Central Analgesic Effects Research Articles

The role of naloxegol in the management of opioid-induced bowel dysfunction.

Opioid-induced constipation (OIC) and other gastrointestinal (GI) symptoms of opioid-induced bowel dysfunction (OIBD) significantly deteriorate patients' quality of life and may lead to noncompliance with opioid schedule and undertreatment of pain. Although traditional oral laxatives are the first-line treatment of OIC, they do not address OIBD pathophysiology, and display numerous adverse effects. OIC treatment includes prokinetics (lubiprostone), opioid switch, and changing route of opioid administration. Targeted management of OIBD comprises the use of purely peripherally acting μ-opioid receptor antagonists (PAMORA): naloxegol and methylnaltrexone. Naloxegol (NKTR-118) is a polymer conjugate of the opioid antagonist naloxone. The polyethylene glycol limits naloxegol capacity to cross the blood-brain barrier (BBB). Naloxegol is substrate for the P-glycoprotein (P-gp) transporter. The central nervous system penetration of naloxegol is negligible due to reduced permeability and its increased efflux across the BBB, related to P-gp transporter. Naloxegol antagonizes μ- and κ-opioid receptors and displays low affinity to δ-opioid receptors in the GI tract, thereby decreasing OIBD symptoms without reversing central analgesic effects. Naloxegol is metabolised through CYP3A4 to six metabolites, with the majority of the dose (68%) excreted with faeces and less (16%) with urine. The dose of naloxegol equals 25 mg administered orally once daily on a fasting condition. Mild or moderate hepatic impairment has no impact on naloxegol dosing; naloxegol was not studied and is not recommended in patients with hepatic failure. Dose reduction (12.5 mg once daily) and caution is recommended in patients with moderate-to-severe renal impairment. Efficacy (bowel movement in 42-49% of patients not responsive to laxatives) and safety of naloxegol were confirmed in studies conducted in patients with OIC and nonmalignant pain. Naloxegol may be useful for cancer patients with OIC, although studies in this population are lacking.

Study The Analgesic And Anti-Inflammatory Activity Of Zingiber Officinale Rhizome Extract Comparison With Ibuprofen In Male Mice

The aim of the present study was to explore the probable analgesic and anti-inflammatory activity of ethanolic extract of Zingiber officinale by using Hot plate test , acetic acid – induced writhing and Carrageenan induced inflammation in male mice. Thirty Albino male mice (average weight 20g) were used and randomly divided in this study (six animals were used in each groups test for Zingiber officinale in doses of 100, 200 and 300 mg/kg B.W, Ibuprofen 20mg/kg B.W and control ( gave distilled water).The results were expressed as the Mean ±SEM and the statistical significance of differences between groups was analyzed by two Way Analysis of Variance (ANOVA) . The extract showed a significant inhibition of writhing response and increase in hot plate reaction time and also caused significant decrease P<0.05 in paw oedema that induced by Carrageenan comparable with Ibuprofen that standard drugs used. We can conclude from the outcome of the present work that Zingiber officinale extract exert an excellent analgesic and anti-inflammatory effect in the mice and exhibit peripheral and central analgesic effect and anti-inflammatory activity, which may be attributed to the various phytochemicals present in rhizomes of Zingiber officinale .

STIMs and Orai1 regulate cytokine production in spinal astrocytes.

BackgroundOur previous study demonstrated that a store-operated calcium channel (SOCC) inhibitor (YM-58483) has central analgesic effects. However, the cellular and molecular mechanisms of such effects remain to be determined. It is well-known that glial cells play important roles in central sensitization. SOC entry (SOCE) has been implicated in many cell types including cortical astrocytes. However, the role of the SOCC family in the function of astrocytes has not been determined. Here, we thoroughly investigated the expression and the functional significance of SOCCs in spinal astrocytes.MethodsPrimary cultured astrocytes were prepared from neonatal (P2–P3) CD1 mice. Expressions of mRNAs and proteins were respectively assessed by real-time PCR and Western blot analysis. SOCE was measured using a calcium imaging system. Live-cell STIM1 translocation was detected using a confocal microscope. Cytokine levels were measured by the enzyme-linked immunosorbent assay.ResultsWe found that the SOCC family is expressed in spinal astrocytes and that depletion of calcium stores from the endoplasmic reticulum by cyclopiazonic acid (CPA) resulted in a large sustained calcium entry, which was blocked by SOCC inhibitors. Using the siRNA knockdown approach, we identified STIM1 and Orai1 as primary components of SOCCs in spinal astrocytes. We also observed thapsigargin (TG)- or CPA-induced puncta formation of STIM1 and Orai1. In addition, activation of SOCCs remarkably promoted TNF-α and IL-6 production in spinal astrocytes, which were greatly attenuated by knockdown of STIM1 or Orai1. Importantly, knockdown of STIM2 and Orai1 dramatically decreased lipopolysaccharide-induced TNF-α and IL-6 production without changing cell viability.ConclusionsThis study presents the first evidence that STIM1, STIM2, and Orai1 mediate SOCE and are involved in cytokine production in spinal astrocytes. Our findings provide the basis for future assessment of SOCCs in pain and other central nervous system disorders associated with abnormal astrocyte activities.

