Antinociceptive Agents Research Articles

Protective Effects of Hydrogen Sulfide Against the ATP-Induced Meningeal Nociception.

We previously showed that extracellular ATP and hydrogen sulfide (H2S), a recently discovered gasotransmitter, are both triggering the nociceptive firing in trigeminal nociceptors implicated in migraine pain. ATP contributes to meningeal nociception by activating the P2X3 subunit-containing receptors whereas H2S operates mainly via TRP receptors. However, H2S was also proposed as a neuroprotective and anti-nociceptive agent. This study aimed to test the effect of H2S on ATP-mediated nociceptive responses in rat meningeal afferents and trigeminal neurons and on ATP-induced degranulation of dural mast cells. Electrophysiological recording of trigeminal nerve activity in meninges was supplemented by patch-clamp and calcium imaging studies of isolated trigeminal neurons. The H2S donor NaHS induced a mild activation of afferents and fully suppressed the subsequent ATP-induced firing of meningeal trigeminal nerve fibers. This anti-nociceptive effect of H2S was specific as an even stronger effect of capsaicin did not abolish the action of ATP. In isolated trigeminal neurons, NaHS decreased the inward currents and calcium transients evoked by activation of ATP-gated P2X3 receptors. Moreover, NaHS prevented ATP-induced P2X7 receptor-mediated degranulation of meningeal mast cells which emerged as triggers of migraine pain. Finally, NaHS decreased the concentration of extracellular ATP in the meningeal preparation. Thus, H2S exerted the multiple protective actions against the nociceptive effects of ATP. These data highlight the novel pathways to reduce purinergic mechanisms of migraine with pharmacological donors or by stimulation production of endogenous H2S.

Curcumin Niosomes (curcusomes) as an alternative to conventional vehicles: A potential for efficient dermal delivery

This research aimed to enhance the skin delivery of curcumin niosome (curcusome) made by a thin film hydration technique. To optimize the cucusome formulations the effect of the ratio of cholesterol:surfactants was investigated. The solid-state and morphology of curcumin in curcusome was characterized by photon correlation spectroscopy, powder x-ray diffractometer (PXRD), scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR). The results showed that the particle size of curcusomes decreased by adding cholesterol. The results showed that the size and zeta potential of nanoparticles can be modulated by the changes in cholesterol and surfactant concentrations. Zeta potential data showed an increase in this value from −0.73 ± 0.31 to −9.31 ± 0.97 mV when the concentration of cholesterol declined from 1.8 to 0%. Maximum entrapment efficiency around 95% was observed for a formulation with the greatest content of cholesterol. Solid-state analysis results ruled out any interaction between excipients and curcumin, and also showed that curcumin was in an amorphous state in the niosomes. Skin permeation test showed that the amounts of the curcumin in skin layers and the receptor chamber was greater for curcusome than when the curcumin solution was used. The skin irritation test of the formulations on Wistar rats showed that the curcumin niosomal gels were not irritant. Finally, curcusome formulations revealed considerable antinociceptive and anti-inflammatory activities compared to the control group in the late phase. The utilizations of the curcusome gel modified the tail-flick latency as compared to the curcumin simple gel, placebo, as well as the simple gel (P < 0.05). These results suggested that nisomes could enhance the efficiency of curcumin as an antinociceptive and anti-inflammatory agent via improvement in drug delivery to the target location.

Quercetin Ameliorates CFA-Induced Chronic Inflammatory Hyperalgesia via Modulation of ROS-Mediated ERK1/2 Signaling and Inhibition of Spinal Glial Activation In Vivo.

