Analgesic Potency Research Articles

Nitric Oxide Donor Sodium Nitroprusside Reduces Racemic Ketamine-But Not Esketamine-Induced Pain Relief.

The anesthetic, analgesic and antidepressant drug ketamine produces dissociation with symptoms of psychosis and anxiety, an effect attributed to neuronal nitric oxide depletion following N-methyl-d-aspartate blockade. There is evidence that dissociation induced by racemic ketamine, containing both ketamine enantiomers (S- and R-ketamine) but not esketamine (the S-isomer) is inhibited by nitric oxide (NO) donor sodium nitroprusside (SNP). We tested whether a similar intervention would reduce racemic and esketamine-induced analgesia in a randomized double-blind placebo-controlled trial. Seventeen healthy volunteers were treated with 0.5 μg.kg-1.min-1 SNP or placebo during a 3-h infusion of escalating doses of racemic ketamine (total dose 140 mg) or esketamine (70 mg). Pain pressure threshold (PPT) and arterial blood samples for measurement of S- and R-ketamine and their metabolites, S- and R-norketamine, were obtained. The data were analyzed with a population pharmacokinetic-pharmacodynamic model that incorporated the measured S- and R- ketamine and S- and R-norketamine isomers as input and PPT as output to the model. The potency of the 2 formulations in increasing PPT from baseline by 100% was 0.47 ± 0.12 (median ± standard error of the estimate) nmol/mL for esketamine and 0.62 ± 0.19 nmol/mL for racemic ketamine, reflecting the 52 ± 27% lower analgesic potency of R-ketamine versus S-ketamine. Modeling showed that SNP had no effect on S-ketamine potency but abolished the R-ketamine analgesic effect. Similar observations were made for S- and R-norketamine. Since SNP had no effect on S-ketamine analgesia, we conclude that SNP interacts on R-ketamine nociceptive pathways, possibly similar to its effects on R-ketamine activated dissociation pathways.

Evaluation of the anti-inflammatory, antinociceptive, and antipyretic potential of ethanolic extract of Aristida depressa Retz through in vitro, in vivo, and in silico models.

Uncontrolled inflammation is a crucial factor in the development of many diseases. Anti-inflammatory molecules based on natural sources are being actively studied, among which Aristida depressa Retz (Ar.dp) has been traditionally used as a paste to heal inflammation. The present study aimed to evaluate the anti-inflammatory, analgesic, and antipyretic potential of an ethanolic extract of A. depressa through a battery of in vivo and in vitro models. The ethanolic extract of A. depressa was prepared by maceration and chemically characterized using high-performance liquid chromatography, which revealed the presence of quercetin, vanillic acid, chlorogenic acid, p-coumaric acid, m-coumaric acid, ferulic acid, cinnamic acid, and sinapic acid; its antioxidant capacity was then screened with the DPPH in vitro assay, which indicated moderate scavenging capacity. A protein denaturation assay was next performed to evaluate the in vitro anti-inflammatory potential of Ar.dp, which showed significant inhibition (44.44%) compared to the standard drug (diclofenac sodium), with 89.19% inhibition at a concentration of 1mg/mL. The in vivo safety profile of Ar.dp was evaluated in accordance with the OECD-425 acute toxicity guidelines and found to be safe up to 5g/kg. The in vivo anti-inflammatory potentials of Ar.dp were evaluated at three different doses (125, 250, and 500mg/kg) in acute (carrageenan-induced edema: 84.60%, histamine-induced paw edema: 84%), sub-chronic (cotton-pellet-induced granuloma: 57.54%), and chronic (complete-Freund's-adjuvant-induced arthritis: 82.2%) models. Our results showed that Ar.dp had significant (p < 0.05) anti-inflammatory effects over diclofenac sodium in the acute and chronic models. Histopathology studies indicated reduced infiltration of paw tissues with inflammatory cells in Ar.dp-treated animals. Similarly, Ar.dp showed significant (p < 0.05) analgesic (yeast-induced-pyrexia model: 23.53%) and antipyretic (acetic-acid-induced writhing model: 51%) effects in a time-dependent manner. In silico studies on the interactions of COX-1 and COX-2 with the eight ligands mentioned earlier confirmed the inhibition of enzymes responsible for inflammation and fever. Based on the findings of the present study, it is concluded that Ar.dp has anti-inflammatory, analgesic, and antipyretic properties that are likely linked to its pharmacologically active phenolic bioactive molecules.

