Significant Antinociceptive Effect Research Articles

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

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

BNT12, a novel hybrid peptide of opioid and neurotensin pharmacophores, produces potent central antinociception with limited side effects

The development of multitarget opioid drugs has emerged as an attractive approach for innovative pain management with reduced side effects. In the present study, a novel hybrid peptide BNT12 containing the opioid and neurotensin (NT)-like fragments was synthesized and pharmacologically characterized. In acute radiant heat paw withdrawal test, intracerebroventricular (i.c.v.) administration of BNT12 produced potent antinociception in mice. The central antinociceptive activity of BNT12 was mainly mediated by μ-, δ-opioid receptor, neurotensin receptor type 1 (NTSR1) and 2 (NTSR2), supporting a multifunctional agonism of BNT12 in the functional assays. BNT12 also exhibited significant antinociceptive effects in spared nerve injury (SNI)-neuropathic pain, complete Freund's adjuvant (CFA)-induced inflammatory pain, acetic acid-induced visceral and formalin-induced pain after i.c.v. administration. Furthermore, BNT12 exhibited substantial reduction of acute antinociceptive tolerance, shifted the dose-response curve to the right by only 1.3-fold. It is noteworthy that BNT12 showed insignificant chronic antinociceptive tolerance at the supraspinal level. In addition, BNT12 exhibited reduced or no opioid-like side effects on conditioned place preference (CPP) response, naloxone-precipitated withdrawal response, acute hyperlocomotion, motor coordination, gastrointestinal transit, and cardiovascular responses. The present investigation demonstrated that the novel hybrid peptide BNT12 might serve as a promising analgesic candidate with limited opioid-like side effects.

Deciphering the Role of the Nucleus Accumbens Shell Area on Spatial Memory Deficits Induced by Neuropathic Pain in Rats

The nucleus accumbens shell (NAcSh) is a major structure associated with distinct aspects of reward and mnemonic information encoding, relying on spatial data to define optimal behavioral strategies. Chronic pain-derived striatal plasticity is considered one underpinning cause of working memory (WM) impairments. However, it is unclear how the NAcSh is involved in these spatial deficits. To address this, we evaluated the impact of unilateral local NAcSh electrical lesions during the execution of a food-reinforced eight-shaped spatial alternation WM task. Behavioral performance was assessed in rats after the onset of the neuropathic pain model—spared nerve injury (SNI). Our findings indicate that the induction of SNI and/or NAcSh lesions did not significantly impact the animals’ performance accuracy or motor activity during the execution of the behavioral task, but altered their response latency patterns. In addition, these manipulations did not induce significant antinociceptive effects. Collectively, these results suggest that the NAcSh may participate in specific aspects of spatial information integration and processing under neuropathic pain conditions.

Three new antinociceptive diterpenoids from the fruits of Rhododendron molle

Investigation of the fruits of Rhododendron molle G. Don led to the isolation of three new grayanane-type diterpenoids, rhodomolleins LIV-LVI (1-3). The structures and absolute configurations of new compounds were fully elucidated by spectroscopic analysis and single-crystal X-ray diffraction, including HRESIMS, 1 D and 2 D NMR data. Compounds 1-3 were evaluated for analgesic activities utilizing an acetic acid-induced writhing test in mice. Compound 1 showed a significant antinociceptive effect with writhe inhibition rates of 72.9% and 100% at doses of 6 mg/kg and 20 mg/kg in mice, respectively. The binding mode of 1 to N-ethylmaleimide-sensitive factor (NSF, PDB: 6IP2) was explored by molecular docking, indicating the presence of hydrogen bond interactions which account for its analgesic activity.

Phellintremulins A-C, antinociceptive sesquiterpenoids from the medicinal fungus Phellinus tremulae

Phellintremulin A (1), a rearranged sesquiterpenoid with an unprecedented bicyclic backbone, and two previously unreported illudane-type sesquiterpenoids, namely phellintremulin B (2) and phellintremulin C (3), together with two known analogues (±)‒4 and (±)‒5, were isolated from cultures of the medicinal fungus Phellinus tremulae. Their structures and absolute configurations were established by means of spectroscopic data and HRESIMS analyses, as well as ECD and NMR calculations. A plausible biogenesis for 1 was discussed. The electrophysiological experiments showed that phellintremulins (A‒C) can inhibit Nav current in DRG neuron cells at 10 μM, with percentage inhibitions of 23.2%, 49.3%, and 31.7%, respectively. The antinociceptive activities of phellintremulins (A‒C) were evaluated via the acetic acid-induced writhing test in mice at a dose of 3 mg/kg. They showed significant antinociceptive effects with percentages of inhibition of 43.8%, 54.4%, and 50.6%, respectively, and phellintremulin B and C expressed more potent analgesic effect than lidocaine.