The Analgesic Effect of Echinophora Platyloba Hydroalcoholic Extract in Male Rats

BACKGROUND AND OBJECTIVES: In traditional Iranian medicine, use of medicinal herbs is prevalent for the treatment and alleviation of pain and inflammation. Echinophora Platyloba is one of the major medicinal herbs with confirmed anti-cancer, anti-microbial, and anti-fungal effects. Therefore, in this study, we aimed to evaluate the analgesic effects of E. platyloba hydroalcoholic extracts in male rats. METHODS: In this experimental study, 42 rats were divided into six groups, i.e., control group, extract groups (80, 100, and 300 mg/kg via intraperitoneal injection), morphine group (1 mg/kg via intraperitoneal injection), and naloxone group (1 mg/kg of naloxone along with 300 mg/kg of the extract). To evaluate the analgesic effects of the extracts, rating, tail flick, and formalin tests were performed. FINDINGS: In the writhing test, doses of 100 and 300 mg/kg of the extracts could decrease the rating score from 43.3±22.61 to 27.31±2.34 (p<0.05) and 29.0±67.91 (p<0.01) in the control group, respectively. In addition, administration of 300 mg/kg of the extract in tail flick test decreased the latency time from 2.84±0.76 to 5.52±1.88 sec in the control group (p<0.05). Moreover, in formalin test, 300 mg/kg of the extract reduced the pain score in both acute and chronic phases from 2.18±0.22 to 0.74±0.13 in the control group (p<0.01). CONCLUSION: According to the present results, E. platyloba hydroalcoholic extracts have central and peripheral analgesic effects.

Biphalin preferentially recruits peripheral opioid receptors to facilitate analgesia in a mouse model of cancer pain - A comparison with morphine

The search for new drugs for cancer pain management has been a long-standing goal in basic and clinical research. Classical opioid drugs exert their primary antinociceptive effect upon activating opioid receptors located in the central nervous system. A substantial body of evidence points to the relevance of peripheral opioid receptors as potential targets for cancer pain treatment. Peptides showing limited blood-brain-barrier permeability promote peripheral analgesia in many pain models. In the present study we examined the peripheral and central analgesic effect of intravenously administered biphalin - a dimeric opioid peptide in a mouse skin cancer pain model, developed by an intraplantar inoculation of B16F0 melanoma cells. The effect of biphalin was compared with morphine - a golden standard in cancer pain management. Biphalin produced profound, dose-dependent and naloxone sensitive spinal analgesia. Additionally, the effect in the tumor-bearing paw was largely mediated by peripheral opioid receptors, as it was readily attenuated by the blood-brain-barrier-restricted opioid receptor antagonist - naloxone methiodide. On the contrary, morphine facilitated its analgesic effect primarily by activating spinal opioid receptors. Both drugs induced tolerance in B16F0 - implanted paws after chronic treatment, however biphalin as opposed to morphine, showed little decrease in its activity at the spinal level. Our results indicate that biphalin may be considered a future alternative drug in cancer pain treatment due to an enhanced local analgesic activity as well as lower tolerance liability compared with morphine.