Limitations of Patient-Controlled Epidural Analgesia Following Abdominoplasty.

Effective postoperative pain management is essential for patient satisfaction and an uneventful postoperative course, particularly in body contouring procedures. Systemic analgesic regimens can be supported by regional procedures, such as the transverse abdominis plane (TAP) block, but these have a limited duration of action. In contrast, thoracic epidural analgesia offers the possibility of a longer-lasting, individualized regional anesthesia administered by a patient-controlled analgesia pump. The aim of this study was to investigate the effects of a patient-controlled epidural analgesia to better classify the clinical value of this procedure in abdominoplasties. This work reviewed the digital medical charts of patients who underwent selective abdominoplasty without combined surgical procedures between September 2018 and August 2022. Evaluated data comprise the postoperative analgesia regimen, including on-demand medication, mobilization time, inpatient length of stay, and clinical outcome. The patients were grouped by the presence of a thoracic epidural catheter. This catheter was placed before anesthetic induction and a saturation dose was preoperatively applied. Postoperative PCEA patients received a basal rate and could independently administer boluses. Basal rate was individually adjusted during daily additional pain visits. The study cohort included 112 patients. Significant differences in the demand for supportive nonepidural opiate medication were shown between the patient-controlled epidural analgesia (PCEA) group (n = 57) and the non-PCEA group (n = 55), depending on the time after surgery. PCEA patients demanded less medication during the early postoperative days (POD 0: PCEA 0.13 (±0.99) mg vs non-PCEA 2.59 (±4.55) mg, P = 0.001; POD 1: PCEA 0.79 mg (±3.06) vs non-PCEA 2.73 (±3.98) mg, P = 0.005), but they required more during the later postoperative phase (POD 3: PCEA 2.76 (±5.60) mg vs non-PCEA 0.61 (±2.01) mg, P = 0.008; POD 4: PCEA 1.64 (±3.82) mg vs non-PCEA 0.07 (±2.01) mg, P = 0.003). In addition, PCEA patients achieved full mobilization later (PCEA 2.67 (±0.82) days vs non-PCEA 1.78 (±1.09) days, P = 0.001) and were discharged later (PCEA 4.84 (±1.23) days vs non-PCEA 4.31 (±1.37) days, P = 0.005). Because the postoperative benefits of PCEA are limited to potent analgesia immediately after abdominoplasty, less cumbersome, time-limited regional anesthesia procedures (such as TAP block) appear not only adequate but also more effective.

Synthesis, characterization, and molecular docking studies of novel hippuric acid anhydrides as potential antiurolithic, analgesic and free radical scavenging agents

Hippuric acid is a biotransformation product in humans which is excreted through urine. Dietary intake of phenolic compounds increases its concentration in urine. Hippuric acid is experimentally proved to be a regulator of calcium oxalate super saturation in human urine and has a solvent effect on oxalate salts. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used analgesics employed in associated renal colic of urolithiasis. The objective of the present study was to chemically link hippuric acid through anhydride linkage to various NSAIDs to synthesize potential mutual prodrugs for urolithiasis and associated renal colic. Hippuric acid was linked to eleven NSAIDs through anhydride linkage by first synthesizing hippuryl chloride using oxalyl chloride as chlorinating agent, followed by its reaction with sodium salts of NSAIDs. Structures of obtained compounds were elucidated using UV spectrophotometry, FTIR spectrometry, 1H NMR and C-13 NMR spectrometry. Synthesized compounds were evaluated for in vitro antioxidant, in vivo acute toxicity, in vivo antiurolithic, in vivo analgesic and in vitro hydrolysis studies. Molecular docking analysis on TNF-α and COX-2 was carried out to determine target protein binding. Synthesized compounds showed stability at acidic pH which indicate potential gastro protective effect of synthesized conjugates. Compounds P9 an P6 showed maximum in vivo antiurolithic activity while P9 and P8 showed maximum in vitro antioxidant activity. All the conjugates except P2 showed significant analgesic activity which show that conjugation of hippuric acid to NSAIDs did not result in loss of analgesic potential. Docking studies showed better affinity with TNF-α as compared to COX-2.

The State of Synthetic Cannabinoid Medications for the Treatment of Pain.

