Antinociceptive Activity Research Articles

Orofacial antinociceptive activity of codeine-associated geraniol in mice: a controlled triple-blind study.

This is a nonclinical, controlled, and triple-blind study to investigate the effects of codeine-associated geraniol on the modulation of orofacial nociception and its potential central nervous system depressing effect in an animal model. The orofacial antinociceptive activity of geraniol in combination with codeine was assessed through the following tests: (i) formalin-induced pain, (ii) glutamate-induced pain, and (iii) capsaicin-induced pain. Six animals were equally distributed into six groups and received the following treatments, given intraperitoneally (i.p.) 30 minutes before the experiments: a) geraniol/codeine 50/30 mg/kg; b) geraniol/codeine 50/15 mg/kg; c) geraniol/codeine 50/7.5 mg/kg; d) geraniol 50 mg/kg; e) codeine 30 mg/kg (positive control); or f) 0.9% sodium chloride (negative control). We performed pain behavior analysis after the injection of formalin (20 µL, 20%), glutamate (20 µL, 25 µM), and capsaicin (20 µL, 2.5 µg) into the paranasal region. Rubbing time of the paranasal region by the hind or front paw was used as a parameter. In the neurogenic phase of the formalin test, the geraniol/codeine at 50/7.5 mg/kg was able to promote the maximum antinociceptive effect, reducing nociception by 71.9% (p < 0.0001). In the inflammatory phase of the formalin test, geraniol/codeine at 50/30 mg/kg significantly reduced orofacial nociception (p < 0.005). In the glutamate test, geraniol/codeine at 50/30 mg/kg reduced the rubbing time by 54.2% and reduced nociception in the capsaicin test by 66.7% (p < 0.005). Geraniol alone or in combination does not promote nonspecific depressing effects on the central nervous system. Based on our findings, we suggest the possible synergy between geraniol and codeine in the modulation of orofacial pain.

Anti-Inflammatory, Analgesic and Anti-Oxidant Effects of Shirakiopsis Indica (Willd). Fruit Extract: A Mangrove Species in the Field of Inflammation Research.

Shirakiopsis indica (Willd)., commonly known as Sa-Mor-Ta-Lay in Thailand, is a mangrove plant belonging to the Euphorbiaceae family. As mangrove plants' medicinal potentials are less explored, this study sought to qualitatively and quantitatively verify the bioactive components of Shirakiopsis indica fruits methanolic extract (SIF-ME) at the side of its analgesic, anti-inflammatory and anti-oxidant effects followed by in-silico studies. The in-vivo assessments of analgesic activity involved the hot plate test, acetic acid-induced writhing test, and formalin-induced licking test. The anti-inflammatory efficacy was assessed through the human RBC membrane stabilization assay (HRBC), protein denaturation assay, and xylene-induced ear edema methods. Antioxidant potential was implemented by the DPPH scavenging method. The SIF-ME consistently displayed significant anti-nociceptive activity in a dose-dependent pattern (p < 0.05). The maximum analgesic activity was found in the highest dose (200 mg/kg; p < 0.001) in a hot plate, acetic acid-induced writhing test 43.47%, and in formalin-induced licking test in both early phase (43.3%; p < 0.01) and late phase (61.84%; p < 0.001%). The extract provided optimal protection against hemolysis (83.41% decrease) at 1000 µg/mL and significantly inhibited protein denaturation (67.34-26.05%) at doses of 1000-62.5 µg/mL. At 200 mg/kg, the extract showed dose-dependent and substantial inhibition (54.07%; p < 0.01) of xylene-induced ear edema. The in-vitro DPPH (IC50 = 469.5 µg/mL) results showed remarkable scavenging activity and concentration-dependent reducing power. The extract demonstrates no acute oral toxicity, as indicated by an LD50 value exceeding 1000 mg/kg body weight. Gas Chromatography-Mass Spectrometry/Mass Spectrometry (GC-MS/MS) analysis was performed which yielded sixty bioactive compounds. In-silico and molecular docking studies revealed favorable pharmacological properties, including good binding affinities and ADME/T profiles. These results support the medicinal use of the plant, which makes it a potential source of analgesic, anti-inflammatory, and antioxidant candidates.