Xylopia aethiopica fruit extract exhibits antidepressant-like effect via interaction with serotonergic neurotransmission in mice

Ethnopharmacological relevanceXylopia aethiopica has been used traditionally to treat some central nervous system disorders including epilepsy. Aim of the studyDespite the central analgesic and sedative effects, there is little evidence for its traditional use for CNS disorders. This study thus assessed the antidepressant potential of Xylopia aethiopica ethanolic fruit extract (XAE). Material and methodsAntidepressant effect was assessed in the forced swim test (FST) and tail suspension test (TST) models in mice. The role of monoamines in the antidepressant effects of XAE was evaluated by selective depletion of serotonin and noradrenaline, whereas involvement of NMDA/nitric oxide was assessed with NMDA receptor co-modulators; d-serine and d-cycloserine and NOS inhibitor, l-NAME. ResultsXylopia aethiopica (30, 100, 300mgkg−1) dose dependently reduced immobility in both FST and TST. The reduced immobility was reversed after 5-hydroxytryptamine (5-HT) depletion with tryptophan hydroxylase inhibitor—p-chlorophenylalanine (pCPA) and after monoamine depletion with vesicular monoamine transporter inhibitor—reserpine. The observed antidepressant effect was not affected by catecholamine depletion with the tyrosine hydroxylase inhibitor, α-methyl-p-tyrosine (AMPT). Similarly XAE did not potentiate the toxicity of a sub-lethal dose of noradrenaline. XAE had a synergistic effect with the glycineB receptor partial agonist, d-cycloserine and nitric oxide synthase inhibitor, l-NAME. However established antidepressant effects of XAE were abolished by NMDA and NOS activation with d-serine and l-arginine. ConclusionThis study shows that Xylopia aethiopica has antidepressant potential largely due to effects on 5-HT neurotransmission with possible glutamatergic effect through the glycineB co-binding site and nitric oxide synthase inhibition.

Comparative analysis of analgesic and anti-inflammatory activity of bark and leaves of Acacia ferruginea DC.

The aim of the present study was to investigate and compare the analgesic and anti-inflammatory activities of hydroalcoholic extracts of bark and leaves of Acacia ferruginea DC. Hydroalcoholic extracts of bark and leaves were evaluated for analgesic activity using hot plate method and acetic acid-induced writhing test, whereas the anti-inflammatory activity was evaluated by carrageenan-induced paw oedema method. Hydroalcoholic extract of the bark at the dose of 50 mg/kg (6.10 ± 0.30) and leaves at a dose of 100 mg/kg (5.72 ± 0.39) after 45 min exhibited significant (P < 0.001) analgesic activity in hot plate test, which was comparable to Tramadol (6.11 ± 0.31) at a dose of 10 mg/kg. However, in acetic acid-induced writhing test, hydroalcoholic extract of both bark (90%) and leaves (90.91%) showed maximum protection from acetic acid at the dose of 100 mg/kg as compared to standard drug (50.91%) at a dose of 5 mg/kg. In the evaluation of anti-inflammatory activity, hydroalcoholic extract of leaves at a dose of 400 mg/kg had significantly (74.68%) inhibited the inflammation as comparable to indomethacin (82.8%) after 3 h of induction of carrageenan. It is concluded that hydroalcoholic extracts of bark and leaves have central analgesic and peripheral analgesic effects, respectively. Both hydroalcoholic extracts of the bark and leaves significantly reduced the paw oedema at a dose of 400 mg/kg and exhibited anti-inflammatory activity.

Lidocaine Inhibits HCN Currents in Rat Spinal Substantia Gelatinosa Neurons

Lidocaine, which blocks voltage-gated sodium channels, is widely used in surgical anesthesia and pain management. Recently, it has been proposed that the hyperpolarization-activated cyclic nucleotide (HCN) channel is one of the other novel targets of lidocaine. Substantia gelatinosa in the spinal dorsal horn, which plays key roles in modulating nociceptive information from primary afferents, comprises heterogeneous interneurons that can be electrophysiologically categorized by firing pattern. Our previous study demonstrated that a substantial proportion of substantia gelatinosa neurons reveal the presence of HCN current (Ih); however, the roles of lidocaine and HCN channel expression in different types of substantia gelatinosa neurons remain unclear. By using the whole-cell patch-clamp technique, we investigated the effect of lidocaine on Ih in rat substantia gelatinosa neurons of acute dissociated spinal cord slices. We found that lidocaine rapidly decreased the peak Ih amplitude with an IC50 of 80 μM. The inhibition rate on Ih was not significantly different with a second application of lidocaine in the same neuron. Tetrodotoxin, a sodium channel blocker, did not affect lidocaine's effect on Ih. In addition, lidocaine shifted the half-activation potential of Ih from -109.7 to -114.9 mV and slowed activation. Moreover, the reversal potential of Ih was shifted by -7.5 mV by lidocaine. In the current clamp, lidocaine decreased the resting membrane potential, increased membrane resistance, delayed rebound depolarization latency, and reduced the rebound spike frequency. We further found that approximately 58% of substantia gelatinosa neurons examined expressed Ih, in which most of them were tonically firing. Our studies demonstrate that lidocaine strongly inhibits Ih in a reversible and concentration-dependent manner in substantia gelatinosa neurons, independent of tetrodotoxin-sensitive sodium channels. Thus, our study provides new insight into the mechanism underlying the central analgesic effect of the systemic administration of lidocaine.