Synthetic cannabinoids are compounds made in the laboratory to structurally and functionally mimic phytocannabinoids from the Cannabis sativa L. plant, including delta-9-tetrahydrocannabinol (THC). Synthetic cannabinoids (SCs) can signal via the classical endogenous cannabinoid system (ECS) and the greater endocannabidiome network, highlighting their signalling complexity and far-reaching effects. Dronabinol and nabilone, which mimic THC signalling, have been approved by the Food and Drug Administration (FDA) for treating nausea associated with cancer chemotherapy and/or acquired immunodeficiency syndrome (AIDS). However, there is ongoing interest in these two drugs as potential analgesics for a variety of otherclinical conditions, including neuropathic pain, spasticity-related pain, andnociplastic pain syndromes including fibromyalgia, osteoarthritis, and postoperative pain, among others. In this review, we highlight the signalling mechanisms of FDA-approved synthetic cannabinoids, discuss key clinical trials that investigate their analgesic potential, and illustrate challenges faced when bringing synthetic cannabinoids to the clinic.

Discovery of a mu-opioid receptor modulator that in combination with morphinan antagonists induces analgesia.

Morphinan antagonists, which block opioid effects at mu-opioid receptors, have been studied for their analgesic potential. Previous studies have suggested that these antagonists elicit analgesia with fewer adverse effects in the presence of the mutant mu-opioid receptor (MOR; S196A). However, introducing a mutant receptor for medical applications represents significant challenges. We hypothesize that binding a chemical compound to the MOR may elicit a comparable effect to the S196A mutation. Through high-throughput screening and structure-activity relationship studies, we identified a modulator, 4-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid (BPRMU191), which confers agonistic properties to small-molecule morphinan antagonists, which induce G protein-dependent MOR activation. Co-application of BPRMU191 and morphinan antagonists resulted in MOR-dependent analgesia with diminished side effects, including gastrointestinal dysfunction, antinociceptive tolerance, and physical and psychological dependence. Combining BPRMU191 and morphinan antagonists could serve as a potential therapeutic strategy for severe pain with reduced adverse effects and provide an avenue for studying G protein-coupled receptor modulation.

Protocol for a pragmatic trial of Cannabidiol (CBD) to improve chronic pain symptoms among United States Veterans

BackgroundChronic pain affects over 100 million Americans, with a disproportionately high number being Veterans. Chronic pain is often difficult to treat and responds variably to medications, with many providing minimal relief or having adverse side effects that preclude use. Cannabidiol (CBD) has emerged as a potential treatment for chronic pain, yet research in this area remains limited, with few studies examining CBD’s analgesic potential. Because Veterans have a high need for improved pain care, we designed a clinical trial to investigate CBD’s effectiveness in managing chronic pain symptoms among Veterans. We aim to determine whether CBD oral solution compared to placebo study medication is associated with greater improvement in the Patient Global Impression of Change (PGIC).MethodsWe designed a randomized, double-blind, placebo-controlled, pragmatic clinical trial with 468 participants. Participants will be randomly assigned in a 1:1 ratio to receive either placebo or a CBD oral solution over a 4-week period. The trial is remote via a smartphone app and by shipping study materials, including study medication, to participants. We will compare the difference in PGIC between the CBD and placebo group after four weeks and impacts on secondary outcomes (e.g., pain severity, pain interference, anxiety, suicide ideation, and sleep disturbance).DiscussionOnce complete, this trial will be among the largest to date investigating the efficacy of CBD for chronic pain. Findings from this clinical trial will contribute to a greater knowledge of CBD’s analgesic potential and guide further research. Given the relative availability of CBD, our findings will help elucidate the potential of an accessible option for helping to manage chronic pain among Veterans.Trial registrationThis protocol is registered at clinicaltrials.gov under study number NCT06213233.

Comparative study of the effects of ibuprofen, acetaminophen, and codeine in a model of orofacial postoperative pain in male and female rats.