Antinociceptive activity of Lepechinia meyenii (Walp.) Epling "pacha sage" extract in a model of acute pain induced in mice

Objetivo: La presente investigación es un estudio experimental que presentó como objetivo determinar el efecto antinociceptivo del extracto hidroalcohólico de las hojas de Lepechinia meyenii (Walp.) Epling “pacha salvia” en dolor inducido por ácido acético en ratones. Material y métodos: El recurso vegetal fue recolectado en el distrito de Molinos, Provincia de Jauja (Junín). Para la obtención del extracto hidroalcohólico se empleó el proceso de maceración, a partir del cual se realizó la marcha fitoquímica y las pruebas de solubilidad. En la evaluación del efecto analgésico se utilizó el método de contorsiones abdominales inducidas por ácido acético, empleando 30 ratones albinos BALB/c divididos en 5 grupos de tratamiento: Control Negativo (suero fisiológico), Control Positivo (tramadol 40mg/kg), y tres grupos experimentales (Extracto hidroalcohólico a dosis de 200mg/kg, 400mg/kg y 600mg/kg). Resultados: Los porcentajes de analgesia del extracto con dosis de 200mg/kg fue 2,9%, con 400mg/kg 6,2% y con 600mg/kg 49,4%, y para el tramadol un 95%. En la marcha fitoquímica se evidenció la presencia de carbohidratos, azúcares reductores, alcaloides, flavonoides, taninos, compuestos fenólicos, saponinas, aminoácidos, quinonas, triterpenoides y/o esteroides. Conclusión: El extracto hidroalcohólico de las hojas de Lepechinia meyenii (Walp.) Epling “pacha salvia” presenta actividad antinociceptiva en dolor inducido por ácido acético en ratones.

Synthesis and antinociceptive activity of 2,2’-(1,4-phenylene)bis[3-aryl-2-azaspiro[3.5]nonan-1-ones

Over the years, azetidin-2-ones, or β-lactams, have received a lot of attention from scientists as potential drug candidates due to their diverse biological activity. Spiro-β-lactams also exhibit biological activity; therefore, it is of interest to synthesize and study the properties of new compounds belonging to this class. The study aims to examine the antinociceptive activity of several synthesized bis(spirolactams), specifically 2,2’-(1,4-phenylene)bis[3-aryl-2azaspiro[3.5]nonan-1-ones]. These bis(spiroazetidine-2-ones) were obtained in the interaction of a twofold excess of the Reformatsky reagent, derived from methyl 1-bromocyclohexane carboxylate and zinc, with N,N-(1,4-phenyle- ne)bis(1-arylmethanimines) by means of boiling them in a 10:1 mixture of toluene and hexamethylphosphorictriamide for four hours. Bis(spiro-β-lactams) on the basis of diimines derived from p-phenylenediamine, 2-methoxybenzaldehyde, p-tolualdehyde, and 3-bromobenzoic aldehyde were synthesized for the first time. The composition and structure of the previously undescribed products were established using IR, [1]H, and 13C NMR spectroscopy and elemental analysis. The antinociceptive activity of the obtained compounds was studied on outbred white mice of both sexes via the hot plate test with an intraperitoneal injection. The effect was estimated two hours after administration. Several synthesized compounds were found to exhibit antinociceptive activity at or above the level of the comparator product – metamizole sodium. Nerve endings can be considered the target of the antinociceptive activity of examined substances since under the effect of these substances, no signs of central action are observed in the behavior of animals. Thus, the conducted studies showed the promise of further search for biologically active substances among the compounds of this series.

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.

Anti-inflammatory and antinociceptive effects of sitagliptin in animal models and possible mechanisms involved in the antinociceptive activity.