Impact of reactive oxygen species (ROS) in development of hyperalgesia has recently motivated scientists to focus on ROS as novel target of anti-hyperalgesic interventions. Studies have indicated the usefulness of ROS scavengers and exogenous antioxidants as anti-nociceptive agents in animal models of neuropathic and inflammatory hyperalgesia. In present study, we suggest the anti-hyperalgesic potential of the dietary antioxidant quercetin on chronic inflammatory hyperalgesia induced by Complete Freund's Adjuvant (CFA). Three doses of quercetin (25, 50 and 75mg/kg bodyweight) for consecutive 7days were used for the study. Thermal hyperalgesia was assessed by paw withdrawal latency (PWL) test and inflammation was checked in terms of changes in paw edema. The insight of molecular signaling during chronic hyperalgesia was analyzed by TNF-α-TNFR1-ERK1/2 pathway in relation to change in ROS level in DRG and spinal cord. CFA-induced hyperalgesia was confirmed by decreased PWL and increased c-Fos activity in dorsal horn of spinal cord, determined by immunohistochemical analysis. It was characterized with elevated level of ROS and TNF-α estimated by ELISA. The activation of ERK1/2 and NF-κB in DRG and spinal cord and over-expression of TNFR1 in DRG were analyzed by Western blotting. Up-regulation of Iba1 and GFAP indicates glial activation in spinal cord. Expression of GFAP and its co-localization with NF-κB were examined by immunofluorescence. All the molecular modulators of hyperalgesia were brought towards normal after quercetin treatment showing its anti-hyperalgesic activity, indicating that repeated quercetin treatment is able to alleviate chronic inflammatory hyperalgesia by attenuating TNF-α-TNFR1-ERK1/2 signaling pathway via modulation of ROS and by suppression of central sensitization via inhibition of spinal glial activation.

Anthocyanin Derived from Purple Sweet Potato Water Extracts Ameliorated Oxidative Stress, Inflammation, Mechanical Allodynia, and Cold Allodynia among Chronic Constriction Injury-Induced Neuropathic Pain in Rats

BACKGROUND: Nerve injury leads to multiple events, including oxidative stress, inflammation, and glial cells activation, which all bring about the neuropathic pain condition. Any alternative novel treatment modalities from natural products are thus highly anticipated, given the account that current treatments for neuropathic pain have not generated any satisfactory efficacy.&#x0D; AIM: This study aims to address the pleiotropic effects of water extracts from the purple sweet potato (PSP) (Ipomoea batatas L.) as an antioxidant, anti-inflammatory, and anti-nociceptive agent to alleviate neuropathic pain behavior.&#x0D; METHODS: This is a randomized post-test control group design using chronic constriction injury (CCI) rat models. Thirty-two Wistar rats (34 survived until the end of study period) fulfilling the eligible criteria were randomized into either treatment or control group. Treatment group received water extracts of PSP containing 400 mg/kg of body weight/d of anthocyanin for 28 days. Antioxidant activity was evaluated from malondialdehyde (MDA) levels, anti-inflammatory activity was evaluated from prostaglandin E2 (PGE2) levels. Neuropathic pain was assessed from the animal’s behavioral responses toward mechanical and cold allodynia.&#x0D; RESULTS: The results showed that mean MDA levels of treatment group were significantly lower than control group (0.291 ± 0.046 μmol vs. 0.394 ± 0.057 μmol; p &lt; 0.001). Furthermore, treatment group’s PGE2 levels were also significantly lower than control’s (0.342 ± 0.096 ng/mL vs. 0.431 ± 0.061 ng/mL; p = 0.004). In addition, neuropathic pain behavior comprising mechanical and cold allodynia were significantly milder among treatment group than in the control group during the observation period (p &lt; 0.05).&#x0D; CONCLUSION: PSP water extracts had been shown to ameliorate oxidative stress, as well as exerted anti-inflammatory and anti-nociceptive effects and was able to suppress neuropathic pain behavior in Wistar rats with peripheral nerve injury.

Synthesis, Anticonvulsant and Antinociceptive Activity of New Hybrid Compounds: Derivatives of 3-(3-Methylthiophen-2-yl)-pyrrolidine-2,5-dione.

The present study aimed to design and synthesize a new series of hybrid compounds with pyrrolidine-2,5-dione and thiophene rings in the structure as potential anticonvulsant and antinociceptive agents. For this purpose, we obtained a series of new compounds and evaluated their anticonvulsant activity in animal models of epilepsy (maximal electroshock (MES), psychomotor (6 Hz), and subcutaneous pentylenetetrazole (scPTZ) seizure tests). To determine the mechanism of action of the most active anticonvulsant compounds (3, 4, 6, 9), their influence on the voltage-gated sodium and calcium channels as well as GABA transporter (GAT) was assessed. The most promising compound 3-(3-methylthiophen-2-yl)-1-(3-morpholinopropyl)pyrrolidine-2,5-dione hydrochloride (4) showed higher ED50 value than those of the reference drugs: valproic acid (VPA) and ethosuximide (ETX) (62.14 mg/kg vs. 252.7 mg/kg (VPA) in the MES test, and 75.59 mg/kg vs. 130.6 mg/kg (VPA) and 221.7 mg/kg (ETX) in the 6 Hz test, respectively). Moreover, in vitro studies of compound 4 showed moderate but balanced inhibition of the neuronal voltage-sensitive sodium (site 2) and L-type calcium channels. Additionally, the antinociceptive activity of the most active compounds (3, 4, 6, 9) was also evaluated in the hot plate test and writhing tests, and their hepatotoxic properties in HepG2 cells were also investigated. To determine the possible mechanism of the analgesic effect of compounds 3, 6, and 9, the affinity for the TRPV1 receptor was investigated.