Evaluation of analgesic and antipyretic activities of Mahanimba (Melia azedarach Linn.) leaf and root powder.

Introduction:Mahanimba (Melia azedarach Linn.) is a deciduous tree of family Meliaceae and its root is mainly used in painful condition such as Gridhrasi (sciatica) in Ayurveda. Ethnomedicinal claims indicate that its leaves are used to treat fever, but its medicinal activities have not been proven by research.Aim:This study was aimed to evaluate the potential analgesic and antipyretic activities of M. azedarach L. leaf powder (MLP) and M. azedarach L. root powder (MRP).Materials and Methods:The root and leaves of M. azedarach were made into powder using guidelines mentioned in the Ayurvedic Pharmacopoeia of India. The analgesic activity of the test drugs was evaluated against acetic acid-induced writhing test in mice and radiant heat-induced pain in albino rats, and antipyretic activity was evaluated against Brewer’s yeast-induced pyrexia using Charles Foster rats.Results:In acetic acid induced writhing in mice, the test drugs MRP (1.3mg/kg) exhibit insignificant reduction in writhing reflex while MLP (1.3mg/kg) did not show any significant effect in comparison to the control group. MRP showed mild-to-moderate insignificant increase in latency of withdrawal response at 60 (26.74%) and 120 min (27.25%), while MLP did not show central analgesic effect in radiant heat model in rats. MRP showed a significant reduction in rectal temperature after 3 and 6 h, while MLP-treated group showed significant reduction after 6 h.Conclusion:MRP has mild-to-moderate peripheral and central analgesic effects, while MLP has not shown significant analgesic effects in both the experimental models. MRP has more pronounced antipyretic effect compared to MLP.

The Central Analgesic Mechanism of YM-58483 in Attenuating Neuropathic Pain in Rats.

Calcium channel antagonists are commonly used to treat neuropathic pain. Their analgesic effects rely on inhibiting long-term potentiation, and neurotransmitters release in the spinal cord. Store-operated Ca(2+)channels (SOCCs) are highly Ca(2+)-selective cation channels broadly expressed in non-excitable cells and some excitable cells. Recent studies have shown that the potent inhibitor of SOCCs, YM-58483, has analgesic effects on neuropathic pain, but its mechanism is unclear. This experiment performed on spinal nerve ligation (SNL)-induced neuropathic pain model in rats tries to explore the mechanism, whereby YM-58483 attenuates neuropathic pain. The left L5 was ligated to produce the SNL neuropathic pain model in male Sprague-Dawley rats. The withdrawal threshold of rats was measured by the up-down method and Hargreaves' method before and after intrathecal administration of YM-58483 and vehicle. The SOCCs in the spinal dorsal horn were located by immunofluorescence. The expression of phosphorylated ERK and phosphorylated CREB, CD11b, and GFAP proteins in spinal level was tested by Western blot, while the release of proinflammatory cytokines (IL-1β, TNF-α, PGE2) was measured by enzyme-linked immunosorbent assay (ELISA). Intrathecal YM-58483 at the concentration of 300μM (1.5nmol) and 1000μM (10nmol) produced a significant central analgesic effect on the SNL rats, compared with control+vehicle (n=7, P<0.001). However, both could not prevent the development of neuropathic pain, compared with normal+saline (P<0.001). Immunofluorescent staining revealed that Orai1 and STIM1 (the two key components of SOCCs) were located in the spinal dorsal horn neurons. Western blot showed that YM-58483 could decrease the levels of P-ERK and P-CREB (n=10, #P<0.05), without affecting the expression of CD11b and GFAP (n=10, #P>0.05). YM-58483 also inhibited the release of spinal cord IL-1β, TNF-α, and PGE2, compared with control+vehicle (n=5, #P<0.001). The analgesic mechanism of YM-58483 may be via inhibiting central ERK/CREB signaling in the neurons and decreasing central IL-1β, TNF-α, and PGE2 release to reduce neuronal excitability in the spinal dorsal horn of the SNL rats.