Sitagliptin is an antidiabetic drug that inhibits dipeptidyl peptidase-4 enzyme. This study aimed to investigate the antinociceptive and anti-inflammatory effects of sitagliptin in formalin and carrageenan tests and determine the possible mechanism(s) of its antinociceptive activity. Male Swiss mice (25-30 g) and male Wistar rats (180-220 g) were used for formalin and carrageenan tests, respectively. In the formalin test, paw licking time and in the carrageenan test, paw thickness were considered as indexes of pain behavior and inflammation respectively. Three doses of sitagliptin (2.5, 5, and 10 mg/kg) were used in these tests. Also, several antagonists and enzyme inhibitors were used to evaluate the role of adrenergic, serotonergic, dopaminergic, and opioid receptors as well as the NO/cGMP/KATP pathway in the antinociceptive effect of sitagliptin (5 mg/kg). Sitagliptin showed significant antinociceptive and anti-inflammatory effects in the formalin and carrageenan tests respectively. In the carrageenan test, all three doses of sitagliptin significantly (P < 0.001) reduced paw thickness. Pretreatment with yohimbine, prazosin, propranolol, naloxone, and cyproheptadine could not reverse the antinociceptive effect of sitagliptin (5 mg/Kg), which indicates that adrenergic, opioid, and serotonin receptors (5HT2) are not involved in the antinociceptive effects. L-NAME, methylene blue, glibenclamide, ondansetron, and sulpiride were able to reverse this effect. NO/cGMP/KATP, 5HT3 and D2 pathways play an important role in the antinociceptive effect of sitagliptin. Additionally significant anti-inflammatory effects observed in the carrageenan test might contribute in reduction of pain response in the second phase of the formalin test.

Evaluation of Anti-nociceptive and Anti-Inflammatory Effects of Markhamia tomentosa Cream Co-Formulated with Eucalyptus Oil

Background: Pain is a noxious, sensory, and emotional experience due to intense stimuli. Pain is intimately linked with nociception. The clinical therapies available at the moment for pain are tricyclic antidepressants, non -steroidal anti-inflammatory drugs, and opioids. There is a need to develop and investigate safer alternatives that minimise the chances of psychological or physical drug dependence and drug dose tolerance. The purpose of this research is to develop an anti-inflammatory and anti-nociceptive formulation (Markhamia tomentosa cream co-formulated with Eucalyptus oil as a permeation enhancer) and evaluate its efficacy. Methods: In this study, Markhamia tomentosa was extracted from its leaves using maceration technique. A qualitative screening of the Markhamia tomentosa ethanolic extract (EEMT) was carried out. Five emulsions (A1-A5) containing varying compositions of Markhamia tomentosa were developed, and a negative control (an emulsion that did not contain Markhamia tomentosa or Eucalyptus oil) was also developed using fusion method. The anti-inflammatory and anti-nociceptive properties of the topical creams were evaluated using mice paw-licking and xylene-induced ear oedema tests. Diclofenac and aspirin administered at 20 mg/kg and 50mg/kg orally, respectively, were used as standards. All experiments were carried out in triplicates. Results: The phytochemical investigation of the Markhamia tomentosa extract showed a marked presence of key phyto-constituents such as saponins, flavonoids, alkaloids, and terpenoids. A1 and A2 had significantly higher percentage of nociception inhibition at phase I—neurogenic and phase II—inflammatory stages compared to Diclofenac 20 mg/kg. A1 and A3 had anti-inflammatory properties more potent than Aspirin 50mg/kg. In both tests, the negative controls did not show any level of potency. All results in this investigation were expressed as mean ± S.D (n=3) and (p&lt;0.05) for all data sets. Formulation A1 had the highest concentration of EEMT. No rash, erythema, or oedema was observed in the Draize test implying that the formulations are safe for topical application. Conclusion: Markhamia tomentosa and eucalyptus oil cream showed potent anti-nociceptive and anti-inflammatory activity. Markhamia tomentosa cream co-formulated with Eucalyptus oil as a permeation enhancer can be used effectively as a non-opioid, anti-nociceptive, and anti-inflammatory cream topically for pain and its symptoms

Antiedema and antinociceptive potential of the essential oil of Pectis elongata Kunt (Asteraceae) from the Brazilian Amazon