Pain management is a primary goal after oral surgeries, but little is known about sex differences in the sensitivity to analgesics. This study aimed to compare the efficacy of three drugs with analgesic potential on heat and mechanical hyperalgesia, spontaneous pain and locomotion on male and female rats subjected to a model of orofacial postoperative pain. Male and female Wistar rats were submitted to intraoral incision or sham surgery, and on postoperative day 3, the effect of the ibuprofen (30 and 100mg/kg), acetaminophen (100 and 300mg/kg) and codeine (3 and 10mg/kg) was assessed on responses to heat and mechanical facial stimulation, facial grooming, and locomotion. Ibuprofen reduced heat and mechanical hyperalgesia and grooming behavior in male and female rats in a non-sedative dose; acetaminophen dose-dependently reduced the mechanical hyperalgesia and abolished the heat hyperalgesia and the grooming behavior but caused sedation in both sexes; codeine dose-dependently reduced the mechanical hyperalgesia in male and female rats, and reduced the heat hyperalgesia, but females were less sensitive than males. It reduced spontaneous facial grooming in both sexes, but induced hyperlocomotion in females. Ibuprofen presented the most favorable profile, since it reduced over 50% heat and mechanical hyperalgesia in male and female rats, and significantly reduced spontaneous pain, without causing sedation or affecting locomotion. The identification of sex differences in the sensitivity and safety profile of frequently used analgesics can help guide the choice of more effective individualized therapies for pain control.

The effects of morphine administration on the central nervous system (CNS): advantages and disadvantages

Morphine, a potent opioid analgesic, plays a critical role in pain management but elicits complex effects on the central nervous system (CNS), demonstrating both beneficial and detrimental outcomes. This paper reviews preclinical studies to examine morphine's interactions with the CNS, notably via binding to opioid receptors, leading to analgesia as well as a series of adverse effects, including addiction, tolerance, and neurological impairments. Acute exposure to morphine alters neurotransmitter activity, gene expression, and neuronal firing rates. In contrast, chronic use results in significant neuronal damage, altered memory functions, increased pain sensitivity, and neuroinflammation, highlighting the drug's impact on neurogenesis and neural cell viability. Additionally, morphine's protective properties against neurotoxic insults are discussed, alongside its potential to disrupt cellular and molecular pathways, culminating in neurotoxicity and cognitive deficits. Given the dual nature of morphine's impact on the CNS - protective vs. harmful, depending on specific conditions such as dosage, disease type, and administration frequency - this paper underscores the necessity for further research to untangle this complex interplay to leverage morphine's pain management benefits while minimizing its risks. A thorough evaluation of morphine administration practices can help reconcile these conflicting results.

Perioperative Craniotomy Excision of Dextra Subtemporal Tumor with Thiopental, Sufentanyl and Invasive Monitor

Intracranial masses can arise from a variety of aetiologies, including congenital, neoplastic, infectious, or vascular processes, each requiring distinct diagnostic and management considerations. Establishing the presence or absence of intracranial hypertension is a critical component of the preoperative evaluation for patients undergoing craniotomy for mass lesions. Hemodynamic is an examination of the physical aspects of blood circulation, cardiac function and physiological characteristics of peripheral vasculature. A 74 year old man was admitted to the hospital because of cephalgia, and left limb weakness. Previously, the patient often felt headaches that came and went since six months ago. Three days before being admitted, the patient felt weak in his left limb and experienced decreasing in consciousness. The patient was given thiopental because the onset of action of thiopental was very short. Administration of intravenous doses of thiopental can cause cerebral vasoconstriction. Sufentanil was administered as an analgesic, because sufentanil is an opioid that has a rapid onset and analgesic potential, compared to fentanyl, intravenous and sufentanil is 5–10 times stronger. This efficacy to maintain adequate cerebral perfusion pressure (CPP), reduce cerebral blood flow (CBF), maintain normal autoregulation, reduce cerebral metabolic rate for oxygen (CMRO2). Arterial cannulation with continuous transduction is considered the gold standard for blood pressure monitoring during anaesthetic procedures. Rapid fluctuations in blood pressure can occur due to patient positioning, surgical manipulation, and the effects of anaesthetics drugs, and close monitoring of these changes is crucial for maintaining hemodynamic stability. The impact of anaesthetic management on CBF is also an integral component of neuroanesthesia, as increases in CBF are associated with increases in cerebral blood volume (CBV). An effective neuro-anesthesia management program that incorporates both invasive blood pressure monitoring and optimization of cerebral perfusion that can help preserving hemodynamic stability and improving outcomes for patients undergoing craniotomy surgery

Scrutiny of Mitragynine and derivatives with analgesic potential using Mep and ligand-MOR interaction