Antinociceptive and anti-inflammatory effect of Passiflora edulis leaves extract in acetic acid-induced pain and carrageenan-induced paw oedema in vivo

Background: In Indonesia, people commonly treat pain and inflammation with herbs. Passiflora edulis leaves extract (PLE) is known to contain many chemical compounds that are useful as analgesic and anti-inflammatory treatments. However, there is very limited scientific literature that reports the results of P. edulis in reducing pain and inflammation. Objective: This research aims to evaluate the antinociceptive and anti-inflammatory effects of PLE. Method: PLE was extracted by Ultrasonic-Assisted Extraction (UAE). The PLE at doses of 20, 40 and 80 mg/200g BW (PLE-20, PLE-40, and PLE-80) and diclofenac sodium (Dic. sod. at a dose of 2.7 mg/200g BW as a positive control group was tested for antinociceptive and anti-inflammatory effects in experimental animal models (n=5). The effect of antinociceptive was evaluated by the wriggling in mice by acetic acid-induced, and the effect of acute anti-inflammatory was evaluated by carrageenan-induced in rats. Result: PLE at doses of 20, 40, and 80 mg/200g BW showed a significant antinociceptive effect at acetic acid-induced wriggling and inhibition of the oedema. Higher doses lead to more pronounced effects. The greater effect of antinociceptive was observed at PLE-80 (64.55%), and inhibition of the oedema was observed at PLE-80 (34.33%). Conclusion: PLE significantly reduced pain and acute inflammation in the animal-tested models.

Chemical composition, antioxidant, antimicrobial, and wound healing effects of Trachyspermum roxburghianum (DC.) H. Wolff essential oil: An in vivo and in silico approach

Ethnopharmacological relevanceTrachyspermum roxburghianum (DC.) H. Wolff, commonly known as ‘Ajamoda,’ is a neglected Indian spice highly used in Ayurveda and folklore remedies as an antimicrobial for chronic wounds and discharges, along with many other disease conditions. Aim of the studyThe objective of the study was to explore chemical composition and to investigate the antioxidant, antimicrobial, analgesic, and wound healing activities of T. roxburghianum fruit essential oil from India. Materials and methodsThe phytochemical characterization of the oil was determined through standard qualitative procedures and the gas chromatography-mass spectrometry (GC-MS) technique. The in vitro antioxidant aptitude was assessed by scavenging DPPH and ABTS radicals. The antimicrobial potential of the oil was investigated using the disc diffusion method, followed by the determination of minimum inhibitory concentration against Gram-positive and Gram-negative bacterial and fungal strains. The analgesic potential was evaluated using thermal and chemically induced pain models in Swiss albino mice. Wound healing was assessed in vivo, including determining wound contraction rates, histopathology, and hydroxyproline estimation, using the excision wound model in Swiss albino mice. ResultsGC-MS analysis identified 55 compounds with major terpenoids, including thymol (13.8%), limonene (11.5%), and others. Substantial radical-scavenging activity was exhibited by T. roxburghianum fruit essential oil (TREO) (IC50 94.41 ± 2.00 μg/mL in DPPH assay and 91.28 ± 1.94 μg/mL in ABTS assay). Microorganisms were inhibited with low MIC (2 μL/mL for the inhibition of Staphylococcus aureus and Bacillus subtilis; 4 μL/mL against Salmonella typhi and 16 μL/mL against Candida albicans). In the cytotoxicity study, no cytotoxicity was observed on the Monkey Normal Kidney Cell line (Vero). Significant antinociceptive effects were observed (25.47 ± 1.10 % of inhibition at 100 mg/kg and 44.31 ± 1.69 % at 200 mg/kg). A remarkable rate of wound closure and epithelization, along with a marked increase in hydroxyproline content, were observed for the oil during wound healing in mice. ConclusionsThe results suggested that oil could be utilized as a potential source of wound healing therapeutics.