Ethnopharmacological relevancePectis elongata, a herbaceous species that is known in northern Brazil as “cominho” or “limãozinho”, is traditionally used in the region for the treatment of fevers, colds, hypotension, genitourinary and gastric disorders, and pain. Aim of the studyDetermine the chemical composition and acute oral toxicity and evaluate whether Pectis elongata essential oil (PeEO) has antiedema and antinociceptive activity. Materials and methodsThe chemical composition was determined using gas chromatography coupled to mass spectrometry (GC/MS) and the degree of toxicity determined by the LD50. The antiedema and antinociceptive potential was evaluated via the λ-carrageenan-induced paw edema test and formalin test, respectively. ResultsCitral (geranial and neral) was characterized as a major component of the PeEO, representing 89% of the total identified compounds. According to OECD criteria (2002), the EO was considered non-toxic since it presented LD50 values over 2000 mg kg−1. Its antiedema potential was observed at doses of 200 and 400 mg kg−1 (p ≤ 0.05). At a dose of 400 mg kg−1, PeEO also showed antinociceptive potential (p ≤ 0.05), both in the neurogenic phase and in the inflammatory phase. ConclusionsPeEO, which is rich in citral, did not induce any characteristic signs of acute oral toxicity and was also efficient in reducing carrageenan-induced paw edema, in addition to presenting antinociceptive potential and acting on both central and peripheral pain. It is thus a promising candidate for the development of a new herbal medicine with anti-inflammatory and analgesic action.

Neuroprotective and Anti-inflammatory Effects of Rubiscolin-6 Analogs with Proline Surrogates in Position 2

Naturally occurring peptides, such as rubiscolins derived from spinach leaves, have been shown to possess some interesting activities. They exerted central effects, such as antinociception, memory consolidation and anxiolytic-like activity. The fact that rubiscolins are potent even when given orally makes them very promising drug candidates. The present work tested whether rubiscolin-6 (R-6, Tyr-Pro-Leu-Asp-Leu-Phe) analogs have neuroprotective and anti-inflammatory effects. These hypotheses were tested in the 6-hydroxydopamine (6-OHDA) injury model of human neuroblastoma SH-SY5Y and lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. The determination of reactive oxygen species (ROS), mitochondrial membrane potential (MMP), Caspase-3 activity, lipid peroxidation and nitric oxide (NO) production allowed us to determine the effects of peptides on hallmarks related to Parkinson’s Disease (PD) and inflammation. Additionally, we investigated the impact of R-6 analogs on serine-threonine kinase (also known as protein kinase B, AKT) and mammalian target of rapamycin (mTOR) activation. The treatment with analogs 3 (Tyr-Inp-Leu-Asp-Leu-Phe-OH), 5 (Dmt-Inp-Leu-Asp-Leu-Phe-OH) and 7 (Tyr-Inp-Leu-Asp-Leu-Phe-NH2) most effectively prevented neuronal death via attenuation of ROS, mitochondrial dysfunction and Caspase-3 activity. Peptides 5 and 7 significantly increased the protein expression of the phosphorylated-AKT (p-AKT) and phosphorylated-mTOR (p-mTOR). Additionally, selected analogs could also ameliorate LPS-mediated inflammation in macrophages via inhibition of intracellular generation of ROS and NO production. Our findings suggest that R-6 analogs exert protective effects, possibly related to an anti-oxidation mechanism in in vitro model of PD. The data shows that the most potent peptides can inhibit 6-OHDA injury by activating the PI3-K/AKT/mTOR pathway, thus playing a neuroprotective role and may provide a rational and robust approach in the design of new therapeutics or even functional foods.

Antinociceptive and anti-inflammatory potential, and chemical characterization of the dichloromethane fraction of Solanum lycocarpum (Solanaceae) ripe fruits by LC-DAD-MS

Ethnopharmacological relevanceSolanum lycocarpum A. St. Hil. (Solanaceae) is a species from the Brazilian Cerrado, exhibiting several medicinal properties, being used by the population in the treatment of ulcers, bronchitis, asthma and hepatitis, which involve inflammatory processes. Aim of this studyThis study aimed to chemically characterize the dichloromethane fraction (DCM), as well as verify its antinociceptive, anti-inflammatory and antioxidant potential. Materials and methodsThe DCM fraction was obtained by partitioning the ethanol extract. The chemical constituents of the DCM fraction were characterized by LC-DAD-MS. The DPPH and FRAP assays were used to evaluate the antioxidant potential. The carrageenan-induced paw edema model was used to assess the anti-inflammatory effects, and the inflammatory infiltrate was evaluated by qualitative and quantitative histological analyses. The antinociceptive action of the DCM fraction was evaluated by acetic acid-induced abdominal writhing test, formalin-induced nociception and hot-plate test. ResultsSteroidal alkaloids solasonine, solasodine and solamargine, as well as the alkaloid peiminine/imperialine and caffeoylquinic acids, were annotated in DCM fraction by LC-DAD-MS. The DCM fraction showed antioxidative action in the in vitro DPPH and FRAP tests, as well as an anti-inflammatory effect for the three evaluated doses of 30, 100 and 300 mg/kg in the fourth and sixth hours after the administration of carrageenan. The histological analyses evidenced considerably reduction in leukocyte migration and the number of polymorphonuclear leukocytes. The study also demonstrated antinociceptive activity for the DCM fraction, which reduced abdominal writhing at three concentrations evaluated, as well as a decrease in paw licking in the formalin-induced nociception test both in the neurogenic phase and the inflammatory phase, with greater effectiveness compared to the anti-inflammatory indomethacin. The DCM fraction also increased the latency time of the animals in the hot plate test 60 min after treatment, although it did not seem to involve the opioidergic system. ConclusionThis work evidenced that the dichloromethane fraction of S. lycocarpum fruit possesses antinociceptive and anti-inflammatory potential, which supports its use in folk medicine for management inflammatory conditions.

