Antinociceptive Agents Research Articles

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.

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.

The conotoxin Contulakin-G reverses hypersensitivity observed in rodent models of cancer-induced bone pain without inducing tolerance or motor disturbance

Abstract As the incidence and survival rates of patients with cancer continues to grow, an increasing number of people are living with comorbidities, which often manifests as cancer-induced bone pain (CIBP). The majority of patients with CIBP report poor pain control from currently available analgesics. A conotoxin, Contulakin-G (CGX), has been demonstrated to be an antinociceptive agent in postsurgical and neuropathic pain states via a neurotensin receptor 2 (NTSR2)-mediated pathway. However, the efficacy and side effect profile of CGX have never been assessed in CIBP. Here, we evaluated CGX's antinociceptive potential in a rodent model of CIBP. We hypothesized that CGX engages the NTSR2 pathway, providing pain relief with minimal tolerance and motor side effects. Our results demonstrated that CGX intrathecal injection in mice with CIBP attenuated both spontaneous pain behaviors and evoked mechanical hypersensitivity, regardless of their sex. Furthermore, the antinociceptive effect of CGX was dependent upon expression of NTSR2 and the R-type voltage-gated calcium channel (Cav2.3); gene editing of these targets abolished CGX antinociception without affecting morphine antinociception. Examination of the side effect profile of CGX demonstrated that, unlike morphine, chronic intrathecal infusion maintained antinociception with reduced tolerance in rats with CIBP. Moreover, at antinociceptive doses, CGX had no impact on motor behavior in rodents with CIBP. Finally, RNAScope and immunoblotting analysis revealed expression of NTSR2 in both dorsal and ventral horns, while Cav2.3 was minimally expressed in the ventral horn, possibly explaining the sensory selectivity of CGX. Together, these findings support advancing CGX as a potential therapeutic for cancer pain.

Isolation and Partial Characterization of 11-Octadecenoic Acid Methyl Ester and Bis (2-ethylhexyl) Phthalate from Celtis integrifolia Lam

Introduction: Celtis integrifolia Lam is a traditional medicinal plant used as a remedy for the cure of diarrhea, measles, bleeding, ecbolic, sore throat and as an antinociceptive agent. Aim: The study was aimed at the isolation and partial characterization of phytocompounds from Celtis integrifolia crude extract. Methodology: The stembark sample was powdered and extracted using maceration technique with methanol. The extract was filtered using cotton wool and clarified using Whatmann No.1 filter paper. The filtrate was concentrated on a rotavapor at 45oC. The crude extract was then reconstituted in water and partitioned successively with n-hexane, ethyl acetate, and n-butanol. The ethyl acetate and the n-hexane fractions were concentrated and subjected to purification on column chromatography. Results: Gradient elution of extract fractions on open-column chromatography yielded two compounds coded CiL1 and CiL2 from the n-hexane and ethyl acetate fractions respectively. The isolated compounds were characterized using spectroscopic data from Fourier transform infrared (FT-IR) spectroscopy, proton nuclear magnetic resonance (1H NMR) spectroscopy, gas chromatography-mass spectrometry (GC-MS) and literature database. Compound CiL1 with Rf = 0.43 in hexane: Ethyl acetate (9:1) was identified as 11-Octadecenoic acid methyl ester while Compound CiL2 isolated from ethyl acetate fraction as a yellow substance with Rf = 0.38 in hexane: ethyl acetate (8:2) was identified as bis (2-ethylhexyl) phthalate. Conclusion: The study showed the presence of 11-octadecenoic acid methyl ester and bis (2-ethylhexyl) phthalate in the stembark extract of Celtis integrifolia Lam. These two phytocompounds are reported for the first time from Celtis integrifolia Lam based on available literature. Since the presence of phytochemical substances is believed to be the basis of any observed pharmacological activity, the study therefore lends credence to the traditional medicinal uses of Celtis integrifolia Lam.