Therapeutic effects of electroacupuncture at different sites on rats with neuropathic pain via the spinal Nrf2/HO-1 pathway: 大鼠脊髓Nrf2/HO-1通路参与不同部位电针调节神经性疼痛效应的机制探讨

ObjectiveThis study aimed to assess the effects of electroacupuncture (EA) at the contralateral, ipsilateral, or bilateral “Zusanli (ST36)” and “Yanglingquan(GB34)” on neuropathic pain caused by chronic contractile injury (CCI) and to explore the role of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in the effects of EA. MethodsMale Sprague-Dawley rats were subjected to the CCI model to induce neuropathic pain. A total of 45 rats were randomly divided into five groups (n = 9): sham, CCI, EA-Co (CCI + EA at contralateral acupoints), EA-Ip (CCI + EA at ipsilateral acupoints), and EA-Bi (CCI + EA at bilateral acupoints). The rats received EA treatment on day 8 after CCI, once every alternate day, for a total of eight times. The time courses of mechanical pain threshold (MWT), hind paw withdrawal latency (HWL), and sciatic functional index (SFI) were determined. The expression levels of 8-hydroxydeoxyguanosine (8-OHdG), glutathione (GSH), superoxide dismutase (SOD) activity, interleukin-6 (IL-6), interleukin-1 beta (IL-1β), and tumor necrosis factor factor-alpha (TNF-α) in the spinal cord were measured. The distribution of Nrf2, its expression of Nrf2 in both the cytosol and nucleus, and the protein levels of its downstream target genes, NQO1 and HO-1, were detected via double immunofluorescence staining and western blotting, respectively. ResultsFollowing CCI, both MWT and HWL in the CCI group significantly decreased from day 14 after surgery (P < 0.001). EA treatment exhibited significant antinociceptive effects induced by CCI by increasing the MWT and HWL values, especially bilateral EA (P < 0.05). The SFI of the CCI group was significantly lower than that of the sham group (P < 0.001). Only bilateral EA improved the SFI scores compared to the CCI group (P < 0.05). 8-OHdG levels in the spinal cord of the CCI group were significantly higher than those in the sham group (P < 0.05), whereas GSH levels and SOD activity in the spinal cord of the CCI group were significantly lower than those in the sham group (P < 0.001 and P < 0.01, respectively). Bilateral EA administration significantly downregulated 8-OHdG levels (P < 0.01) and upregulated GSH levels and SOD activity in the spinal cord (P < 0.01). CCI significantly enhanced the production of IL-1β, IL-6, and TNF-α in the spinal cord compared with that in the sham group (all P < 0.001). Meanwhile, the effects of EA were also accompanied by markedly decreased expression of IL-1β and IL-6 in the spinal cord (P < 0.05). TNF-α levels were only decreased in the EA-Ip and EA-Bi groups compared with those in the CCI group (P < 0.001). Confocal microscopy revealed that Nrf2 was mainly localized in the neurons of the spinal cord. Notably, EA treatment enhanced nuclear translocation of Nrf2 in neurons. CCI significantly decreased the production of Nrf2, HO-1, and NQO1 in the spinal cord compared to the sham group (P < 0.001), and bilateral EA up-regulated the protein levels of Nrf2 and its target genes HO-1 and NQO1(all P < 0.001). ConclusionOur results suggest that bilateral EA is an optimal therapeutic strategy for neuropathic pain. The effects of EA on neuropathic pain may be mediated by the restoration of the Nrf2 pathway in the spinal cord.

Investigating the Bioactive Potential of Persicaria hydropiper: GC-MS Profiling and In vivo Exploration of Antinociceptive and Antidiarrheal Effects