Gano oil: A novel antinociceptive agent extracted from Ganoderma lucidum inhibits paw oedema and relieves pain by hypnotic and analgesic actions of fatty acid amides

Ethnopharmacological relevanceLingzhi or Reishi - Ganoderma lucidum (Fr.) P. Karst is an extensively used medicinal mushroom in folklore and traditional medicine in south East Asia to treat a number of diseases. Lingzhi is known as ‘mushroom of immortality’ in Chinese folklore. In Traditional Chinese Medicine it is considered as a panacea to cure all diseases.Aim of the study: This study aims to evaluate antinociceptive effect of Gano oil, a novel fatty acid rich extract obtained from G. lucidum and identification of the active principle. Materials & methodsGano oil extracted from Ganoderma lucidum was evaluated for inhibition of formalin-induced paw oedema on Swiss albino mice by oral administration as well as topical application. Antinociceptive activity of Gano oil was tested by acetic acid – induced abdominal writhing test as well as hot plate test. Free radical scavenging activity was determined by DPPH assay. COX enzyme inhibiting activity was assayed using different concentrations of Gano oil exposed to LPS stimulated RAW 264.7 cell line. NF-kB inhibiting activity of Gano oil was assayed using Lentix-293T P65 Ds Red stable cell line by fluorescent imaging and flow cytometry analysis. Chemical profile of Gano oil was ascertained by HPTLC analysis and active principle was identified by HRLCMS analysis. ResultsThe oral administration of Gano oil at doses of 10,25, 50 mg/kg b.wt showed 42, 58 and 73% inhibition of paw oedema while topical applications at dose of 1,5 and 10% reduced 33, 50 and 58% oedema respectively. Acetic acid writhing test showed that Gano oil inhibited 44.44% contortions (p < 0.001) and while in hot plate method Gano oil at 25 mg/kg b. wt showed response latency of 30.0 ± 2.08 s for 120 min compared to base 1.65 ± 0.32 s (p < 0.01). Gano oil at 100 μg/ml inhibited 50% COX enzyme activity (p < 0.01). High throughput flurescent imaging and flow cytometry assay revealed marked ability of Gano oil to inhibit NF-kB activity. Gano oil was found to possess dose dependent free radical scavenging activity as evident from DPPH assay. HPTLC analysis of Gano oil indicated the chemical figure print. HR LC-MS analysis showed the major chemical components were fatty acid amides namely, Oleamide, C18H35NO, M+281, Hexadecanamide, C16H33NO, M+255 and 9-oxo-10 (E) Octadecadienoic acid, C18H30O3 M+294. ConclusionFatty acid rich Gano oil extracted from G.lucidum is a novel antinociceptive agent capable to inhibit oedema by oral administration as well as topical application. The results indicate the pharmacological interest, clinical significance and therapeutic use. The finding suggests that Gano oil might be a potent natural product based analgesic. The effect might be assigned to the fatty acid amide constituents especially oleamide which has been demonstrated to have analgesic and hypnotic actions.

Pyrrolidin-2-one linked benzofused heterocycles as novel small molecule monoacylglycerol lipase inhibitors and antinociceptive agents.