ANTI-INFLAMMATORY ACTIVITY OF PLANTAGO MAJOR LEAF EXTRACTS IN VITRO ON EPITHELIAL CELLS OF THE ORAL CAVITY

The large plantain has been widely used since ancient times to treat many diseases, including constipation, cough and ulcers. The purpose of this study is to review the traditional use, botanical characteristics, pharmacological activity, phytochemical effects and toxicity of Plantago major. Some o f its traditional properties, including wound healing, antipyretic, antitussive, anti-infective, anti-hemorrhagic, anti-inflammatory, diuretic, laxative, astringent and hemostatic, have been confirmed by recent studies. Phytochemical studies have shown that Plantago major contains volatile compounds, triterpenoids, phenolic acids and flavonoids. Current pharmacological studies have proven some of the traditional uses of Plantago major. However, additional studies of this plant are needed, since it can be used for the production of various natural preparations.The healing properties of the great plantain have been recognized all over the world for hundreds of years. This plant contains a number of effective chemical components, such as flavonoids, alkaloids, terpenoids, phenolic acid derivatives, iridoid glycosides, fatty acids, polysaccharides and vitamins, which contribute to its specific therapeutic effect. Accordingly, studies have shown that the large plantain is effective as a wound healing agent, as well as as an anti-cancer, antidiabetic, antidiarrheal, anti-inflammatory, antinociceptive, antibacterial and antiviral agent. It also fights fatigue and cancer, is an antioxidant and neutralizes free radicals.

Essential Oils from the Genus Piper Promote Antinociception by Modulating TRP Channels and Anti-Inflammatory Effects in Adult Zebrafish.

The Piper genus, known for its pharmacological potential, comprises 2,263 species primarily found in tropical regions. Despite recent advancements in pain therapies, the demand for more effective and well-tolerated analgesics and anti-inflammatories, particularly for chronic pain, remains. This study assessed the effects of essential oils from Piper caldense, Piper mosenii, and Piper mikanianum on nociceptive behavior induced by formalin and capsaicin, as well as their anti-inflammatory impact induced by carrageenan, using adult zebrafish models. Results indicated non-toxic essential oils with antinociceptive properties in both neurogenic and inflammatory phases of formalin-induced nociception through interaction with the TRPA1 receptor. Additionally, P. mosenii essential oil also blocked the nociceptive effect of capsaicin, a TRPV1 receptor agonist. Furthermore, essential oils from P. caldense and P. mikanianum exhibited significant anti-inflammatory effects by reducing carrageenan-induced abdominal edema. These findings highlight the pharmacological potential of Piper's essential oils as antinociceptive and anti-inflammatory agents.

Synthesis, molecular docking, electrochemical and fluorimetric analysis of new caffeic and cinnamic acid-conjugated hemorphin derivatives designed as potential anticonvulsant and antinociceptive agents

Based on the pharmacophore model of opioid receptors, our team recently synthesized a series of short‐chain hemorphin peptide analogs containing non‐natural amino acids. They demonstrated anticonvulsant and antinociceptive activity with low neurotoxicity. In the present study, a series of novel bioconjugates of N-modified hemorphin analogs containing second pharmacophore cinnamic acids (CA) or caffeic (KA) were synthesized by a traditional solid-phase Fmoc chemistry method for peptide synthesis. Electrochemical and fluorimetric analysis, in vivo anticonvulsant and antinociceptive activity in mice were conducted on the compounds. The three CA acid- (H4-CA, H5-CA, and H7-CA) and three KA acid- (H4-KA, H5-KA, and H7-KA) conjugated hemorphin derivatives exhibited potency at the highest doses of 2 µg/5 µl, administered by intracerebroventricular (icv) mode, against seizure spread in the maximal electroshock test (MES) in mice. The KA-conjugated H5-KA derivate, at the lowest dose, was the only compound that suppressed clonic seizures in the subcutaneous pentylenetetrazol (scPTZ) test. Except for the H5-CA, all tested CA acid- and KA acid-conjugated peptide derivates had the potency to increase the latency for clonic seizures in a dose-dependent mode. The activity against the psychomotor seizures in the 6-Hz test was detected only for the H4-CA (0.5 µg) and H4-KA (0.5 µg and 1 µg), respectively. All investigated peptides showed a more pronounced antinociceptive effect in the “intraplantar formalin” test compared to the “hot plate” test. Shorter chain analogs showed a better antinociceptive profile against tonic pain. The data suggest a DOR and KOR-mediated mechanism of action. According to the docking analysis, H7-CA showed a different antinociceptive profile than other investigated peptides. The novel peptide derivates did not exhibit neurotoxicity in the rotarod test. Our findings suggest that conjugated CA and KA morphine peptides can be used to develop novel morphine-related analogs with anticonvulsant and antinociceptive activity.

