scholarly journals Newly Discovered Action of HpTx3 from Venom of Heteropoda venatoria on Nav1.7 and Its Pharmacological Implications in Analgesia

Toxins ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 680
Author(s):  
Xinzhou Wu ◽  
Zhouquan Wang ◽  
Yu Chen ◽  
Dehong Xu ◽  
Peng Zhang ◽  
...  
Keyword(s):  
Voltage Dependence ◽  
Molecular Probe ◽  
Dependent Manner ◽  
Hot Plate ◽  
Current Voltage ◽  
Pain Models ◽  
Steady State Inactivation ◽  
Relationship Of ◽  
Dose Dependent ◽  
Pore Blocker

It has been reported that Heteropodatoxin3 (HpTx3), a peptidic neurotoxin purified from the venom of the spider species Heteropoda venatoria, could inhibit Kv4.2 channels. Our present study newly found that HpTx3 also has potent and selective inhibitory action on Nav1.7, with an IC50 of 135.61 ± 12.98 nM. Without effect on the current–voltage (I-V) relationship of Nav1.7, HpTx3 made minor alternation in the voltage-dependence of activation and steady-state inactivation of Nav1.7 (4.15 mV and 7.29 mV, respectively) by interacting with the extracellular S3–S4 loop (S3b–S4 sequence) in domain II and the domain IV of the Nav channel subtype, showing the characteristics of both pore blocker and gate modifier toxin. During the interaction of HpTx3 with the S3b–S4 sequence of Nav1.7, the amino acid residue D in the sequence played a key role. When administered intraperitoneally or intramuscularly, HpTx3 displayed potent analgesic activity in a dose-dependent manner in different mouse pain models induced by formalin, acetic acid, complete Freund’s adjuvant, hot plate, or spared nerve injury, demonstrating that acute, inflammatory, and neuropathic pains were all effectively inhibited by the toxin. In most cases HpTx3 at doses of ≥ 1mg/kg could produce the analgesic effect comparable to that of 1 mg/kg morphine. These results suggest that HpTx3 not only can be used as a molecular probe to investigate ion channel function and pain mechanism, but also has potential in the development of the drugs that treat the Nav1.7 channel-related pain.

scholarly journals Characterization of receptors mediating the actions of dopamine on an identified inhibitory motoneurone of the cockroach

1991 ◽  
Vol 155 (1) ◽  
pp. 203-217 ◽  
Author(s):  
J. P. Davis ◽  
R. M. Pitman
Keyword(s):  
Periplaneta Americana ◽  
Voltage Dependence ◽  
Negative Resistance ◽  
Membrane Potentials ◽  
Dopaminergic Agonists ◽  
Current Voltage ◽  
Voltage Dependent ◽  
Inward Currents ◽  
Ly 171555 ◽  
Relationship Of

1. The effects of a number of dopaminergic agonists and antagonists upon the soma of a prothoracic inhibitory motoneurone of the cockroach (Periplaneta americana) have been recorded under voltage-clamp conditions. 2. Dopamine generates inward currents that are extremely voltage-dependent: currents increase rapidly at membrane potentials more negative than about −120 to −150 mV and also show a peak at membrane potentials of approximately −20 mV. As a result of this voltage-dependence, dopamine induces a region of negative resistance in the current-voltage relationship of the neurone. 3. The dopaminergic agonists apomorphine, bromocriptine, ergometrine and A-6,7-DTN mimic the action of dopamine on this neurone, all having a similar voltage-dependence to that of dopamine. The selective D-1 receptor agonist SK&F82526 and the D-2 agonist LY 171555, however, were both inactive on the preparation. 4. Responses to dopamine were suppressed by a number of D-1 and D-2 receptor antagonists, indicating that the pharmacological profile of the dopamine-sensitive receptor in this insect preparation is different from that of vertebrate dopamine receptors.

scholarly journals RAPHANUS SATIVUS LINN. A NEW ANTINOCICEPTIVE FOR DIABETIC NEUROPATHY IN RATS DETERMINED BY RANDALL SELITTO APPROACH

2019 ◽  
pp. 529-534
Author(s):  
SAMBIT KUMAR SAHOO ◽  
STHITAPRAGNYA PANDA
Keyword(s):  
Sciatic Nerve ◽  
Raphanus Sativus ◽  
Diabetic Control ◽  
Nerve Degeneration ◽  
Control Group ◽  
Histopathological Analysis ◽  
Dependent Manner ◽  
Hot Plate ◽  
End Of Treatment ◽  
Dose Dependent