Phytochemicals, antioxidant, antinociceptive and anti-inflammatory potential of the aqueous extract of Teucrium stocksianum bioss

BackgroundDespite availability of a substantial number of potent synthetic drugs, medicinal plants are still playing a key role in the discovery of novel and effective drug molecules. Numerous researchers are focusing on the plant based medicines due to its strong safety profiles. Teucrium species exhibit profound antidiabetic, analgesic and spasmolytic activities. The methanolic extract and essential oil of Teucrium stocksianum possess strong antinociceptive activity. The aim of the current research study was to determine the phytochemicals, antioxidant, analgesic and anti-inflammatory potential of the aqueous extract of Teucrium stocksianum Bioss (AETS).MethodPhytochemical screening was carried out according to standard procedures. The antioxidant potential of the extract was ascertained with the stable organic free radical (2, 2-diphenyl-1-picryl-hydrazyl). Three different pain models, including acetic acid induced writhing, formalin induced paw licking and tail immersion tests were carried out for the determination of antinociceptive potential, while the anti-inflammatory activity was evaluated through carrageenan induced paw edema test in mice. The antinociceptive and anti-inflammatory potentials of AETS were assessed at 100, 200 and 300 mg/kg body weight, while acute toxicity were observed at 1500 mg/kg body weight in various groups of mice.ResultsPhytochemical screening has shown the occurrence of flavonoids saponins, reducing sugars, terpenoids and tannins. AETS exhibited profound antioxidant activity and has shown maximum activity (60.06 ± 0.846) at 250 μg/ml. In the three pain models AETS displayed marked dose dependent antinociceptive potential. AETS exhibited 63.5, 67.61 and 64 % activity in acetic acid induced, formalin induced paw licking and tail immersion tests respectively. The antinociceptive effect of AETS and reference standard drug TramadolR was significantly reversed by Naloxone, endorsed the central analgesic potential of AETS. Similarly the extract also reversed the paw edema in dose dependent manner. AETS displayed significant (53.81 %) anti-inflammatory effects at a dose of 300 mg/kg that persisted till 5th h. In acute toxicity test AETS was found safe at 1500 mg/kg body weight.ConclusionsAETS exhibited profound antioxidant activity. The test sample displayed marked antinociceptive potential in all the test procedures, indicating the peripheral and central analgesic effects of AETS. The plant extract also displayed marked anti-inflammatory activity at all test doses.

Analgesic and Antiinflammatory Activities of the Essential Oil of the Unique Plant Zhumeria majdae

The analgesic and anti-inflammatory properties of Zhumeria majdae essential oil were investigated in mice and rats. The analgesic activity of the oil was assessed by acetic acid-induced writhing and Eddy's hot plate methods while the acute anti-inflammatory effect was investigated by inflammatory paw edema in rat. Z majdae oil significantly decreased the number of acetic acid-induced writhes in mice compared with animals that received vehicle only. Also it exhibited a central analgesic effect as evidenced by a significant increase in reaction time in the hot plate method. The oil also significantly reduced carrageenan induced paw edema in rats. The inhibitory activity of Z. majdae essential oil was found to be very close to that of the standard drug, diclofenac sodium (50 mg/kg). The studied oil was analyzed by GC and GC-MS and seventeen constituents were identified, representing 99.2% of the oil. The major components of the oil were characterized as linalool (63.4%) and camphor (27.5%), which might be responsible for these observed activities. The results suggest that Z. majdae essential oil possesses biologically active constituent(s) that have significant activity against acute inflammation and have central and peripheral antinociceptive effects which support the ethnomedicinal claims of the plant application in the management of pain and inflammation.

Analgesic and anti-inflammatory activities of Citrus aurantium L. blossoms essential oil (neroli): involvement of the nitric oxide/cyclic-guanosine monophosphate pathway.