Aims: This study aimed to investigate the impact of methanol-derived leaf extracts from the Persicaria hydropiper plant on the GCMS analysis and in-vivo antinociceptive and antidiarrheal activities.&#x0D; Study Design: The GCMS analysis was used to analyze the phytochemicals of the methanolic extract of Persicaria hydropiper (MEPH). The research aimed to investigate the possible in-vivo activities, including the antinociceptive and antidiarrheal activity, of the plant's chemical ingredient, which is of pharmaceutical significance. Whether the changes seen in experimental animals have statistical significance.&#x0D; Methodology: Potential antinociceptive and antidiarrheal properties of MEPH were studied after phytochemicals were found by GCMS analysis of the plant. Swiss albino mice assessed antidiarrheal activity using the castor oil-induced method and antinociceptive activities at various dosages using the hotplate and glutamate-induced nociception methods, respectively.&#x0D; Results: The MEPH GCMS analysis revealed that 65 phytochemicals were found which have greater pharmacological activities. In contrast, MEPH inhibited peripheral nociception in the glutamate-induced paw licking nociceptive paradigm with percent inhibitions of 86.53 and 93.59, respectively. In addition, the hot plate test revealed a significant antinociceptive effect. Where the castor oil-induced antidiarrheal method showed 80.16 and 87% of inhibition of diarrhea compared to the standard loperamide's value of 84.19%. Each pharmacological model was experimented using the dose of 200 and 400 mg/kg.Conclusion: Several pathological conditions, including dysentery, Persistent diarrhea, arthritis and other pain, inflammation related diseases, may benefit in the future from the use of plant-derived pharmacological agents due to their antinociceptive and antidiarrheal activities.

Guettarda uruguensis (Rubiaceae): antioxidant and anti-inflammatory plant with quercetin and esters of p-coumaric acid

Guettarda (Rubiaceae) is a genus known for its diverse range of bioactive compounds, with demonstrated anti-inflammatory and antioxidant properties. Guettarda uruguensis Cham. & Schltdl., commonly known as ‘jasmim uruguaio’ or ‘veludinho,’ is a native species of the Atlantic Forest that get interested in its potential therapeutic applications. In this study, we evaluated the phenolic content and antioxidant activity of the crude ethanol extract obtained from G. uruguensis leaves (EBGF) and fractions, as well as the antinociceptive, anti-inflammatory, and toxicity activity of the EBGF. Our findings revealed that the EBGF and its fractions contain polyphenolic compounds, including long-chain esters of p-coumaric acid and quercetin, which contribute to their potent antioxidant activity. The EBGF exhibited significant anti-inflammatory and antinociceptive effects, highlighting its potential as a natural product for treating pain and inflammation. Our study supports G. uruguensis as a promising source of bioactive compounds with pharmacological potential.

In vivo analgesic, anti-inflammatory and molecular docking studies of S-naproxen derivatives

In the current studies two naproxen derivatives (NPD) were evaluated for analgesic and anti-inflammatory properties. The acetic acid and hot plate animal models were used to screen the compounds for analgesic potential. While the anti-inflammatory potential was evaluated through animal paw edema, induced by several inflammatory mediators (carrageenan, bradykinin, and prostaglandin E2), the xylene-induced ear edema was also used as an inflammatory model. Both NPDs showed significant (p < 0.001) antinociceptive effects in the acetic acid-induced writhing paradigm. In the case of the hot plate, the NPD 1 at the tested dose of 5 mg/kg enhanced the latency time after 60 min of injection, which remained significant (p < 0.001) up to the end of the experiment duration. The maximum percent inhibition of NPD 1 was 87.53. The naloxone injection significantly lowered the latency time of NPD 1 as compared to NPD 2. Regarding the anti-inflammatory effect, both of the tested NPDs demonstrated a significant reduction in paw edema against various inflammatory mediators, as mentioned above; however, the anti-inflammatory effect of NPD 1 was better. The maximal percent inhibition by NPD 1 and 2 was 43.24 (after 60 min) and 45.93 (after 90 min). A considerable effect also resulted from xylene-induced ere edema. Further, a molecular docking study was carried out to investigate the binding modes of the NPD. The docking analysis revealed that the NPD significantly interacted with the COX2 enzyme. Furthermore, molecular dynamics simulation was carried out for the docked complexes. The MD simulation analysis revealed the high stability of the two naproxen derivatives.

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.

Screening of the action mechanisms involved in the antinociceptive effect of isopulegol and its complex in cyclodextrin using acute nociception models in mice