Objective: The objective of the study was to evaluate the antinociceptive effect of Raphanus sativus Linn. using Randall Selitto method. Methods: Streptozotocin, lard, casein, cholesterol, DL-methionine, yeast powder, quercetin, thiobarbituric acid, 2-nitrobenzoic acid (5, 5, Dithiobis), hematoxylin, and hydrogen peroxide were used. A diet rich in fat content was fed to the animals for a period of 2 weeks. After a stabilization period of 2weeks, the treatment period started and continued for a period of 8weeks. The nociceptive parameters were assessed once a week by Randall Selitto method and hot plate test. After treatment, the animals were sacrificed, and antioxidant parameters were assessed using sciatic nerve homogenate and histopathological analysis of sciatic nerve. Results: Treatment R. sativus extract (RSE 100 mg/kg and 200 mg/kg) appreciably declined the levels of blood glucose in a dose-dependent manner, and it was comparable with standard quercetin. A significant increase in pain threshold levels was observed by the treatment RSE in hot plate method after the 4th week compared to diabetic control, and it was consistent until the end of treatment (p<0.01, p<0.001). In Randall Selitto method RSE produced a significant increase in paw withdrawal threshold after the 4th week compared to diabetic control, and it was consistently increased until the end of treatment. RSE (100 and 200 mg/kg) significantly restored the levels of antioxidant enzymes and decreased lipid peroxidation in a dose-dependent fashion in comparison with the diabetic control group. RSE (100 mg/kg and 200 mg/kg) attenuated the nerve degeneration and axonal swelling along with quercetin. Conclusion: The findings from the current study showed the antinociceptive and antioxidant effect of R. sativus in neuropathic pain in diabetes.

Nitrous Oxide Revisited

2005 ◽  
Vol 103 (4) ◽  
pp. 845-854 ◽  
Author(s):  
Philippe Richebé ◽  
Cyril Rivat ◽  
Cyril Creton ◽  
Jean-Paul Laulin ◽  
Pierre Maurette ◽  
...  
Keyword(s):  
Nitrous Oxide ◽  
Morphine Tolerance ◽  
Acute Tolerance ◽  
Dependent Manner ◽  
Analgesic Effects ◽  
Pain Models ◽  
Opioid Induced Hyperalgesia ◽  
Incisional Pain ◽  
Fentanyl Administration ◽  
Dose Dependent

Background Although opioids are unsurpassed analgesics for surgery, they also induce an N-methyl-D-aspartate-dependent enhancement of postoperative hyperalgesia. Because nitrous oxide (N2O) has anti-N-methyl-D-aspartate properties, the purpose of this study was to evaluate nitrous oxide ability to prevent such an opioid-induced hyperalgesia in rats. Methods First, preventive effects of 50/50% N2O-O2 on the development of delayed hyperalgesia observed after inflammatory pain (hind paw carrageenan injection on D0) were examined for several days. Second, the ability of nitrous oxide (10-40%) to limit opioid-induced hyperalgesia induced by fentanyl was evaluated in nonsuffering rats. Third, antihyperalgesic effects of various nitrous oxide concentrations (20-50%) were assessed in both inflammatory and incisional pain models in fentanyl-treated rats (4 x 100 microg/kg subcutaneously). Finally, the analgesic effect of a single dose of morphine was evaluated 24 h after fentanyl administration and nitrous oxide (D0) to assess its preventive effect on acute morphine tolerance in both nonsuffering and hind paw-incised rats. Results When applied on D0, nitrous oxide reduced delayed hyperalgesia induced by inflammation. Exposure to nitrous oxide on D0 also reduced opioid-induced hyperalgesia in nonsuffering rats in a dose-dependent manner. In fentanyl-treated rats with inflammatory or incisional pain, nitrous oxide strongly limited both magnitude and duration of hyperalgesia. Moreover, nitrous oxide exposure on D0 opposed development of acute tolerance to analgesic effects of morphine administered on D1 in both nonsuffering and incised fentanyl-treated rats. Conclusions Nitrous oxide, an N-methyl-D-aspartate receptor antagonist, prevented the enhancement of pain sensitivity induced by both nociceptive inputs and fentanyl and opposed acute morphine tolerance. Results suggest that perioperative nitrous oxide use reduces exaggerated postoperative pain and morphine consumption.