Mitragynine and derivatives with analgesic activity were scrutinized to unravel key structural features necessary for biological activities and interactions with the m-opioid receptor (MOR). Molecular electrostatic potential (MEP) scrutiny showed the anionic and phenolic sites, as well as the hydrophobic region of opioids, important for analgesic activity, susceptible to electrophilic attack by a biological target and that the presence of bulky substituents at C9 and C7 can hinder analgesia, through steric hindrance, and increase the positive MEP region in the phenolic site. Scrutiny of the interaction with the MOR showed the most active opioids, in general, having the tertiary N atom of the anionic site closest to the C atom from the COOH of the Asp147 residue of the MOR. Furthermore, opioids present hydrogen bond interactions between the H atom from the OCH3 of the phenolic site with the phenolic O atom from the OH of the Tyr148 residue of the MOR and of the H atom from the OH of this residue with the O atom from the OCH3 of the hydrophobic region. The accumulated insights led to the design of new derivatives and the identification of two (2) of them as promising derivatives for synthesis and biological assays.

Lippia alba essential oil: A powerful and valuable antinociceptive and anti-inflammatory medicinal plant from Brazil

Ethnopharmacological relevanceIn Brazilian popular medicine, Lippia alba leaves are used in teas to treat pain and inflammatory diseases. Aim of the studyto evaluate the chemical composition, antinociceptive, and anti-inflammatory activities of Lippia alba essential oil and its major compound geraniol. Material and methodsLippia alba leaves were collected in Pará state, Brazil. The leaf essential oil was obtained using a modified Clevenger-type extractor. Then, the oil was analyzed by GC and GC-MS analyses. To evaluate the toxicity of LaEO and geraniol, the doses of 50, 300, and 2000 mg/kg were used in a mouse model. For antinociception tests, abdominal contortion, hot plate, and formalin tests were used; all groups were treated with LaEO and geraniol at doses of 25, 50, and 100 mg/kg; and to evaluate inflammation using the ear edema model. ResultsThe constituents identified in the highest content were oxygenated monoterpenes: geraniol (37.5%), geranial (6.7%) and neral (3.8%). The animals treated with LaEO and geraniol demonstrated atypical behaviors with aspects of lethargy and drowsiness, characteristics of animals in a state of sedation; the relative weights showed no significant difference compared to the controls. In the abdominal contortion test, LaEO at 25 mg/kg, 50 mg/kg doses, and 100 mg/kg reduced the number of contortions, representing a percentage reduction of 84.64%, 81.23%, and 66.21% respectively. In the hot plate test, LaEO and geraniol increased the latency time at doses of 25, 50, and 100 mg/kg in all test periods; there was no statistical difference between LaEO and geraniol. In the first phase of the formalin test, only doses of 25 mg/kg and 100 mg/kg of LaEO showed significant activity, reducing the latency time by 53.40% and 58.90%. LaEO at doses of 25 mg/kg and 100 mg/kg reduced the size of the edema, demonstrating an anti-inflammatory activity of 59.38% (25 mg/kg) and 50% (100 mg/kg). ConclusionLippia alba essential oil and geraniol showed central/peripheral analgesic and anti-inflammatory potential and can be used as an alternative or complementary treatment to conventional drugs. More studies are needed to evaluate its action mechanisms and its analgesic effects.

Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2B6 Genotype and Methadone Therapy.

Methadone is a mu (μ) opioid receptor agonist used clinically in adults and children to manage opioid use disorder, neonatal abstinence syndrome, and acute and chronic pain. It is typically marketed as a racemic mixture of R- and S-enantiomers. R-methadone has 30-to 50-fold higher analgesic potency than S-methadone, and S-methadone has a greater adverse effect (prolongation) on the cardiac QTc interval. Methadone undergoes stereoselective metabolism. CYP2B6 is the primary enzyme responsible for catalyzing the metabolism of both enantiomers to the inactive metabolites, S- and R-2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (S- and R-EDDP). Genetic variation in the CYP2B6 gene has been investigated in the context of implications for methadone pharmacokinetics, dose, and clinical outcomes. Most CYP2B6 variants result in diminished or loss of CYP2B6 enzyme activity, which can lead to higher plasma methadone concentrations (affecting S- more than R-methadone). However, the data do not consistently indicate that CYP2B6-based metabolic variability has a clinically significant effect on methadone dose, efficacy, or QTc prolongation. Expert analysis of the published literature does not support a change from standard methadone prescribing based on CYP2B6 genotype (updates at www.cpicpgx.org).