The analgesic and anti-inflammatory properties of Citrus aurantium L. blossoms essential oil (neroli) were investigated in mice and rats. The analgesic activity of neroli was assessed by acetic acid-induced writhing and Eddy's hot plate methods, while acute and chronic anti-inflammatory effects were investigated by inflammatory paw edema in rat and the cotton pellet-induced granuloma tissue model, respectively. Mechanistic studies were conducted using L-nitro arginine methyl ester (L-NAME), an inhibitor of NO synthase. Neroli significantly decreased the number of acetic acid-induced writhes in mice compared to animals that received vehicle only. Also, it exhibited a central analgesic effect, as evidenced by a significant increase in reaction time in the hot plate method. The oil also significantly reduced carrageenan-induced paw edema in rats. The inhibitory activity of neroli (especially at 40mg/kg) was found to be very close to the standard drug, diclofenac sodium (50mg/kg). In cotton pellet-induced granuloma, neroli was effective regarding the transudate and granuloma formation amount. Neroli was analyzed by gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS) and twenty-three constituents, representing 91.0% of the oil, were identified. The major components of neroli were characterized as linalool (28.5%), linalyl acetate (19.6%), nerolidol (9.1%), E,E-farnesol (9.1%), α-terpineol (4.9%), and limonene (4.6%), which might be responsible for these observed activities. The results suggest that neroli possesses biologically active constituent(s) that have significant activity against acute and especially chronic inflammation, and have central and peripheral antinociceptive effects which support the ethnomedicinal claims of the use of the plant in the management of pain and inflammation.

Organ-specific Microcirculatory Mass Transport of Oxycodone in Humans

To begin to address the problem of heterogeneity of distribution of oxycodone (OC) in humans, we developed an organ-specific microcirculatory capillary-tissue exchange 2-compartment model for studying regional OC mass transport. The model was developed in silico. It quantifies OC's organ-specific mass transport rates, clearances and recycling, and it considers the effects of blood flow on OC's convective and diffusive transport. What is new is the finding that OC undergoes local recycling at the level of organ-specific capillary-tissue exchange units in humans. Results indicate recycled OC occurs in sufficient amounts to function as a reusable source of circulating OC; which has important implications for OC dosing. Results show the brain, which is central to OC effects only receives about 8% of OC delivered to all organs via the microcirculation. This suggests that differential regulation of receptor binding, trafficking, internalization, or desensitization in the brain likely plays a dominant role in OC's central analgesic effects. Organ-specific OC mass transport kinetics provide new information for OC dosing in pain management. The model promotes patient safety in opioid prescribing because it allows predictions to be made about the relative contribution that OC recycling makes to circulating OC levels. The model indicates that pharmacologic modulation of the microcirculation may give way to site-specific delivery of opioids in the future. Our study demonstrates that translation of bench in silico research data into clinical practice, although still challenging, is feasible and can assist in OC dose regimen design for patient safety.

Phytochemical Constituents and Analgesic Activity of Ethyl Acetate Fraction of Punicagranatum L (Punicaceae)

Purpose: To investigate the active fraction of pomegranate fruit extract and screen it for analgesic activity.Methods: The analgesic activity of pomegranate ethyl acetate fraction (EtOAc) was examined using three models of pain: writhing, hot tail flick and plantar tests. EtOAc was administered by oral gavage in doses of 100, 150 and 200 mg/kg, p.o., for all the tests and compared to aspirin (100 mg/kg, p.o.) which was used as standard drug. Phytochemical studies of EtOAc were carried out by high performance liquid chromatography (HPLC) with ultraviolet (UV) detection and mass spectrometry (MS).Results: In the writhing test, the index of pain inhibition (IPI) was 41 % for EtOAc (200 mg/kg, p.o.) and 56 % for aspirin. In the hot tail flick test, EtOAc (200 mg/kg, p.o.) showed analgesia reaching its peak at 60 min with maximum possible analgesia (MPA) of 30.5 %, compared with 43.8 % for aspirin. Plantar test showed that pain was reduced by EtOAc in a dose-dependent manner and compared well with aspirin at 100 mg/kg, p.o., dose. The 200 mg/kg dose showed the highest effect, prolonging withdrawal latency in the left hind paw to 11.9 ± 0.3 compared to aspirin with 13.4 ± 0.2 (p &lt; 0.001). HPLC analysis of EtOAc revealed the presence of gallic acid, ellagic acid and punicalagins A &amp; B. Confirmation of their structures was achieved by mass spectroscopy.Conclusion: EtOAc has a central and peripheral analgesic effect that is most likely due to the presence of gallic acid and ellagic acid.Keywords: Analgesia, Pomegranate, Gallic acid, Ellagic acid, Punicalagins, Phytochemical constituents