Eighteen pyrrolidin-2-one linked benzothiazole, and benzimidazole derivatives (10-27) were designed and synthesized. The structure of the compounds was confirmed by elemental and spectral (IR, 1 H-NMR and MS) data analysis. All the compounds were screened by human monoacylglycerol lipase (hMAGL) inhibition assay. Three benzimidazole compounds, 22 (4-Cl phenyl), 23 (3-Cl,4-F phenyl) and 25 (4-methoxy phenyl) were found to be the most potent, having an IC50 value of 8.6, 8.0 and 9.4nm, respectively. Among them, the halogen-substituted phenyl derivatives, compound 22 (4-Cl phenyl) and compound 23 (3-Cl,4-F phenyl), showed micromolar potency against fatty acid amide hydrolase (FAAH), having an IC50 value of 35 and 24µm, respectively. Benzimidazole derivative having 4-methoxyphenyl substitution (compound 25) was found to be a selective MAGL inhibitor (IC50 =9.4nm), with an IC50 value above 50µm against FAAH. In the formalin-induced nociception test, compound 25 showed a dose-dependent reduction of pain response in both acute and late phases. At 30mg/kg dose, it significantly reduced the pain response and showed greater potency than the reference drug gabapentin (GBP).

Multitargeted Compounds Derived from (2,5-Dioxopyrrolidin-1-yl)(phenyl)-Acetamides as Candidates for Effective Anticonvulsant and Antinociceptive Agents.

We developed a focused set of original hybrid pyrrolidine-2,5-dione derivatives with potent anticonvulsant and antinociceptive properties. These hybrid compounds demonstrated broad-spectrum protective activity in a range of mouse models, such as the maximal electroshock (MES) test, the pentylenetetrazole-induced seizures (scPTZ), and the 6 Hz (32 mA) seizures. Compound 22 showed the most potent anticonvulsant activity (ED50 MES = 23.7 mg/kg, ED50 6 Hz (32 mA) = 22.4 mg/kg, ED50scPTZ = 59.4 mg/kg). In addition, 22 revealed potent efficacy in the formalin-induced tonic pain. These in vivo activities of 22 are likely mediated by several targets and may result from the inhibition of central sodium/calcium currents and transient receptor potential vanilloid 1 (TRPV1) receptor antagonism. Finally, the lead compound 22 revealed drug-like absorption, distribution, metabolism, excretion, toxicity (ADME-Tox) properties in the in vitro assays, making it a potential candidate for further development in epilepsy and neuropathic pain indications.

Tuning Down the Pain - An Overview of Allosteric Modulation of Opioid Receptors: Mechanisms of Modulation, Allosteric Sites, Modulator Syntheses.

Opioid signaling plays a central role in pain perception. As such, it remains the main target in the development of antinociceptive agents, despite serious side effects involved. In recent years, hopes for improved opioid painkillers are rising, together with our understanding of allosterism and biased signaling mechanisms. In this review, we focus on recently discovered allosteric modulators of opioid receptors, insights into phenomena underlying their action, as well as on how they extend our understanding of mechanisms of previously known compounds. A brief overlook of their synthesis is also presented.

Antinociceptive activity of Schinus terebinthifolia leaf lectin (SteLL) in sarcoma 180-bearing mice

Ethnopharmacology relevanceSchinus terebinthifolia Raddi leaves have been used in folk medicine due to several properties, including antitumor and analgesic effects. The variable efficacy and adverse effects of analgesic drugs have motivated the search for novel antinociceptive agents. It has been reported that the S. terebinthifolia leaf lectin (SteLL) has antitumor activity against sarcoma 180 in mice. Aim of the studyThis work aimed to evaluate whether SteLL would reduce cancer pain using an orthotopic tumor model. Materials and methodsA sarcoma 180 cell suspension was inoculated into the right hind paws of mice, and the treatments (150 mM NaCl, negative control; 10 mg/kg morphine, positive control; or SteLL at 1 and 2 mg/kg) were administered intraperitoneally 24 h after cell inoculation up to 14 days. Spontaneous nociception, mechanical hyperalgesia, and hot-plate tests were performed. Further, the volume and weight of the tumor-bearing paws were measured. ResultsSteLL (2 mg/kg) improved limb use during ambulation. The lectin (1 and 2 mg/kg) also inhibited mechanical hyperalgesia and increased the latency time during the hot-plate test. Naloxone was found to reverse this effect, indicating the involvement of opioid receptors. The tumor-bearing paws of mice treated with SteLL exhibited lower volume and weight. ConclusionSteLL reduced hyperalgesia due to sarcoma 180 in the paws of mice, and this effect can be related to its antitumor action.