MP-13, a novel chimeric peptide of morphiceptin and pepcan-9, produces potent antinociception with limited side effects

Pharmacological investigations have substantiated the potential of bifunctional opioid/cannabinoid agonists in delivering potent analgesia while minimizing adverse reactions. Peptide modulators of cannabinoid receptors, known as pepcans, have been investigated before. In this study, we designed a series of chimeric peptides based on pepcans and morphiceptin (YPFP-NH2). Here, we combined injections of pepcans and morphiceptin to investigate the combination treatment of opioids and cannabis and compared the analgesic effect with chimeric compounds. Subsequently, we employed computational docking to screen the compounds against opioid and cannabinoid receptors, along with an acute pain model, to identify the most promising peptide. Among these peptides, MP-13, a morphiceptin and pepcan-9 (PVNFKLLSH) construct, exhibited superior supraspinal analgesic efficacy in the tail-flick test, with an ED50 value at 1.43 nmol/mouse, outperforming its parent peptides and other chimeric analogs. Additionally, MP-13 displayed potent analgesic activity mediated by mu-opioid receptor (MOR), delta-opioid receptor (DOR), and cannabinoid type 1 (CB1) receptor pathways. Furthermore, MP-13 did not induce psychological dependence and gastrointestinal motility inhibition at the effective analgesic doses, and it maintained non-tolerance-forming antinociception throughout a 7-day treatment regimen, with an unaltered count of microglial cells in the periaqueductal gray region, supporting this observation. Moreover, intracerebroventricular administration of MP-13 demonstrated dose-dependent antinociception in murine models of neuropathic, inflammatory, and visceral pain. Our findings provide promising insights for the development of opioid/cannabinoid peptide agonists, addressing a crucial gap in the field and holding significant potential for future research and development. PerspectiveThis article offers insights into the combination treatment of pepcans with morphiceptin. Among the chimeric peptides, MP-13 exhibited potent analgesic effects in a series of preclinical pain models with a favorable side-effect profile.

A Comprehensive Study Involving Comparison of Analgesics for Effective Pain Management in Pancreatitis

Pancreatitis is an inflammatory condition of the pancreas, which serves as both an exocrine organ for food digestion and an endocrine organ for regulating blood sugar levels. The disease is typically accompanied by moderate to severe pain, necessitating the use of analgesics for effective pain management. This research aims to evaluate and compare the efficacy of various analgesics in alleviating pain associated with pancreatitis. Ultimately, the study aims to gain a comprehensive understanding of the outcomes resulting from different pain management strategies in individuals with pancreatitis. A comparative research study was conducted at Basaveshwara General Hospital in Kalaburagi, Karnataka, over a period of six months, involving 100 patients selected from both general and university hospital settings. The findings revealed that out of 100 patients, 76% were males, and 24% were females affected by pancreatitis. Throughout the study, a total of 164 analgesics were administered, with the highest frequency of potent analgesics prescribed within the age group of 5-46 years. Notably, Nalbuphine emerged as the most commonly prescribed analgesic via the parenteral route, constituting 39% of the total prescriptions. For cases with mild to moderate pain, Paracetamol was the preferred analgesic, accounting for 35.3% of the prescriptions. This research investigates the variations in analgesic prescriptions for pancreatitis pain management, tailoring prescriptions to the severity of pain, with non-opioid analgesics recommended for mild to moderate pain levels

Honokiol alleviates monosodium urate-induced gouty pain by inhibiting voltage-gated proton channels in mice.

To investigate whether honokiol (HNK) acted as an analgesic in connection with inhibiting the voltage-gated proton channel (Hv1). The model of gouty arthritis was induced by injecting monosodium urate (MSU) crystals into the hind ankle joint of mice. HNK was given by intragastric administration. Ankle swelling degree and mechanical allodynia were evaluated using ankle joint circumference measurement and von Frey filaments, respectively. Hv1 current, tail current, and action potential in dorsal root ganglion (DRG) neurons were recorded with patch-clamp techniques. HNK (10, 20, 40mg/kg) alleviated inflammatory response and mechanical allodynia in a dose-dependent manner. In normal DRG neurons, 50µM Zn2+ or 2-GBI significantly inhibited the Hv1 current and the current density of Hv1 increased with increasing pH gradient. The amplitude of Hv1 current significantly increased on the 3rd after MSU treatment, and HNK dose-dependently reversed the upregulation of Hv1 current. Compared with MSU group, 40mg/kg HNK shifted the activation curve to the direction of more positive voltage and increased reversal potential to the normal level. In addition, 40mg/kg HNK reversed the down-regulation of tail current deactivation time constant (τtail) but did not alter the neuronal excitability of DRG neurons in gouty mice. HNK may be a potential analgesic by inhibiting Hv1 current.