Structure-Activity Relationships of a Novel Cyclic Hexapeptide That Exhibits Multifunctional Opioid Agonism and Produces Potent Antinociceptive Activity.

The cyclic peptide c[d-Lys2, Asp5]-DN-9 has recently been identified as a multifunctional opioid/neuropeptide FF receptor agonist, displaying potent analgesic activity with reduced side effects. This study utilized Tyr-c[d-Lys-Gly-Phe-Asp]-d-Pro-NH2 (0), a cyclic hexapeptide derived from the opioid pharmacophore of c[d-Lys2, Asp5]-DN-9, as a chemical template. We designed, synthesized, and characterized 22 analogs of 0 with a single amino acid substitution to investigate its structure-activity relationship. Most of these cyclic hexapeptide analogs exhibited multifunctional activity at μ and δ opioid receptors (MOR and DOR, respectively) and produced antinociceptive effects following subcutaneous administration. The lead compound analog 15 showed potent agonistic activities at the MOR, κ opioid receptor (KOR), and DOR in vitro and produced a strong and long-lasting analgesic effect through peripheral MOR and KOR in the tail-flick test. Further biological evaluation identified that analog 15 did not cause significant side effects such as tolerance, withdrawal, or reward liability.

Botulinum toxin type a antinociceptive activity in trigeminal regions involves central transcytosis

ObjectiveBotulinum toxin type A (BoNT-A) provides lasting pain relief in patients with craniofacial pain conditions but the mechanisms of its antinociceptive activity remain unclear. Preclinical research revealed toxin axonal transport to the central afferent terminals, but it is unknown if its central effects involve transsynaptic traffic to the higher-order synapses. To answer this, we examined the contribution of central BoNT-A transcytosis to its action in experimental orofacial pain. Material and methods:Male Wistar rats, 3–4 months old, were injected with BoNT-A (7 U/kg) unilaterally into the vibrissal pad. To investigate the possible contribution of toxin's transcytosis, BoNT-A-neutralizing antiserum (5 IU) was applied intracisternally. Antinocicepive BoNT-A action was assessed by duration of nocifensive behaviors and c-Fos activation in the trigeminal nucleus caudalis (TNC) following bilateral or unilateral formalin (2.5%) application into the vibrissal pad. Additionally, cleaved synaptosomal-associated protein of 25 kDa (cl-SNAP-25) immunoreactivity was analyzed in the bilateral TNC. Results:Unilaterally injected BoNT-A reduced the nocifensive behaviors and bilateral c-Fos activation induced by formalin, which was accompanied by the toxin's enzymatic activity on both sides of the TNC. BoNT-A antinociceptive or enzymatic activities were prevented by the specific neutralizing antitoxin. BoNT-A contralateral action occurred independently from ipsilateral side nociception or contralateral trigeminal nerve-mediated axonal traffic. ConclusionHerein, we demonstrate that antinociceptive action of pericranially administered BoNT-A involves transsynaptic transport to second order synapses and contralateral trigeminal nociceptive nuclei. These results reveal more complex central toxin activity, necessary to explain its clinical effectiveness in the trigeminal region-related pain states.