Anti-inflammatory and antinociceptive effects of Curcuma kwangsiensis and its bioactive terpenoids in vivo and in vitro

Ethnopharmacological relevance“Curcumae Radix”, the dried rhizomes of Curcuma kwangsiensis documented in Chinese pharmacopoeia, has been traditionally used for the treatment of inflammatory and pain diseases, such as jaundice and red urine, cleaning the heart-fire and depression, arthralgia, and dysmenorrhea. However, according to literature surveys, anti-inflammatory and antinociceptive studies of C. kwangsiensis have been seldom reported so far. Aim of the studyThe current study focuses on the anti-inflammatory and antinociceptive effects of C. kwangsiensis and discovering the bioactive compounds for its traditional usages both in vivo and in vitro, which could provide scientific justification about its traditional use. Material and methodsThe anti-inflammatory and antinociceptive assays of various layers (ME, EA, AQS) from C. kwangsiensis were achieved by carrageenan-induced paw edema and acetic acid-induced writhing animal models, respectively. The most bioactive part, EA layer was further phytochemically investigated by multiple step chromatography techniques. The structures of these isolates were unambiguously elucidated by means of extensive spectroscopic and chemical methods, and comparison with corresponding data of the reported literature. Four major sesquiterpenoids (4, 6, 14, and 15) were achieved for their anti-inflammatory and antinociceptive assays by the two aforementioned animal models in vivo. All the isolated compounds were evaluated for their anti-inflammatory effects via detecting inflammatory mediator releases (COX-2, IL-1β, and TNF-α) in RAW 264.7 macrophage cells induced by LPS. ResultsThe ME and EA layers significantly alleviated the paw edema caused by carrageenan and decreased the number of writhes induced by acetic acid at the dose of 200 and/or 100 mg/kg in comparison to the control group (p < 0.01/0.05), and the EA layer exhibited better activity than that of ME layer. Subsequent phytochemical investigation on EA layer of C. kwangsiensis exhibited that three new terpenoid compounds (1–3), identified as (12Z,14R)-7β-hydroxylabda-8(17),12-diene-14,15,16-triol (1), (12Z,14S)- 7β-hydroxlabda-8(17),12-diene-14,15,16-triol (2), and (4S)-hydroxy-(8)-methoxy-(5S)-(H)-guaia1(10),7(11)-dien-12,8-olide (3), together with twenty-two known analogs were isolated. Furthermore, four major sesquiterpenoids (4, 6, 14, and 15) significantly relieved the paw edema and number of writhes at 100 and/or 50 mg/kg (p < 0.05/0.01). Likewise, the majority of sesqui- and diterpenoids isolated could remarkably inhibited the secretion of inflammatory mediators (COX-2, IL-1β, and TNF-α) in LPS-stimulated RAW 264.7 macrophages cells at the concentration of 20 μg/mL, comparable to DXM used as the positive control. All the results suggested that EA layer from C. kwangsiensis possessed the anti-inflammatory and antinociceptive activities, and these sesqui- and diterpenoids could be the effective constituents responsible for relieving inflammation. ConclusionThe present studies undoubtedly determined the anti-inflammatory and antinociceptive material basis of C. kwangsiensis, including the EA layer and its precise components, which presented equivalent or better anti-inflammatory effects than that of positive control (ASP/DXM) in vivo and in vitro. These results not only would account for scientific knowledge for traditional use of C. kwangsiensis, but also provide credible theoretical foundation for the further development of anti-inflammatory and antinociceptive agents.

Synthesis, characterization, and in vivo pharmacological evaluation of novel mannich bases derived from 1,2,4-triazole containing a naproxen moiety.

A new series of 1,2,4-triazole-5-thione Mannich derivatives containing a naproxen moiety (1a-o) was designed and synthesized to create naproxen analogs, with the aim of developing novel anti-inflammatory/analgesic agents with improved safety profiles. Target compounds were synthesized using classical Mannich reaction (i.e. one-pot three component condensation reaction), by reacting triazole molecule (1), formaldehyde, and diverse secondary amines in ethanol. The synthesized compounds were investigated using FT-IR, 1H NMR, 13C NMR and mass spectroscopies, as well as elemental analysis. Compounds were then evaluated for their potential antinociceptive and anti-inflammatory activities using some validated invivo methods. Data obtained from acetic acid induced-writhing and carrageenan-induced paw edema tests revealed that all compounds induced peripherally-mediated antinociceptive activities, as well as notable anti-inflammatory effects. The results of hot-plate and tail-clip tests indicated that compounds 1a, 1b, 1c, 1d, 1g, and 1j have also centrally-mediated antinociceptive activities in addition to their peripherally-mediated effects. Molecular docking studies were performed to investigate the putative binding modes of the interactions between all compounds and COX-1/COX-2 enzymes using AutoDock Vina software. Docking of the compounds into the COX-2 active site produced binding interactions that are essential for COX-2 inhibitory activity. None of the compounds in the serial, except for 1m and 1j, induced significant gastrointestinal irritation. Overall, the results indicated that triazol Mannich bases bearing a naproxen moiety potentially represent a novel class of antinociceptive and anti-inflammatory agent with an improved gastric safety profile.