Analgesic, Antipyretic and Anti-inflammatory Activities of the Egyptian Spitting Cobra; Naja nubiae Venom

Objectives: Although many venomous snakes represent a potential human health threat, their venoms provide a rich source of active components, many of which have been recently identified, and used as potential candidates for pharmacological therapeutic purposes. The current study was designed to evaluate the analgesic, antipyretic and antiinflammatory activities of the Egyptian spitting cobra Naja nubiae venom. Methods: The venom of N. nubiae was intraperitoneally injected at two dose levels (1/10 and 1/5 LD50). The peripheral and central analgesic effects were examined using acetic acidinduced abdominal writhing in mice and tail immersion test in rats, respectively. Brewer’s yeast-induced pyrexia in rats was carried out to determine the antipyretic activity of the same doses, whereas the anti-inflammatory activity was tested using carrageenan-induced paw edema in mice. Results: The results showed that N. nubiae venom produced a significant analgesic activity in acetic acid-induced abdominal constriction response in mice and thermal nociception in rat. Moreover, the venom revealed a significant antipyretic effect on yeast-induced pyrexia. In paw edema, venom exhibited a significant activity with a maximum percentage of inhibition reaching 60.1% on both doses after 5 hour treatment, which was more powerful when compared with the standard drug; diclofenac sodium (38.6%). Histologically, the venom induced a moderate inflammatory cells infiltration in the dermis of paw. Conclusion: These results suggest potential analgesic, antipyretic, and anti-inflammatory activities of the Egyptian spitting cobra crude venom.

Evaluation of peripheral and central analgesic activity of ethanolic extract of Clerodendrum infortunatum Linn. in experimental animals

Background: Clerodendrum infortunatum Linn. (Verbenaceae) is an important and widely used medicinal plant. Though variously used in Ayurveda, Unani, and Homeopathy system of medicine in the case of ailments such as diarrhoea, skin disorders, venereal and scrofulous complaints, wounds, post-natal complications, as anti-helminthic, and external applications on tumors, the plant needs thorough investigation for its specific medicinal activity. This study evaluates both the central and peripheral analgesic effect of the ethanolic extract of the leaves of C. infortunatum Linn. (EECI) in the experimental animals. Methods: Acute toxicity test was done following the Organization of Economic Co-operation and Development guidelines. EECI (100 mg/kg, 200 mg/kg, and 400 mg/kg body weight [b.w.] p.o) was evaluated for central analgesic activity by the tail flick method and peripheral analgesic activity by the acetic acid (0.7%) induced writhing test, respectively. Using aspirin (300 mg/kg b.w. and 100 mg/kg b.w.) as the standard drug. Results: EECI significantly decreased the number of writhing in writhing test at all the doses (p&lt;0.01) and increased the reaction time in tail-flick method (p&lt;0.01) at all the doses. EECI in the dosage of 400 mg/kg b.w. produced effects which was comparable with that of the standard drug aspirin (p&lt;0.001) in writhing test (p&lt;0.001) and tail flick method (p&lt;0.001). Conclusion: The study showed significant central and peripheral analgesic activity of EECI which may be attributed to the inhibition of prostaglandin synthesis, phospholipase A2, and tumor necrosis factor alpha. C. infortunatum Linn. as a commercial source of analgesic drug should be subjected to further research.