Phytochemical Investigation, Proximate Composition, Acute Toxicity, Anti-Inflammatory and Antinociceptive Activities of Extracts of Caesalpinia Pulcherrima Linn Flower

The management and treatment of inflammation and pains have continued to gain increasing interest in recent times due to the challenge they pose to health. The study evaluated the phytoconstituents, proximate content, acute toxicity, antioxidant, anti-inflammatory, and antinociceptive properties of Caesalpinia pulcherrima flower extracts using different solvents. The bioactive chemical constituents, acute toxicity, and antioxidant property were investigated via standard methods while the anti-inflammatory and analgesic activities were determined using formalin-induced inflammation and acetic acid-induced writhing methods respectively. Phytochemicals determined were alkaloids, glycosides, saponins, tannins, phenolics, terpenoids, and steroids. The moisture, crude fibre, crude lipid and total ash content determined were 6.20 ± 0.01%, 15.00 ± 0.07%, 1.80 ± 0.03% and 7.00 ± 0.00% respectively. The n-hexane extract possessed the chief % inhibition (86.49 ± 0.30) and for ascorbic acid 88.29 ± 0.00 at 500 μg/mL extract from the antioxidant study. The acetone extract displayed the greatest significant anti-inflammatory potential at both 100 and 200 mg/kg dose at four hours, being the most effective and there exist a momentous reduction at p 0.05 in the writhes’ number in a manner depended on dose in the acetone and n-hexane extracts. At 5000 mg/kg, there was 100% mortality when the crude extracts were orally administered to the Swiss mice. This study ratifies that Caesalpinia pulcherrima flower extract is a potential spring of phytomedicine which could be applied for managing of inflammation, pain and oxidative stress-related infections but higher dosages could potentially be lethal.

All-Hydrocarbon Stapled Peptide Multifunctional Agonists at Opioid and Neuropeptide FF Receptors: Highly Potent, Long-Lasting Brain Permeant Analgesics with Diminished Side Effects.

Our previous study reported the multifunctional agonist for opioid and neuropeptide FF receptors DN-9, along with its cyclic peptide analogues c[D-Cys2, Cys5]-DN-9 and c[D-Lys2, Asp5]-DN-9. These analogues demonstrated potent antinociceptive effects with reduced opioid-related side effects. To develop more stable and effective analgesics, we designed, synthesized, and evaluated seven hydrocarbon-stapled cyclic peptides based on DN-9. In vitro calcium mobilization assays revealed that most of the stapled peptides, except 3, displayed multifunctional agonistic activities at opioid and neuropeptide FF receptors. Subcutaneous administration of all stapled peptides resulted in effective and long-lasting antinociceptive activities lasting up to 360 min. Among these stapled peptides, 1a and 1b emerged as the optimized compounds, producing potent central antinociception following subcutaneous, intracerebroventricular, and oral administrations. Additionally, subcutaneous administration of 1a and 1b caused nontolerance antinociception, with limited occurrence of constipation and addiction. Furthermore, 1a was selected as the final optimized compound due to its wider safety window compared to 1b.

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.

Antinociceptive Effect of the Combination of a Novel α4β2* Agonist with Donepezil in a Chronic Pain Model.

Chronic pain presents a major challenge in contemporary medicine, given the limited effectiveness and numerous adverse effects linked to available treatments. Recognizing the potential of the cholinergic pathway as a therapeutic target, the present work evaluates the antinociceptive activity of a combination of Cris-104, a novel α4β2* receptor agonist, and donepezil, a central anticholinesterase agent. Isobolographic analysis revealed that equimolar combination was approximately 10 times more potent than theoretically calculated equipotent additive dose. Administration of Cris-104 and donepezil combination (3 μmol/kg) successfully reversed hyperalgesia and mechanical allodynia observed in rats subjected to spinal nerve ligation (SNL). The combination also modulated neuroinflammation by reducing astrocyte activation, evident in the decreased expression of glial fibrillary acidic protein (GFAP) in the spinal cord. The observed synergism in combining a nicotinic receptor agonist with an anticholinesterase agent underscores its potential for treating chronic pain. This alternative therapeutic distinct advantage, including dose reduction and high selectivity for the receptor, contribute to a more favorable profile with minimized adverse effects.

Antinociceptive and antiinflammatory activities of crude leave extract and solvent fractions of Commelina latifolia Hochst. ex C.B.Clarke (Commelinaceae) leaves in murine model.