Sigma-1 receptor antagonists: promising players in fighting neuropathic pain.

Sigma-1 receptors (S1Rs) are strongly correlated to neuropathic pain (NP), since their inactivation may decrease allodynia or dysesthesia, promoting analgesic effects. In the recent patent landscape, S1R antagonists endowed with nanomolar S1Rs affinity emerged as potent antinociceptive agents. So far, three patented compounds have been proposed for counteracting NP. Particularly PV-752 and AV1066, disclosed by the University of Pavia (Italy) and Anavex, respectively, showed good analgesic activity in preclinical studies. Moreover, E-52862 developed by Esteve (Spain) has been proved to be effective, both in preclinical and Phase II clinical trials, against several symptoms of NP. These patents ascertain S1R antagonists as potential drugs, alone or in combination with other analgesic drugs, for managing NP in humans.

Effect of Opioid-Free Anaesthesia on Perioperative Period: A Review

Balanced anaesthesia relies on the administration of opioids in the perioperative period as antinociceptive agents. There is no clear evidence that intraoperative opioids result in reduction of postoperative pain scores. Opioid-free anaesthesia (OFA), combination of various opioids-sparing techniques leading to no administration of intraoperative systemic, neuraxial or intracavitary opioids, arises from the attempt to develop anti-hyperalgesic techniques to improve postoperative pain control.

An evaluation of the anti-hyperalgesic effects of cannabidiolic acid-methyl ester in a preclinical model of peripheral neuropathic pain.

Chronic neuropathic pain (NEP) is associated with growing therapeutic cannabis use. To promote quality of life without psychotropic effects, cannabinoids other than Δ9-tetrahydrocannabidiol, including cannabidiol and its precursor cannabidiolic acid (CBDA), are being evaluated. Due to its instability, CBDA has been understudied, particularly as an anti-nociceptive agent. Adding a methyl ester group (CBDA-ME) significantly enhances its stability, facilitating analyses of its analgesic effects in vivo. This study examines early treatment efficacy of CBDA-ME in a rat model of peripherally induced NEP and evaluates sex as a biological variable. After 14 consecutive days of intraperitoneal CBDA-ME administration at 0.01, 0.1 and 1 μg·kg-1 , commencing 1 day after surgically implanting a sciatic nerve-constricting cuff to induce NEP, the anti-nociceptive efficacy of this cannabinoid was assessed in male and female Sprague-Dawley rats relative to vehicle-treated counterparts. In females, 2 and 4 μg·kg-1 daily doses of CBDA-ME were also evaluated. Behavioural tests were performed for hind paw mechanical and thermal withdrawal thresholds once a week for 8 weeks. At endpoint, in vivo electrophysiological recordings were obtained to characterize soma threshold changes in primary sensory neurons. In males, CBDA-ME elicited a significant concentration-dependent chronic anti-hyperalgesic effect, also influencing both nociceptive and non-nociceptive mechanoreceptors, which were not observed in females at any of the concentrations tested. Initiating treatment of a peripheral nerve injury with CBDA-ME at an early stage post-surgery provides anti-nociception in males, warranting further investigation into potential sexual dimorphisms underlying this response.

Zerumbone Modulates α2A-Adrenergic, TRPV1, and NMDA NR2B Receptors Plasticity in CCI-Induced Neuropathic Pain In Vivo and LPS-Induced SH-SY5Y Neuroblastoma In Vitro Models.