Isopulegol, a terpene compound commonly present in the essential oils of several aromatic plants, may present a number of important pharmacological activities. Besides the screening of the antinociceptive effect of the monoterpene isopulegol (ISO) and its inclusion complex in β-cyclodextrins (ISO/CD), this study also aimed at investigating the signaling pathways involved in the antinociceptive response. The effects of ISO and ISO/CD on the central nervous system (CNS) were evaluated through open-field and rota-rod assays and the antinociceptive effects in formalin models, abdominal contortions by acetic acid, hot-plate and plantar mechanical hypernociception. Male and female mice (Mus musculus), weighing between 20–30 g, were divided into 6-animal groups. The oral administration of isopulegol and its complex showed significant antinociceptive effects in the 10, 5 and 1 mg/kg doses for both the formalin and abdominal contortion assays, with highlights on the 10 mg/kg dose of ISO and ISO/CD in both assays. Likewise, the 10 mg/kg dose was selected for the evaluation of the effects on the CNS, central and peripheral antinociceptive effect and screening of the signaling pathways involved in the analgesic potential. ISO and ISO/CD, both in the 10 mg/kg dose v.o., did not show any alteration to the parameters evaluated of the CNS and the results pointed to a possible acute antinociceptive action in the tests of formalin, abdominal contortion, hot-plate and plantar mechanical hypernociception, suggesting the involvement of these signaling pathways: opioid, potassium channel, cholinergic, nitric oxide, cyclic guanosin monophosphate, vaniloid and glutamatergic. The results suggest that ISO and ISO/CD carry a promising antinociceptive potential as a possible alternative to the pharmacological treatment of pain, showing that the inclusion of ISO in cyclodextrins enhance its pharmacological properties, once that the complexation process involves much lower amounts of the compound – what contributes to a better bioavailability and weaker probability for the development of undesired effects.

Effect of spirocyclopiperazinium salt compound LXM-15 on spinal nerve injury in rats.

Currently available therapies for neuropathic pain show limited efficacy. This study aimed to investigate the anti-nociceptive effect of the spirocyclopiperazinium salt compound LXM-15 in spinal nerve ligation (SNL) rats and to explore the potential mechanisms. Mechanical allodynia and thermal hyperalgesia tests were used to evaluate the effects of LXM-15 in SNL rats. The expression of CaMKIIα, CREB, JAK2, STAT3, c-fos and TNF-α was detected by western blotting, ELISA or qRT-PCR analysis. Receptor blocking test was performed to explore possible target. Administration of LXM-15 (1, 0.5, 0.25 mg/kg, i.g.) dose-dependently attenuated mechanical allodynia and thermal hyperalgesia in rats subjected to SNL (p < 0.01, p < 0.05), and the effects were completely blocked by peripheral α7 nicotinic or M4 muscarinic receptor antagonist (p > 0.05). LXM-15 significantly decreased the overexpression of phosphorylated CaMKIIα, CREB, JAK2 and STAT3 proteins and the mRNA levels of TNF-α and c-fos (p < 0.01, p < 05). All of the effects could be blocked by α7 or M4 receptor antagonist. Furthermore, LXM-15 reduced the protein expression of TNF-α and c-fos (p < 0.01, p < 0.05). No significant acute toxicity or abnormal hepatorenal function was observed. This is the first study to report that LXM-15 exerts significant anti-nociceptive effect on SNL rats. This effect may occur by activating peripheral α7 nicotinic and M4 muscarinic receptors, further inhibiting the CaMKIIα/CREB and JAK2/STAT3 signalling pathways, and finally inhibiting the expression of TNF-α and c-fos. Existing treatments for neuropathic pain show limited efficacy with severe adverse reactions. This paper is the first to report that LXM-15, a new spirocyclopiperazinium salt compound, exerts a significant anti-nociception in SNL rats without obvious toxicity. The underlying mechanisms include activating peripheral α7 nicotinic and M4 muscarinic receptors, then inhibiting the signalling pathways of CaMKIIα/CREB and JAK2/STAT3 and the expressions of TNF-α and c-fos. This study sheds new light on the development of novel analgesic drugs with fewer side effects.

Antinociceptive, Sedative and Excitatory Effects of Intravenous Butorphanol Administered Alone or in Combination with Detomidine in Calves: A Prospective, Randomized, Blinded Cross-Over Study.

(1) Background: The diagnostic and therapeutic procedures performed under sedation or general anesthesia in bovines are numerous. The analgesic drugs that can be legally used are few, making perioperative analgesia challenging. (2) Methods: Calves were administered butorphanol 0.1 mg kg-1 alone (SB) or combined with 0.02 mg kg-1 of a detomidine (DB) IV. The antinociceptive effect (trigeminocervical reflex threshold (TCRt)), as well as the behavioral (sedation and excitation) and physiological (heart and respiratory rate) changes were investigated. Five time windows were defined: BL (30 min pre-injection), T1 (0-30 min post-injection (PI)), T2 (31-60 min PI), T3 (61-90 min PI) and T4 (91-120 min PI). (3) Results: Both groups had a significative increase in TCRt at T1-T4 compared to the BL. The TCRt was significatively higher in DB than in SB at T1, T2 and T4. Heart rate decreased significatively in DB compared to that in BL. Calves were significantly more sedated in the DB group, and significantly more excited in the SB group compared to the BL. (4) Conclusions: Butorphanol alone has a statistically significant antinociceptive effect, but it elicits marked excitation, limiting its clinical applicability under this dosing regimen. The co-administration of detomidine eliminated the excitatory effect and induced consistent sedation and a significantly more pronounced antinociceptive effect.