Green preparation, charetrization, in vitro/in vivo safety assessment and in vivo pain management of nortriptyline HCl loaded in niosome (norosome) manufactured by ecofriendly green method

Pain is an unfavorable feeling that is generally triggered by endogenous or exogenous harmful stimulation and has a strong emotional impact. The objective of this experimentation was to increase the cutaneous absorption of nortriptyline HCl (NOR) encapsulated in a niosome (norosomes) produced by an ultrasonic approach for the management of antinociceptive and anti-inflammatory disorders. Exploring the implications of the cholesterol:surfactant ratio on norosome compositions, the study revealed that increasing cholesterol significantly enlarged the norosome diameter from 66.84 ± 5.70 to 293.06 ± 36.54 nm (p < 0.05). More research revealed that changes in the cholesterol:surfactant ratio could influence the surface charge (19.27 ± 0.89 to 16.30 ± 0.78 mV) and entrapment efficiency (EE%) (7.90 ± 1.59 to 87.44 ± 2.11%) (p < 0.05). The amorphous nature of NOR in the niosome was shown by solid-state research. The dermal absorption study revealed that NOR was present at larger levels in dermal layers (41.79 ± 2.38%) and the receiver area (28.67 ± 1.33%) for norosome gel than for NOR-Carbopol gel. The norosomal’s cell safety was 84%, and the MTT study indicated a reduction in norosome cytotoxicity. The skin irritation analysis conducted on Wistar rats showed that the niosome component used did not cause irritation to the skin. Eventually, in comparison to the control group, norosome formulation demonstrated significant antinociceptive and anti-inflammatory (246.16 ± 53.60 s) actions in the late stage formalin test, tail-flick latency (5.18 ± 0.18 s), and hot plate latency (12.57 ± 1.78 s) (p < 0.05). These findings suggest that niosomes have the potential to enhance the effectiveness of NOR as an antinociceptive and anti-inflammatory agent by improving drug delivery to the targeted site.

Evaluation of the anti-nociceptive profile of essential oil from Melissa officinalis L. (lemon balm) in acute and chronic pain models

Ethnopharmacological relevanceMelissa officinalis L. (Lamiaceae) is a medicinal plant native to Mediterranean regions and found in other parts of the world. Extracts and essential oil from this widely cultivated culinary medicinal herb are used in traditional medicine to manage a variety of disorders that include epilepsy and pain. Aim of the studyTo assess the anti-nociceptive potentials of Melissa officinalis essential oil (MO) and probe the involvement of adrenergic, opioidergic, serotonergic and potassium adenosine triphosphate (KATP) mechanisms in its anti-nociceptive effects. Material and methodsWe employed formalin-, acetic acid and hot plate-induced nociception to study the acute anti-nociceptive effects of MO. The sciatic nerve injury (CCI) model of neuropathic pain was utilized to study the anti-nociceptive effects of MO on chronic pain. Effects of MO on anxiety, cognitive deficits, oxidative stress and inflammation in the CCI rats were evaluated on elevated plus maze, open field test, novel object recognition, oxidative stress parameters and pro-inflammatory cytokines, respectively. The possible mechanism(s) of MO's anti-nociceptive effects were elucidated using prazosin, yohimbine, propranolol, glibenclimide, naloxone and metergoline, which are acknowledged antagonists for α1–, α2– and β–adrenergic, potassium adenosine triphosphate (KATP), opioidergic and serotonergic systems, respectively. ResultsMO significantly attenuated acetic acid- and formalin-induced nociception; prolonged the mean reaction time of rats on hot plate before and following sciatic nerve chronic injury (CCI). MO ameliorated anxiety, cognitive deficits and oxidative stress, reduced pro-inflammatory cytokine levels and produced a near total restoration of injured sciatic nerves in CCI rats. Naloxone, metergoline and glibenclimide significantly blocked, while prazosin, yohimbine and popranolol failed to block the anti-nociceptive effects of MO in formalin-induced nociception. ConclusionsMO contains biologically active compounds with potential anti-nociceptive properties that modulate KATP, opioidergic and serotonergic pathways. These support the development of bioactive compounds from MO as anti-nociceptive agents.