Ethnopharmacological relevance: In the past, Ethiopian traditional medicine employed the leaves of the native Commelina latifolia Hochst. ex C.B. Clarke plant to treat wounds, pain, and malaria. Aim of the study: The crude extract and solvent fractions of C. latifolia Hochst. ex C.B. Clarke leaves were examined in the present investigation to determine their ability to have an antiinflammatory effect and provide an antinociceptive effect in animal models. Materials and methods: The leaves of C. latifolia were extracted with 80% methanol, and the CL crude extract was further fractionated with chloroform, pure methanol, and distilled water. The carrageenan-induced paw edema model was used to test the extracts' ability to reduce inflammation. The hotplate model and the acetic acid-induced writhing test on rodents were used to test the extracts' potential antinociceptive effect to reduce pain. Results: Inflammation was decreased by 64.59% with CL crude extract (400mg/kg); 56.34% (400mg/kg) of methanol fraction, 64.59% of aqueous fraction (400mg/kg), and 38.27% of chloroform fraction in the carrageenan-induced inflammatory model. All extracts demonstrated a considerable lengthening of the nociception reaction time in the hot plate test, with a maximum antinociceptive effect of 78.98% (crude extract) and 71.65% (solvent fractions). At a dosage of 400mg/kg, the natural C. latifolia crude extract and aqueous fraction demonstrated considerable antinociceptive effects against acetylsalicylic acid (ASA) during the writhing test (48.83% and 45.37than%, respectively). The current findings support Ethiopia's traditional user's assertions that the herb can alleviate inflammation and pain.

Oral treatment with Berberine reduces peripheral nociception: Possible interaction with different nociceptive pathways activated by different allogeneic substances

Ethnopharmacological relevanceBerberine was identified in extracts of Berberis ruscifolia Lam., a plant used in traditional medicine as an analgesic. Its presence may be involved in the reported pharmacological activity of this species. However, there is still a lack of scientific research concerning its analgesic activity in the peripheral nervous system. Aim of the studyTo investigate Berb-induced antinociception in the formalin test and to evaluate several pathways related to its pharmacological antinociceptive effects in chemical models of nociception in mice. Materials and methodsThe antinociceptive activity of Berb was assessed by inducing the paw licking in mice with different allodynic agents. In the formalin test, the antiedematous and antithermal effect of Berb was evaluated simultaneously in the same experiment. Other nociceptive behavior produced by endogenous [prostaglandin E2 (PGE2), histamine (His), glutamate (Glu) or bradykinin (BK)] or exogenous [capsaicin (Caps) and cinnamaldehyde (Cin)] chemical stimuli, and activators as protein kinase A (PKA) and C (PKC), were also evaluated.The in vivo doses for p.o. were 3 and 30 mg/kg. ResultsBerb, at 30 mg/kg p.o., showed a significant inhibition of the nociceptive action in formalin in both phases being stronger at the inflammatory phase (59 ± 9%) and more active than Asp (positive control) considering the doses evaluated. Moreover, Berb inhibited the edema (34 ± 10%), but not the temperature in the formalin test. Regarding the different nociceptive signaling pathways evaluated, the most relevant data were that the administration of p.o. of Berb, at 30 mg/kg, caused significant inhibition of nociception induced by endogenous [His (72 ± 11%), PGE2 (78 ± 4%), and BK (51 ± 7%)], exogenous [Cap (68 ± 4%) and Cinn (57 ± 5%)] compounds, and activators of the PKA [(FSK (86 ± 3%)] and PKC [(PMA(86 ± 6%)] signaling pathway. Berb did not inhibit the nociceptive effect produced by Glu. ConclusionThe present study demonstrated, for the first time, the potential of Berb in several nociceptive tests, with the compound present in B. ruscifolia contributing to the analgesic effect reported for this species.

