio-guided fractionation was performed by sequential liquid-liquid partitioning with hexane (Hex), dichloromethane (DCM), and ethyl acetate (EtOAc), yielding the following fractions: ELFM-Hex and EBFM-Hex, ELFM-DCM and EBFM-DCM, and ELFM-EtOAc and EBFM-EtOAc. The biological activity of EBFM, ELFM, and their respective fractions were evaluated using the formalin-induced pain test and the hot plate test, followed by an assessment of their mechanisms of action. The UHPLC-MS/MS analysis was conducted using electrospray ionization (ESI) in both positive and negative modes. Metabolite annotation was facilitated by MS/MS libraries and molecular networks constructed on the GNPS platform. ResultsThe reactivity time to formalin in the neurogenic phase was reduced from 84.7 ± 7.6 s (100%) to 37.3 ± 4.7 s (44%), 33.1 ± 6.3 s (39%), 40.7 ± 7.4 s (48%), 57.2 ± 2.6 s (77%), 49.7 ± 4.1 s (58%), 46.8 ± 8.1 s (55%), and 52.4 ± 5.3 s (61%) after treatment with ASA, morphine, EBFM, ELFM, ELFM-Hex, ELFM-DCM, and ELFM-EtOAc at doses of 30 mg/kg, respectively. In the inflammatory phase, the reactivity time to formalin was reduced from 124.3 ± 25.9 s (100%) to 49.7 ± 4.7 s (40%), 9.8 ± 4.3 s (8%), 32.5 ± 8.5 s (26%), 59.8 ± 16.8 s (48%), and 54.4 ± 7.3 s (44%) after treatment with ASA, morphine, EBFM, ELFM, and ELFM-Hex at doses of 30 mg/kg, respectively. A reversal of the antinociceptive action of EBFM and ELFM was observed in the inflammatory phase after treatment with atropine, a muscarinic antagonist, and naloxone, an opioid antagonist, respectively. In the hot plate test, EBFM showed Antinociceptive Activity (AA) of 62.6 ± 9.2% after 90 min; however, there was a reversal of AA to 8.6 ± 2.8% when naloxone was used. The UHPLC-MS/MS metabolite analysis revealed the presence of loliolide (3), luteolin (13), lupeol (14), gallic acid (15), chlorogenic acid (16), pygenic acid A (17), and other metabolites from the alkaloids and fatty acids classes.

Monnieriside A from Evolvulus linarioides promotes antinociceptive effects in models of inflammatory and postoperative pain in male mice

Monnieriside A (MoA) is a chromone isolated from Evolvulus linarioides. This study investigated the antinociceptive potential of MoA in mice. MoA (0.01–100 mg/kg, i.p.) inhibited nociception in the inflammatory phase of the formalin test without causing motor impairment. MoA (0.1–100 mg/kg, i.p.) also reduced hindpaw mechanical allodynia caused by either intraplantar injection of Complete Freund’s Adjuvant (CFA) or surgical paw incision to simulate postoperative pain. Postoperative antinociception was accompanied by reduced IL-1β levels in the incised paw, assessed by ELISA. The antinociceptive action of MoA (100 mg/kg, i.p.) was preserved in IL-10 knockout mice submitted to paw incision, indicating that IL-10 is not essential to the antinociceptive effect. Interestingly, MoA (100 mg/kg, i.p.) increased the expression of TGF-β in IL-10 knockout mice, which could be a compensation mechanism leading to an antinociceptive effect in the absence of IL-10.

An In Silico Approach to Exploring the Antinociceptive Biological Activities of Linalool and its Metabolites.

Pain is characterized by the unpleasant sensory and emotional sensation associated with actual or potential tissue damage, whereas nociception refers to the mechanism by which noxious stimuli are transmitted from the periphery to the CNS. The main drugs used to treat pain are nonsteroidal anti-inflammatory drugs (NSAIDs) and opioid analgesics, which have side effects that limit their use. Therefore, in the search for new drugs with potential antinociceptive effects, essential oils have been studied, whose constituents (monoterpenes) are emerging as a new therapeutic possibility. Among them, linalool and its metabolites stand out. The present study aims to investigate the antinociceptive potential of linalool and its metabolites through a screening using an in silico approach. Molecular docking was used to evaluate possible interactions with important targets involved in antinociceptive activity, such as α2-adrenergic, GABAergic, muscarinic, opioid, adenosinergic, transient potential, and glutamatergic receptors. The compounds in the investigated series obtained negative energies for all enzymes, representing satisfactory interactions with the targets and highlighting the multi-target potential of the L4 metabolite. Linalool and its metabolites have a high likelihood of modulatory activity against the targets involved in nociception and are potential candidates for future drugs.