Synthesis and biological evaluation of a peptide-remifentanil conjugate as a novel bifunctional mu/delta-opioid receptor agonist for the treatment of pain

For the treatment of pain, the design of a bifunctional mu-opioid receptor (MOR)/delta-opioid receptor (DOR) agonist is an effective strategy to seek safer opioids with higher antinociceptive efficacy and diminished adverse side effects. Herein, we describe the design, synthesis, and evaluation of a novel bivalent ligand (SW-WL-2) with a methyl 1-(3-methoxy-3-oxopropyl)-4-(phenylamino) piperidine- 4-carboxylate moiety (remifentanil derivative) covalently linked to a dermorphin-like structure (H-Dmt-N-Me-D-Ala-Aba-Gly-NH2, BVD03) at the C-terminus. Our results showed that SW-WL-2 behaved as a potent dual agonist of MOR and DOR with significant and prolonged antinociceptive effects in acute pain models in vivo. Furthermore, SW-WL-2 exhibited reduced or no opioid-like side effects such as physical dependence or respiratory depression, in contrast to an equipotent analgesic dose of morphine or BVD03. Thus, SW-WL-2 should be used as a new lead compound for the discovery of safer opioid drugs for the treatment of pain.

Pharmacokinetics and effects of codeine in combination with acetaminophen on thermal nociception in horses.

Codeine and acetaminophen in combination have proven to be an effective analgesic treatment for moderate-to-severe and postoperative pain in humans. Studies have demonstrated that codeine and acetaminophen, when administered as sole agents, are well tolerated by horses. In the current study, we hypothesized that administration of the combination of codeine and acetaminophen would result in a significant thermal antinociceptive effect compared with administration of either alone. Six horses were administered oral doses of codeine (1.2 mg/kg), acetaminophen (20 mg/kg), and codeine plus acetaminophen (1.2 mg/kg codeine and 6-6.4 mg/kg acetaminophen) in a three-way balanced crossover design. Plasma samples were collected, concentrations of drug and metabolites determined via liquid chromatography-mass spectrometry, and pharmacokinetic analyses were performed. Pharmacodynamic outcomes, including effect on thermal thresholds, were assessed. Codeine Cmax and AUC were significantly different between the codeine and combination group. There was considerable inter-individual variation in the pharmacokinetic parameters for codeine, acetaminophen, and their metabolites in horses. All treatments were well tolerated with minimal significant adverse effects. An increase in the thermal threshold was noted at 1.5 and 2 h, from 15 min through 6 h and 0.5, 1, 1.5, and 3 h in the codeine, acetaminophen, and combination groups, respectively.

Chemical profiling and evaluation of toxicological, antioxidant, anti-inflammatory, anti-nociceptive and tyrosinase inhibitory potential of Portulacaria afra using in-vitro, in-vivo and in-silico studies