Phytochemical and pharmacological profiling of extracts of Pterygota alata (Roxb.) R. Br. leaves deciphered therapeutic potentialities against pain, hyperglycemia and diarrhea via in vivo approaches

Background and aimPterygota alata (Roxb.) R. Br. is a large, broad-leaved evergreen plant in the family Malvaceae (formerly Sterculiaceae). The present study aimed to investigate the phytochemical and pharmacological properties of methanolic extract of the leaves (200 mg/kg bw and 400 mg/kg bw) of P. alata focusing on analgesic, hypoglycemic, and anti-diarrheal potentials on the Swiss Albino mice model. MethodsGas chromatography and mass spectrometry (GC-MS) technique was employed to identify the bioactive compounds from the plant species. The tail flicking procedure and acetic acid-induced writhing inhibition were carried out to estimate central and peripheral analgesic properties. The anti-diarrheal property of the herbaceous extractive was assessed employing the castor oil-induced antidiarrheal approach, while the hypoglycemia was estimated employing the tail-tipping method. ResultsThe study reported a total of thirty-seven phytoconstituents by using GC-MS analysis, where erucamide (25.5 %), 8,11,14-Docosatrienoic acid, methyl ester (14.58 %), methyl linoleate (12.67 %), and methyl palmitate (9.23 %) were most abundant in the plant species. In evaluating central analgesia, the leaf extract of P. alata exerted significant central analgesic (200 mg/kg bw and 400 mg/kg bw) efficacy. The acetic acid-induced writhing was inhibited by 45.84 % and 66.67 % at both doses, demonstrating a promising peripheral analgesic effect compared to diclofenac sodium (75.00 %). On the contrary, hypoglycemic actions remained dosage and time-dependent. In the antidiarrheal activity assay, the number of diarrheal feces was reduced significantly by 40.00 % (200 mg/kg) and 68.00 % (400 mg/kg), correspondingly, which was comparable to the positive control loperamide (72.00 %). In addition, the study of acute oral toxicity revealed that the extracts of the plant species were found to be safe, with a median lethal dose (LD50) value greater than 1000 mg/kg. ConclusionThe current study supports the assertion that the P. alata plant species is rich in numerous phytoconstituents and has the potential for traditional application in managing pain, hyperglycemia, and diarrhea. Nonetheless, additional investigation is necessary to extract and identify the bioactive compounds from the plant, which is crucial for advancing the discovery of novel medicinal compounds aimed at addressing a range of health conditions.

Analgesic and Anti-inflammatory Potential of the New Tetrahydropyran Derivative (2s,6s)-6-ethyl-tetrahydro-2h-pyran-2-yl) Methanol.

The development of analgesic and anti-inflammatory drugs plays a crucial role in modern medicine, aiming to alleviate pain and reduce inflammation in patients. Opioids and nonsteroidal anti-inflammatory drugs are groups of drugs conventionally used to treat pain and inflammation, but a wide range of adverse effects and ineffectiveness in some pathological conditions leads us to search for new drugs with analgesic and anti-inflammatory properties. In this regard, the authors intend to investigate the ((2s,6s)-6-ethyl-tetrahydro-2h-pyran- 2-yl) methanol compound (LS20) on pain and acute inflammation. Male Swiss mice were evaluated using acetic acid-induced abdominal writhing, formalin, and tail-flick as models of nociceptive evaluation and edema paw, air pouch and cell culture as models of inflammatory evaluation besides the rotarod test for assessment of motor impairment. The compound showed an effect on the acetic acid-induced abdominal writhing, formalin and tail-flick tests. Studying the mechanism of action, reversion of the antinociceptive effect of the compound was observed from previous intraperitoneal administration of selective and non-selective opioid antagonists on the tail flick test. In addition, the compound induced an antiedematogenic effect and reduced leukocyte migration and the production of pro-inflammatory cytokines in the air pouch model. LS20 was able to maintain cell viability, in addition to reducing cell production of TNF-α and IL-6. In summary, the LS20 compound presented an antinociceptive effect, demonstrating the participation of the opioid system and an anti-inflammatory effect related to the inhibition of pro-inflammatory cytokine production. The compound also demonstrated safety at the cellular level.