Zerumbone has shown great potential in various pathophysiological models of diseases, particularly in neuropathic pain conditions. Further understanding the mechanisms of action is important to develop zerumbone as a potential anti-nociceptive agent. Numerous receptors and pathways function to inhibit and modulate transmission of pain signals. Previously, we demonstrated involvement of the serotonergic system in zerumbone’s anti-neuropathic effects. The present study was conducted to determine zerumbone’s modulatory potential involving noradrenergic, transient receptor potential vanilloid type 1 (TRPV1) and N-methyl-D-aspartate (NMDA) receptors in chronic constriction injury (CCI)-induced in vitro and lipopolysaccharide (LPS)-induced SH-SY5Y in vitro neuroinflammatory models. von Frey filament and Hargreaves plantar tests were used to assess allodynia and hyperalgesia in the chronic constriction injury-induced neuropathic pain mouse model. Involvement of specific adrenoceptors were investigated using antagonists— prazosin (α1-adrenoceptor antagonist), idazoxan (α2-adrenoceptor antagonist), metoprolol (β1-adrenoceptor antagonist), ICI 118,551 (β2-adrenoceptor antagonist), and SR 59230 A (β3-adrenoceptor antagonist), co-administered with zerumbone (10 mg/kg). Involvement of excitatory receptors; TRPV and NMDA were conducted using antagonists capsazepine (TRPV1 antagonist) and memantine (NMDA antagonist). Western blot was conducted to investigate the effect of zerumbone on the expression of α2A-adrenoceptor, TRPV1 and NMDA NR2B receptors in CCI-induced whole brain samples of mice as well as in LPS-induced SH-SY5Y neuroblastoma cells. Pre-treatment with α1- and α2-adrenoceptor antagonists significantly attenuated both anti-allodynic and anti-hyperalgesic effects of zerumbone. For β-adrenoceptors, only β2-adrenoceptor antagonist significantly reversed the anti-allodynic and anti-hyperalgesic effects of zerumbone. β1-adrenoceptor antagonist only reversed the anti-allodynic effect of zerumbone. The anti-allodynic and anti-hyperalgesic effects of zerumbone were both absent when TRPV1 and NMDA receptors were antagonized in both nociceptive assays. Zerumbone treatment markedly decreased the expression of α2A-adrenoceptor, while an up-regulation was observed of NMDA NR2B receptors. Expression of TRPV1 receptors however did not significantly change. The in vitro study, representing a peripheral model, demonstrated the reduction of both NMDA NR2B and TRPV1 receptors while significantly increasing α2A-adrenoceptor expression in contrast to the brain samples. Our current findings suggest that the α1-, α2-, β1- and β2-adrenoceptors, TRPV1 and NMDA NR2B are essential for the anti-allodynic and antihyperalgesic effects of zerumbone. Alternatively, we demonstrated the plasticity of these receptors through their response to zerumbone’s administration.

P. domestica Extract Mediated Silver Nanoparticles and their Antinociceptive Activity for Pain Management in Children

Because of the environmentally-friendly design and low cost, bio-mediated synthesis of nanoparticles has become popular in recent years. In this research, we utilized an aqueous extract of Prunus domestica (P. domestica) to produce silver nanoparticles (AgNPs). Different spectroscopic and microscopic studies have performed to characterize the as-produced AgNPs. The X-ray diffraction (XRD) findings showed the formation of crystalline face-centered cubic (fcc) NPs. Furthermore, the analysis of Fourier transform infrared (FT-IR) spectroscopy verified that the P. domestica leaf extract not only worked as a bioreducing agent and also capped the AgNP surface by serving as a stabilizing agent. The prepared AgNPs were tested for their antinociceptive (abdominal constriction response) activities. It was revealed that AgNPs suggestively reduced the chemically-persuaded nociception, which was equivalent to the effect of P. domestica extract. Further, these results conclude the use of P. domestica extract mediated AgNPs as antinociceptive agent for pain management in children.

Aromatic-Amine Pendants Produce Highly Potent and Efficacious Mixed Efficacy μ-Opioid Receptor (MOR)/δ-Opioid Receptor (DOR) Peptidomimetics with Enhanced Metabolic Stability.