Proximate analysis, phytochemical screening, and bioactivities evaluation of Cissus rotundifolia (Forssk.) Vahl. (Fam. Vitaceae) and Sansevieria cylindrica Bojer ex Hook. (Fam. Dracaenaceae) growing in Egypt

Objectives This work aimed to carry out a proximate analysis, phytochemical screening, and bioactivities evaluation of the nonflowering aerial parts of each of Cissus rotundifolia (Forssk.) Vahl. (Fam. Vitaceae) and S. cylindrica Bojer ex Hook. (Fam. Dracaenaceae) growing in Egypt. Materials and methods The total phenolic contents (TPC) and total flavonoid contents were estimated spectrophotometrically. The oral acute toxicity of each of the two plant extracts was evaluated. Analgesic activities of both plants were evaluated using hot plate and writhing test using indomethacin as a reference drug. Anti-inflammatory activities were evaluated using carrageenan-induced rat-paw edema. Antiulcerative activities were measured using indomethacin-induced ulcer in pyloric-ligated rats. Thioacetamide-induced acute hepatic encephalopathy was used to evaluate the hepatoprotective effects of the plants. Results and conclusion Proximate analysis of air-dried nonflowering aerial parts of each of C. rotundifolia and S. cylindrica yielded a moisture content of 7.95 and 7.52%, total ash of 8.35 and 9.83%, water-soluble ash of 3.96 and 2.94%, acid-insoluble ash of 2.14 and 3.42%, crude fiber content of 8.52 and 13.43%, and methanolic extractive value of 41 and 35%, respectively. Phytochemical analysis of C. rotundifolia extract indicated the presence of triterpenes, carbohydrates, and/or glycosides, tannins, flavonoids, coumarins, and saponins, whereas S. cylindrica extract showed the presence of sterols, carbohydrates, and/or glycosides, flavonoids, coumarins, and saponins. Total phenolic content of C. rotundifolia and S. cylindrica were 3.18 and 4.82 mg (GAE)/g, respectively, whereas total flavonoid contents of C. rotundifolia and S. cylindrica were 1.35 and 4.13 mg (QE)/g plant dry weight, respectively. Both extracts showed no toxicity up to 1 g/kg body weight. Both methanolic extracts showed significant central and peripheral analgesic effects. C. rotundifolia extract showed percentages of edema inhibition higher than or equal to the reference drug indomethacin in carrageenan-induced paw edema assay, whereas S. cylindrica extract showed percentages of edema inhibition less than that of the reference drug indomethacin. In the ulcer model induced by indomethacin, the groups pretreated with both plants received significant protection against ulcer formation. In the thioacetamide-induced acute hepatopathic encephalopathy model, rats treated with S. extract showed significant improvement in their plasma AST and ALT, whereas rats treated with C. rotundifolia extract showed increased levels of their ALT and AST.

Opioid-induced respiratory depression: ABCB1 transporter pharmacogenetics

Opioid-related respiratory depression (RD) is a serious clinical problem as it causes multiple deaths and anoxic brain injuries. Morphine is subject to efflux via P-glycoprotein transporter encoded by ABCB1, also known as MDR1. ABCB1 polymorphisms may affect blood-brain barrier transport of morphine and therefore individual response to its central analgesic and adverse effects. This study aimed to determine specific associations between common ABCB1 genetic variants and clinically important outcomes including RD and RD resulting in prolonged stay in hospital with intravenous morphine in a homogenous pediatric surgical pain population of 263 children undergoing tonsillectomy. Children with GG and GA genotypes of ABCB1 polymorphism rs9282564 had higher risks of RD resulting in prolonged hospital stays; adding one copy of the minor allele (G) increased the odds of prolonged hospital stay due to postoperative RD by 4.7-fold (95% confidence interval: 2.1-10.8, P=0.0002).

First evidence of the analgesic activity of govaniadine, an alkaloid isolated from Corydalis govaniana Wall.

In this work, govaniadine, an alkaloid isolated from Corydalis govaniana Wall. was evaluated for its analgesic activity by writhing and hot-plate tests. Govaniadine did not display any toxic effects in mice up to 20 mg/kg during 24 h assessment study. The acetic acid-induced writhing was significantly reduced by pretreatment with govaniadine in a dose-dependent manner (1.25–5.0 mg/kg, intraperitoneally (i.p.)). Furthermore, molecular docking study has shown that this alkaloid binds the COX-2 enzyme. In the hot-plate test, govaniadine at dose of 2.5 and 5 mg/kg, i.p. displayed analgesic effect at all time points (30, 60, 90 and 120 min). The analgesic effect of govaniadine was significantly antagonised by naloxone administration. Our results demonstrate for the first time that the peripheral and central analgesic effects of govaniadine could be in part related to the involvement of COX-2 activity and by its interaction with the opioid system.