Antinociceptive action of cannabidiol on thermal sensitivity and post-operative pain in male and female rats

This study investigated the antinociceptive potential of cannabidiol (CBD) in male and female Wistar rats. The assessment and analysis included tail withdrawal to thermal stimulation (tail flick test) and mechanical allodynia induced by plantar incision injury (von Frey test). CBD reduced acute thermal sensitivity in uninjured animals and post-operative mechanical allodynia in males and females. In the tail flick test, CBD 30 mg/kg i.p. was required to induce antinociception in males. During the proestrus phase, females did not show a statistically significant antinociceptive response to CBD treatment despite a noticeable trend. In contrast, in a separate group of rats tested during the late diestrus phase, antinociception varied with CBD dosage and time. In the post-operative pain model, CBD at 3 mg/kg decreased mechanical allodynia in males. Similarly, this dose reduced allodynia in females during proestrus. However, in females during late diestrus, the lower dose of CBD (0.3 mg/kg) reduced mechanical allodynia, although the latency to onset of the effect was slower (90 min). The effectiveness of a 10-fold lower dose of CBD during the late diestrus stage in females suggests that ovarian hormones can influence the action of CBD. While CBD has potential for alleviating pain in humans, personalized dosing regimens may need to be developed to treat pain in women.

Role of vitamin C in multimodal analgesia for sleeve gastrectomy: a prospective randomized controlled trail

Background &amp; Objective: The laparoscopic sleeve gastrectomy is a popular intervention in morbidly obese patient. Postoperative pain relief is a major challenging issue in this procedure with known adverse effects on the respiratory excursion and the ability to cough by the patient. Various analgesic protocols have been tries to conquer this pain. Vitamin C is a micronutrient, water soluble vitamin with antioxidant and antinociceptive actions. We assessed the effect of vitamin C when used as a component of the multimodal analgesic technique in this cohort of the patients.&#x0D; Methodology: After obtaining the ethical committee approval and trial registration, 50 patients scheduled for laparoscopic sleeve gastrectomy were enrolled in this study. The patients were randomly divided into two equal groups according to the study protocol. Group C received vitamin C 500 mg every 8 h for 5 days perioperatively, while Group N received placebo in the same fashion. The surgery was performed under routine general anesthesia. We monitored hemodynamic, VAS, rescue analgesia profile, and gastrointestinal side effects in the immediately after operation, and then at 1, 2, 4, 8, 12, and at 24 h postoperatively. The postoperative morphine consumption was noted as a primary objective of the study. Independent sample T test, Mann-Whitney test, chi square test or Kruskal Wallis test were utilized to detect statistical differences between the studied groups. P &lt; 0.05 was considered significant.&#x0D; Results: Postoperative morphine consumption was lower in Group C than in Group N (16.36 ± 2.37 vs. 20 ± 4.13 mg, P = 0.001). The frequency of morphine was significantly lower in Group C than in Group N (P = 0.009). VAS was lower in Group C than Group N at 4, 8, and 12 h postoperatively (P = 0.02, 0.001, 0.001), while other parameters where comparable.&#x0D; Abbreviation: CBC: complete blood count; IRB: Institutional Research Board; LFTs: liver function tests; LSG: laparoscopic sleeve gastrectomy; MABP: mean arterial blood pressure; NMDA: N-methyl D-aspartate; OSAS: obstructive sleep apnea syndrome; PACTR: Pan African Clinical Trial Registry; PEEP: positive end expiratory pressure.; PFT: pulmonary function tests; RFTs: renal function tests; TFTs: thyroid function test; TOF: train of four; VAS: visual analogue score.&#x0D; Preregistration: Institutional Research Board, Mansoura Faculty of Medicine (IRB # R.20.02.738, Feb 15-2020). Pan African clinical trial registry (PACTR- 202003565796463, date of registration: March 02-2020).&#x0D; Conclusion: Vitamin C via its antioxidant, antinociceptive properties and NMDA-receptor antagonist action can be used as a part of multimodal analgesic techniques. Vitamin C acts as co-analgesic, improves postoperative pain profile, and reduces the needs for other analgesic modalities.&#x0D; Key words: Vitamin C; Analgesia; VAS; Pain; Sleeve Gastrectomy&#x0D; Citation: Aboelelea M, Abedelkhalek M, Mamoun M. Role of vitamin C in multimodal analgesia for sleeve gastrectomy: a prospective randomized controlled trial. Anaesth. pain intensive care 2023;27(1):82−88.&#x0D; DOI: 10.35975/apic.v27i1.2110&#x0D; Received: October 02, 2022; Reviewed: October 25, 2022; Accepted: December 09, 2022