Portulacaria afra Jacq (Portulacaceae) is a medicinal plant used traditionally in the treatment of pain and inflammation. This study aimed to evaluate the phytochemical composition, toxicity, antinociceptive, and enzyme inhibition potential of P. afra. The methanol extract (PAME) was prepared through maceration and fractionated with ethanol to ethanol fraction of P. afra (ETPA). Both PAME and ETPA were found to be rich in total phenolic (TPC) and total flavonoid contents (TFC). Similarly, PAME showed the highest antioxidant potential through ABTS 93.16 ± 0.05 mg TE /g of dry extract (D.E.) while ETPA showed maximum results (462 ± 1.44 mg TE/g) in the CUPRAC method. The RP-UHPLC-MS analysis of PAME showed tentative identification of 101 compounds in the positive mode and 14 compounds in the negative mode of ionization while GC–MS profiling gave a total of 15 compounds. The acute oral toxicity study of PAME revealed the safety and biocompatibility of the extract up to a dose of 5000 mg/kg orally in rats. In-vitro data revealed that varying concentrations of P. afra significantly (p < 0.05) inhibited heat-induced BSA denaturation compared to indomethacin in a concentration-dependent manner. PAME suppressed carrageenan-induced paw edema at the 4th hr with maximum inhibition. The analgesic efficacy of PAME was determined by the hotplate, writhing method, and tail-flicking rat models. In the hot plate method, PAME treated groups showed a significant effect (p < 0.0001). While in the writhing model, the PAME treated groups showed a significant (p < 0.0001) anti-nociceptive effect at 200 mg/kg and 400 mg/kg compared to the control group. Similarly, PAME treated groups in the tail flicking model showed a significant (p < 0.001) anti-nociceptive effect at 200 mg/kg and 400 mg/kg. A dose-dependent increase in latency time (8.78 ± 0.090 at (30 min), 11.39 ± 0.005 at (60 min), 12.14 ± 0.01 at (90 min) 15.19 ± 0.03 at (120 min), p < 0.0001 was observed, compared to the control group. Similarly, the extract and fraction showed significant inhibitory potential against tyrosinase in in vitro and in-silico studies. Conclusively the current study unveiled P. afra as a novel non-toxic source with good total antioxidant-mediated anti-inflammatory and analgesic potential.

Evaluation of the antinociceptive effect of valerian and hops combination in experimental animal models: Involvement of the opioid system

Pain is a common undertreated worldwide complaint. The need to explore the antinociceptive potential of alternative herbal products is essential. Although used as a mild sedative, limited evidence focused on the potential antinociceptive effect of valerian and hops combination. The present study was carried out to evaluate the in vivo anti-nociceptive effect of the valerian-hops combination to justify its use as an effective and safe analgesic agent. Anti-nociceptive effects of valerian-hops combination (50, 100, and 200 mg/kg) were assessed in swiss albino mice for performing the acetic acid-induced writhing test, the paw licking test using formalin, the paw licking test using glutamate, and the tail immersion test. The effects were compared to those of diclofenac or morphine in the presence or absence of the opioid receptor antagonist naloxone. Valerian-hops” extract of 100 and 200 mg/kg demonstrated a significant reduction in the number of writhing episodes induced by acetic acid compared to the control (p < 0.05), a significant reduction in the licking number at doses of 100 and 200 mg/kg in the late phase formalin-induced paw licking, significantly reduced the number of lickings after glutamate injection compared to control (p < 0.05). And significantly increased pain reaction after 60 and 90 min of tail immersion test, this effect was opposed by naloxone treatment. The valerian-hops combination produced a significant antinociceptive effect that involved the opioid system. Further studies are required to fully uncover the underlying active constituents and their mechanisms.

Phenolic Composition, Wound Healing, Antinociceptive, and Anticancer Effects of Caralluma europaea Extracts.

Caralluma europaea (Guss.) is an important medicinal plant widely used in Morocco for various traditional purposes. Our work aimed to evaluate the phenolic composition, wound healing, antinociceptive, and anticancer activities of C. europaea extracts. Moreover, this study assessed the beneficial effect of C. europaea phytocompounds on the TRADD, cyclooxegenase-2, Wnt/β-catenin, and tyrosine kinase signaling pathways. The wound healing effect of C. europaea formulations against skin burn was evaluated for 21 days. The cytotoxic effect of the C. europaea extracts was evaluated against human leukemic (K562 and HL60) and liver cancer cell lines (Huh-7) using the MTT test. All the phytoconstituents identified by UHPLC in the polyphenols were docked for their inhibitory power on protein casein kinase-1, glycogen synthase kinase-3-β, cyclooxegenase-2, tyrosine kinase, and TRADD. Luteolin and kaempferol are the main compounds identified in C. europaea polyphenols. The group treated with polyphenols showed the greatest wound contractions and all tested extracts presented a significant antinociceptive effect. Polyphenols showed a remarkable antitumoral activity against the K562, HL60 and Huh-7 cell lines. Saponins exerted an important cytotoxic effect against the Huh-7 cell line, whereas no cytotoxicity was observed for the hydroethanolic and flavonoids extracts. Hesperetin and trimethoxyflavone presented the highest docking G-score on tyrosine kinase and cyclooxygenase, respectively.