Efficacy of Oral Magnesium on Bone Regeneration and Implant Stability in Immediate Dental Implants: A Randomized Controlled Trial.

The successful osseointegration around immediate implants requires high quality and quantity of osteogenesis around them. The role of magnesium as a boneenhancing mineral, and as an adjunctive analgesic has been well documented in orthopedic literature. However, there is a paucity of literature in its role in successful osseointegration around immediate implants. This randomized controlled trial sought to assess the promising impact of magnesium on osseointegration by examining various aspects of implant stability, correlating them with serum bone markers, and establishing a foundation for future research on its potential as a potent analgesic. Immediate implant placement was done after the extraction of the indicated mandibular molar tooth, and all the patients were segregated into 2 groups (Placebo- Lactose, and Magnesium citrate). Bone regenerate in the peri-implant area was assessed radiographically immediate post-operatively, on the 6th week and 12 weeks. Implant stability was measured immediate post-operatively, at the 4th week and 12th week. Serum parameters were procured pre-operatively and post-operatively for serum calcium, serum alkaline phosphatase (ALP), and serum parathyroid hormone at the 8th week, and serum vitamin D3 levels preoperatively. 54 immediate implants placed showed the demographics and baseline serum, clinical, and radiographic parameters were comparable in both groups. Analysis of Implant Stability Quotient at 12th week showed statistically significant difference in intervention group both on intergroup and intragroup analysis. Radiodensity measurement showed a statistically significant difference in both intragroup and intergroup analysis in the intervention group at the 6th and 12th week. In bone gap analysis, the difference in mean change in the horizontal bone gap (HG) at 6 weeks was non-significant while the difference in HG at the 12th week was significant in the intervention group. On intragroup analysis, mean change HG at 6 weeks and 12 weeks both were significant only in intervention group. Intergroup analysis of vertical bone gap (VG) 12 and VG 12-0 (mean difference in the vertical bone gap from 12th week-day 0) showed a statistically significant difference in the intervention group. On intragroup analysis, VG 12 was significantly better in the intervention group. On serum analysis, ALP post-operatively was found to be significantly raised (P=0.013) in intervention group. Numerical rating Scale (NRS) analysis showed a significant decrease in post-op day 5 and 7, (P=0.017) and (P=0.002) respectively. The oral magnesium citrate supplementation after immediate implant placement helps in enhancing the stability of the immediate implants, along with improved radiodensity around them which was found to be statistically significant. It also helps in reducing the horizontal, and vertical gap around the implant and has significant analgesic potential.

Evaluation of anti- inflammatory and analgesic activity of Bhasmas in experimental animal models

Acute toxicity studies of both the bhasmas showed no mortality at 2000 mg/kg.The Scanning electron microscopy of both Tamra and Lauha bhasma indicated the nanomaterial characteristics which justifies claim of Ayurvedic bhasmas as ancient nanomaterials. Tamra and Lauha bhasma were found to be effective as anti-inflammatory agent in acute models of inflammation. It inhibits all phases of inflammation induced by carrageenan. Tamra and Lauha bhasma were found to be effective as anti-inflammatory agent in chronic model of inflammation. It significantly inhibits wet as well as dry weight of cotton pellet granuloma at highest doses only. Analgesic activity of both Tamra and Lauha bhasma in hot plate and tail immersion models were found to be significant at 120-240 mins. Analgesic activity of both Tamra and Lauha bhasma in acetic acid models were found to be non-significant in nature, while found to be significant at late phase in formalin induced model. Tamra and Lauha bhasma also were found to have significant anti-arthritic activity in animal study.The whole pharmacological investigations were indicated that activity was only significant at therapeutic and more than therapeutic dose but nonsignificant at dose lower than therapeutic doses. The obtained results indicates the anti-inflammatory and analgesic potential of both these bhasmas probably by inhibiting inflammatory mediators.