We previously reported a novel SAR campaign that converted a metabolically unstable series of μ-opioid receptor (MOR) agonist/δ-opioid receptor (DOR) antagonist bicyclic core peptidomimetics with promising analgesic activity and reduced abuse liabilities into a more stable series of benzylic core analogues. Herein, we expanded the SAR of that campaign and determined that the incorporation of amines into the benzylic pendant produces enhanced MOR-efficacy in this series, whereas the reincorporation of an aromatic ring into the pendant enhanced MOR-potency. Two compounds, which contain a piperidine (14) or an isoindoline (17) pendant, retained the desired opioid profile in vitro, possessed metabolic half-lives of greater than 1 h in mouse liver microsomes (MLMs), and were active antinociceptive agents in the acetic acid stretch assay (AASA) at subcutaneous doses of 1 mg/kg.

Involvement of monoaminergic targets in the antidepressant- and anxiolytic-like effects of the synthetic alkamide riparin IV: Elucidation of further mechanisms through pharmacological, neurochemistry and computational approaches

Despite recent advances, current antidepressants have considerable limitations: late onset of action and the high profile of refractoriness. Biomedical research with natural products has gained growing interest in the last years, and had provide useful candidates for new antidepressants. Riparins are a group of natural alkamides obtained from Aniba riparia, which had marked neuroactive effects, mainly as antidepressant and antinociceptive agents. We made modifications of the basic structure of riparins, originating a synthetic alkamide, also known as riparin IV (RipIV). RipIV demonstrated a superior analgesic effect than its congeners and a marked antidepressant-like effect. However, the basic mechanism for the central effects of RipIV remains unknown. Here, we aimed to investigate the participation of monoaminergic neurotransmission targets in the antidepressant-like effects of RipIV. To do this, we applied a combined approach of experimental (classical pharmacology and neurochemistry) and computer-aided techniques. Our results demonstrated that RipIV presented antidepressant- and anxiolytic-like effects without modifying locomotion and motor coordination of mice. Also, RipIV increased brain monoamines and their metabolite levels. At the higher dose (100 mg/kg), RipIV increased serotonin concentrations in all studied brain areas, while at the lower one (50 mg/kg), it increased mainly dopamine and noradrenaline levels. When tested with selective receptor antagonists, RipIV antidepressant effect showed dependence of the activation of multiple targets, including D1 and D2 dopamine receptors, 5-HT2A/2, 5-HT3 receptors and α2 adrenergic receptors. Molecular docking demonstrated favorable binding conformation and affinity of RipIV to monoamine oxidase B (MAO-B), serotonin transporter (SERT), α1 receptor, D2 receptor, dopamine transporter (DAT) and at some extent GABA-A receptor. RipIV also presented a computationally predicted favorable pharmacokinetic profile. Therefore, this study demonstrated the involvement of monoaminergic targets in the mechanism of RipIV antidepressant-like action, and provide evidence of it as a promising new antidepressant.

Neuro-Behavioral Profile and Toxicity of the Essential Oil of Dorema ammoniacum Gum as an Anti-seizure, Anti-nociceptive, and Hypnotic Agent with Memory-enhancing Properties in D-Galactose Induced Aging Mice.

In this study, we focused on the neuro-behavioral profile, toxicity, and possible mechanisms of action of Dorema ammoniacum gum essential oil (DAG-EO). For this purpose, passive avoidance and Y-maze tests were performed to evaluate the potential effect of DAG-EO in the attenuation of memory impairment induced by 49 days administration of D-galactose and acute injection of scopolamine. Anticonvulsant and anti-nociceptive activities of DAG-EO were evaluated in the pentylenetetrazole and ‎maximal electroshock-induced models of seizure and acetic acid-induced writhing tests, respectively. To find the possible mechanism of action, flumazenil and naloxone were used. Furthermore, the possible side effects were determined in the open field, grip strength, and ‎rotarod tests. Our findings supported that 7-day administration of DAG-EO (50 and 100 mg/kg) improves memory impairment induced following administration of D-galactose and scopolamine. It was also revealed that DAG-EO possesses a dose-dependent sedative-hypnotic (100 mg/kg), anticonvulsant (ED50 ≈ 170 mg/kg), and anti-nociceptive (ED50 ≈ 175 mg/kg) activities possibly mediated via directly and/or indirectly modulation of GABAA and opioid receptors. No side effect was observed except muscle relaxation which was less than that of diazepam. The output of this study confirms anti-seizure, anti-nociceptive, sedative-hypnotic, and memory-enhancing properties of DAG-EO by modulation of GABAA receptors.