Wikstroemia indica (L.) C. A. Mey. Exerts analgesic activity by inhibiting NaV1.7 channel

Ethnopharmacological relevanceWikstroemia indica (L.) C. A. Mey. is traditionally used for the treatment of gastrointestinal disorders, respiratory illnesses, skin infections, and inflammatory conditions. Despite extensive evidence of its biological potential, including antipyretic, antimicrobial, antifungal, anti-inflammatory, and diuretic properties, there are currently no reports indicating its analgesic effects. Aim of the studyCrude extracts from W. indica stems were examined for anti-nociceptive activity. Additionally, an in-depth investigation was conducted to uncover the molecular basis for the possible analgesic phenomenon. Materials and methodsW. indica stems were subjected to ethanol extraction. To evaluate the in vivo analgesic activity, both chemical and physical-induced pain models were employed. Additionally, single-cell electrophysiological recordings were performed on human embryonic kidney 293T (HEK293T) cells expressing NaV1.7 channel. ResultsCrude extracts derived from W. indica exhibited significant efficacy in mitigating the pain sensation, as evidenced by their substantial effects in both acetic acid-induced and heat-induced pain models. Further screening unveiled osthenol as a key bioactive compound responsible for mediating the analgesic properties of W. indica. Osthenol directly interacts with the pore domain of NaV1.7 channels, leading to channel inhibition. Importantly, this interaction is independent of any changes in the channel gating modifier domain. ConclusionBoth W. indica and osthenol demonstrate potential as effective anti-nociceptive agents in preclinical studies. Their analgesic effects are likely achieved by inhibiting the NaV1.7 channel, which is crucial in pain initiation, transmission, and modulation. These results elucidate the molecular basis of the W. indica as a pain-relieving medication. Additionally, osthenol holds great potential in advancing the development of anti-nociceptive drugs targeting the NaV1.7 channel.

Study of anti-inflammatory and antinociceptive properties of new derivatives of condensed 3-aminothieno[2,3-b]pyridines and 1,4-dihydropyridines

Background. α-сyanothioacetamide derivatives are promising targets for the search for effective and safe antinociceptive agents with antipyretic and antiexudative activity. The aim. To conduct in vivo experimental study of anti-inflammatory and analgesic effects of new thienopyridines and 1,4-dihydropyridines derivatives. Materials and methods. The synthesized cyanothioacetamide derivatives were subjected to virtual bioscreening using Swiss Target Prediction online service. 140 laboratory rats were randomly distributed into intact and control (dextran edema) groups, reference groups (acetylsalicylic acid and nimesulide) and ten experimental groups for the investigated derivatives of thieno[2,3-b]pyridine and 1,4-dihydropyridine. The anti-inflammatory activity of the compounds at a dose of 5 mg/kg was evaluated by modeling acute dextran edema of rat paw. Determination of analgesic activity was carried out in the hotplate analgesic assay on 130 rats in comparison with sodium metamizole. Results. 1,4-dihydropyridines AZ331 and AZ420, as well as thienopyridine derivative AZ023 were determined to have strong anti-inflammatory activity (2.5 times more effective than nimesulide and 2.2 times more effective than acetylsalicylic acid). Compounds AZ023, AZ331 and AZ383 showed pronounced analgesic activity. The time of stay on the heated plate for rats of experimental groups that were fed with AZ331 and AZ383 for prophylactic purpose was respectively 9.56 and 9.93 times more than the same index in the reference group. The animals receiving AZ023 were characterized by an increase in the latent reaction time up to 241.2 seconds, which is 14.53 times higher than that in the rats received sodium metamizole. Conclusion. New thienopyridine and 1,4-dihydropyridine derivatives with high antiinflammatory and analgesic activity were synthesized and studied; they were recognized as promising targets for further preclinical studies.

Antinociceptive Action of 4-(5′-Dimethylamino)-Naphthalenesulfonyl-2(3H)-Benzoxazolone (W3D) on Animal Models of Pain via Inhibitory Effects on NO and iNOS

The new synthetic anti-inflammatory agent, 4-(5′-dimethylamino)-naphthalenesulfonyl-2(3H)-benzoxazolone (W3D), has demonstrated definite biological activity both in vitro and in vivo. In this study, we investigated the antinociceptive effects of W3D on various animal pain models. Our results showed that W3D, at doses of 12.5 and 25 mg/kg, significantly reduced acetic acid-induced mice writhing by 65.9% and inhibited the pain response in the second phase of formalin-induced pain from 167.75 ± 6.76 s to 97.25 ± 9.63 s. Moreover, W3D prolonged the latent period on the tail-immersion test, which was stronger than the positive drug, aspirin (50 mg/kg). However, W3D did not show analgesic activity on the hot plate test, indicating no central pain response. Furthermore, the antinociceptive effects of W3D were not antagonized by naloxone, EGTA, CaCl2, and reserpine. However, L-Arginine was able to reverse the antinociceptive effect, indicating that W3D's antinociceptive effect does not depend on opioid receptors, Ca2+ concentration, or monoamine content. Instead, it is closely associated with nitric oxide (NO) content. In addition, W3D was found to alleviate nocifensive behavior and improve brain histopathology by inhibiting NO, inducible nitric oxide synthase (iNOS), and calcitonin gene-related peptide in nitroglycerin-induced migraine mice, with more than 50% inhibition ratio at only 12.5 mg/kg orally. However, noradrenaline, dopamine, and 5-hydroxytryptamine levels were not significantly altered after treatment with W3D. In conclusion, the presented data suggest that W3D can be considered a new non-steroidal anti-inflammatory and antinociceptive agent for the treatment of peripheral pain and migraine mediated by NO and iNOS.

Chemical profile, in vitro bioactivities, and antinociceptive effect of Red Pitaya extracts on zebrafish

Aqueous and ethanolic extracts of red pitaya (Hylocereus polyrhizus) peel, pulp, and seeds were evaluated for their chemical composition by UPLC-Q-TOF-MSE, antioxidant capacity (DPPH and ABTS assays), cytotoxicity and in vitro antiproliferative effect (MTT assay), antinociceptive activity and in vivo toxicity (Zebrafish model). A total of 25 compounds were identified in the extracts, mostly betacyanins, phenolic acids, flavonoids, and organic acids. The seeds extracts displayed both the highest radical scavenging activity and total phenol content. The pulp aqueous extract and ethanolic extracts exhibited some cytotoxicity against Vero cells, depending on the concentration and exposure time. These extracts were also able to inhibit S-180 cells proliferation, however only the peel ethanolic extract showed moderate to high selective indexes (SI: 4.06, 18.63), suggesting that its antiproliferative effect is not associated with the cytotoxic effect towards non-cancer cells, such as Vero cells. Regarding the antinociceptive activity, after adjusting the dose to exclude the sedation effect, the seeds ethanolic extract displayed antinociceptive activity at the inflammatory phase, similar to morphine. The extracts (1.0, 2.5 or 5.0 mg/mL) showed to be safe for zebrafish. In summary, these findings highlight the red pitaya as a promising natural source of bioactive, both in its edible and inedible parts, which can be better probed, for instance as anticancer and antinociceptive agents. In addition, the regular consumption of red pitaya can contribute to the health promotion, and the prevention of chronic diseases.

Design, synthesis, and analgesia evaluation of novel Transient Receptor Potential Vanilloid 1 (TRPV1) agonists modified from Cannabidiol (CBD)

Pain-relief is a long-term research hotspot with huge demand in clinical treatment. The analgesics currently used have several side effects, such as being addictive and causing gastrointestinal bleeding. Therefore, new drugs and targets in analgesic field are both desirable. Transient Receptor Potential Vanilloid 1 (TRPV1) plays an essential role in pain perception and regulation, providing a new strategy for the development of antinociceptive agents. Here, a series of novel TRPV1 agonists were designed and synthesized based on Cannabidiol (CBD), a widely used pain-relieving agent with weak agonistic activity on TRPV1. According to the results of systematic in vitro and in vivo biological assays, compound 10f was finally identified as a promising TRPV1 agonist, with higher target affinity, stronger analgesic activity, and weak side effect of hyperthermia. Molecular docking simulations revealed a significant hydrogen bond interaction between 10f and Arg557, an amino acid residue key to the activity of TRPV1 protein. Taken together, compound 10f can be used as a lead compound for further optimization.

Chemical composition, antinociceptive and anti-inflammatory effects in mice of the essential oil of Psidium cattleyanum Sabine leaves

Ethnopharmacological relevanceOne of the native species of the genus most often mentioned by traditional people is Psidium cattleyanum Sabine, which is used mostly to treat disorders of the respiratory, genitourinary, and digestive systems. These symptoms are mainly treated by the decoction of the leaves. Additionally, there are gaps in the in vivo and toxicity investigations of this species. Aim of the studyThe aim of this study was evaluate antinociceptive and anti-inflammatory potential of essential oil from P. cattleyanum leaves in vivo. Materials and methodsGas chromatography-mass spectrometry (GC/MS) was used to examine the essential oil of P. cattleyanum. The acute toxicity test was then done with a 2000 mg/kg dosage. The oil at 50, 100, and 200 mg/kg orally, as well as the reference medications Morphine 10.0 mg/kg IP and/or Indomethacin 20.0 mg/kg IP, were tested using nociception (abdominal writhing, formalin, and tail immersion) and inflammatory models (paw edema and peritonitis). ResultsThe phytochemical assay showed a high concentration of β-caryophyllene (46.68%) and α-caryophyllene (10.81%). In the in vivo assays, P. cattleyanum essential oil proved to be an important antinociceptive agent, reaching 76.96% inhibition of abdominal writhing with acetic acid and 67.12% in the formalin assay. An increase in latency time in the tail test was also reported. In the test with carrageenan, the oil showed significant inhibition compared to the control. A decrease in the migration of leukocytes was also reported in the group treated with P. cattleyanum, reaching 60.49% at the dose of 200 mg/kg. ConclusionsThe essential oil from the leaves of P. cattleyanum has anti-inflammatory and antinociceptive action and has potential for application in the pharmaceutical and food industry.

The role of L-arginine/NO/cGMP/KATP channel pathway in the local antinociceptive effect of berberine in the rat formalin test.

Berberine is an isoquinoline alkaloid naturally produced by several types of plants. Berberine has extensive pharmacological effects, such as anti-diabetic, anti-inflammatory, and antioxidant effects. In the current study, we assess the antinociceptive effects of berberine and its association with the l-arginine (l-Arg)/NO/cGMP/KATP channel pathway via intraplantar administration in rats. To examine the antinociceptive properties of berberine, the formalin test was conducted. The number of rat paw flinches was counted for an h. l-Arg (precursor of nitric oxide, 3-30 μg/paw), l-NAME (NO synthase inhibitor, 10 and 100 μg/paw), methylene blue (guanylyl cyclase inhibitor, 100 and 200 μg/paw), and glibenclamide (ATP-sensitive potassium channel blocker, 10 and 30 μg/paw) were locally injected, respectively, into the right hind paws of rats as a pre-treatment before berberine injection to understand how the l-Arg/NO/cGMP/KATP pathway plays a role in the antinociceptive effect of berberine. The ipsilateral injection of berberine into the right paw (0.1-100 μg/paw) showed a dose-dependent antinociceptive effect in both the first and second phases of the formalin test, almost similar to morphine (25 μg/paw). Intraplantar injection of l-Arg (30 µg/paw) increased the antinociceptive effect of berberine in the second phase. In addition, injection of l-NAME, methylene blue, and glibenclamide caused a reduction in the antinociceptive effect of berberine throughout the second phase in a dose-dependent manner. However, the antinociceptive effects of berberine in the first phase of the rat formalin test were not affected by this pathway. As a novel local antinociceptive agent, berberine can exert a peripheral antinociceptive effect via the l-Arg/NO/cGMP/KATP channel pathway.

Anti-nociceptive potential of an isatin-derived dual fatty acid amide hydrolase-monoacylglycerol lipase inhibitor.

Recently, we have reported an isatin-derived carbohydrazone, 5-chloro-N'-(6-chloro-2-oxoindolin-3-ylidene)-2-hydroxybenzohydrazide (SIH 3) as dual nanomolar FAAH (fatty acid amide hydrolase)-MAGL (monoacylglycerol lipase) inhibitor with good CNS penetration and neuroprotective activity profile. In this study, we further investigated the pharmacological profile of compound SIH 3 in the neuropathic pain model along with acute toxicity and ex vivo studies. Chronic constrictive injury (CCI) was used to induce neuropathic pain in male Sprague-Dawley rats and the anti-nociceptive activity of the compound SIH 3 was investigated at 25, 50, and 100mg/kg ip. Subsequently, locomotor activity was measured by rotarod and actophotometer experiments. The acute oral toxicity of the compound was assessed as per the OECD guidelines 423. Compound SIH 3 showed significant anti-nociceptive activity in the CCI-induced neuropathic pain model without altering the locomotor activity. Furthermore, compound SIH 3 showed an excellent safety profile (up to 2000mg/kg, po) in the acute oral toxicity study and was also non-hepatotoxic. Further, ex vivo studies revealed that the compound SIH 3 produces a significant antioxidant effect in oxidative stress induced by CCI. Our findings suggest that the investigated compound SIH 3 has the potential to be developed as an anti-nociceptive agent.

Significant pharmacological activities of benzoquinazolines scaffold.

Benzoquinazolines, the essential constituents of numerous well-known heterocyclic systems, have occupied a prominent position and played a significant part in the synthesis of various pharmaceutical compounds. The wide range of pharmacological effects attributed to benzoquinazolines has been the subject of extensive study. These include their roles as anticancer, antimicrobial, anti-monoamine oxidase, anticonvulsant, antiviral, antinociceptive, antioxidant, antineoplastic, antituberculosis, antiplatelet, and antiphlogistic agents. This work provides an attempt at a literature review of the pharmacological activities of benzoquinazoline derivatives, including an up-to-date account of recent research findings, and suggests avenues for future exploration in the pursuit of more potent and specific analogues for a wide range of biological targets using this platform.

Anxiolytic, analgesic and anti-inflammatory effects of Citrus maxima (Burm.) Merr. Seed extract in Swiss albino mice model

BackgroundCitrus maxima (Burm.) Merr. is traditionally used for its diverse pharmacological properties. Therefore, there remains a possibility that the seed extract may contain some bioactive compounds. The present study was carried out to evaluate the anxiolytic, analgesic, and anti-inflammatory effects of methanolic seed extract of Citrus maxima (MECM).MethodThe effect of MECM on the rodent central nervous system was evaluated using the hole-board and elevated plus-maze method. Analgesic effect was measured with the acetic acid-induced writhing and formalin-induced paw licking method. The anti-inflammatory effect was examined using a formalin and carrageenan-induced mice paw edema model.ResultsThe MECM at doses of 200 mg/kg and 400 mg/kg significantly (p < 0.01) increased the number of head dipping in the hole-board test. Additionally, the test subjects entered into the open arm and spent more time in it at an increased rate (p < 0.01) in the elevated plus-maze test. In the acetic acid-induced writhing method, the extract showed high potential (p < 0.001) as an analgesic agent. In the case of formalin-induced pain assessment, MECM demonstrated a significant effect (p < 0.01) at the early phase as a centrally acting anti-nociceptive agent and very high potential (p < 0.001) to reduce pain during the late phase as a peripherally acting analgesic. The extract also showed potency (p < 0.01) as an anti-inflammatory agent in formalin and carrageenan-induced mice paw edema test.ConclusionThe findings of the current study indicate that MECM can be a promising new candidate for searching novel anxiolytic, analgesic, and anti-inflammatory compounds through further investigation.

Binding preference at the μ-opioid receptor underlies distinct pharmacology of cyclopropyl versus valeryl analogs of fentanyl

Illicitly manufactured fentanyl is driving the current opioid crisis, and various fentanyl analogs are appearing in recreational drug markets worldwide. To assess the potential health risks posed by fentanyl analogs, it is necessary to understand structure-activity relationships for these compounds. Here we compared the pharmacology of two structurally related fentanyl analogs implicated in opioid overdose: cyclopropylfentanyl and valerylfentanyl. Cyclopropylfentanyl has a three-carbon ring attached to the carbonyl group on the fentanyl scaffold, whereas valerylfentanyl has a four-carbon chain at the same position. In vitro assays examining μ-opioid receptor (MOR) coupling to G proteins in CHO cells showed that cyclopropylfentanyl is a full agonist (EC50 = 8.6 nM, %Emax = 113%), with potency and efficacy similar to fentanyl (EC50 = 10.3 nM, %Emax = 113%). By contrast, valerylfentanyl is a partial agonist at MOR (EC50 = 179.8 nM, %Emax = 60%). Similar results were found in assays assessing MOR-mediated β-arrestin recruitment in HEK cells. In vivo studies in male CD-1 mice demonstrated that both fentanyl analogs induce naloxone-reversible antinociception and respiratory suppression, but cyclopropylfentanyl is 100-times more potent as an antinociceptive agent (ED50 = 0.04 mg/kg, s. c.) than valerylfentanyl (ED50 = 4.0 mg/kg, s. c.). Molecular simulation results revealed that the alkyl chain of valerylfentanyl cannot be well accommodated by the active state of MOR and may transition the receptor toward an inactive state, converting the fentanyl scaffold to a partial agonist. Taken together, our results suggest that cyclopropylfentanyl presents much greater risk of adverse effects when compared to valerylfentanyl. Moreover, the summed findings may provide clues to the design of therapeutic opioids with reduced adverse side effects.