scholarly journals Biophysical Characterization of Epigallocatechin-3-Gallate Effect on the Cardiac Sodium Channel Nav1.5

Molecules ◽  
2020 ◽  
Vol 25 (4) ◽  
pp. 902 ◽  
Author(s):  
Mohamed-Yassine Amarouch ◽  
Han Kurt ◽  
Lucie Delemotte ◽  
Hugues Abriel
Keyword(s):  
Md Simulations ◽  
Inactivation Kinetics ◽  
Free Energy Barrier ◽  
Dependent Manner ◽  
Biophysical Characterization ◽  
Inactivation Curve ◽  
Cardiac Sodium Channel ◽  
Dependent Inhibition ◽  
Steady State Inactivation ◽  
Dose Dependent

Epigallocatechin-3-Gallate (EGCG) has been extensively studied for its protective effect against cardiovascular disorders. This effect has been attributed to its action on multiple molecular pathways and transmembrane proteins, including the cardiac Nav1.5 channels, which are inhibited in a dose-dependent manner. However, the molecular mechanism underlying this effect remains to be unveiled. To this aim, we have characterized the EGCG effect on Nav1.5 using electrophysiology and molecular dynamics (MD) simulations. EGCG superfusion induced a dose-dependent inhibition of Nav1.5 expressed in tsA201 cells, negatively shifted the steady-state inactivation curve, slowed the inactivation kinetics, and delayed the recovery from fast inactivation. However, EGCG had no effect on the voltage-dependence of activation and showed little use-dependent block on Nav1.5. Finally, MD simulations suggested that EGCG does not preferentially stay in the center of the bilayer, but that it spontaneously relocates to the membrane headgroup region. Moreover, no sign of spontaneous crossing from one leaflet to the other was observed, indicating a relatively large free energy barrier associated with EGCG transport across the membrane. These results indicate that EGCG may exert its biophysical effect via access to its binding site through the cell membrane or via a bilayer-mediated mechanism.

scholarly journals Voltage-dependent inactivation of slow calcium channels in intact twitch muscle fibers of the frog.

1989 ◽  
Vol 94 (5) ◽  
pp. 937-951 ◽  
Author(s):  
G Cota ◽  
E Stefani
Keyword(s):  
Steady State ◽  
Rate Constant ◽  
Voltage Dependence ◽  
Muscle Fibers ◽  
Dependent Manner ◽  
Inactivation Curve ◽  
Voltage Dependent ◽  
Steady State Inactivation ◽  
Intact Muscle ◽  
Ca2 Channels

Inactivation of slow Ca2+ channels was studied in intact twitch skeletal muscle fibers of the frog by using the three-microelectrode voltage-clamp technique. Hypertonic sucrose solutions were used to abolish contraction. The rate constant of decay of the slow Ca2+ current (ICa) remained practically unchanged when the recording solution containing 10 mM Ca2+ was replaced by a Ca2+-buffered solution (126 mM Ca-maleate). The rate constant of decay of ICa monotonically increased with depolarization although the corresponding time integral of ICa followed a bell-shaped function. The replacement of Ca2+ by Ba2+ did not result in a slowing of the rate of decay of the inward current nor did it reduce the degree of steady-state inactivation. The voltage dependence of the steady-state inactivation curve was steeper in the presence of Ba2+. In two-pulse experiments with large conditioning depolarizations ICa inactivation remained unchanged although Ca2+ influx during the prepulse greatly decreased. Dantrolene (12 microM) increased mechanical threshold at all pulse durations tested, the effect being more prominent for short pulses. Dantrolene did not significantly modify ICa decay and the voltage dependence of inactivation. These results indicate that in intact muscle fibers Ca2+ channels inactivate in a voltage-dependent manner through a mechanism that does not require Ca2+ entry into the cell.

scholarly journals Extracellular Ca2+ Modulates the Effects of Protons on Gating and Conduction Properties of the T-type Ca2+ Channel α1G (CaV3.1)

2003 ◽  
Vol 121 (6) ◽  
pp. 511-528 ◽  
Author(s):  
Karel Talavera ◽  
Annelies Janssens ◽  
Norbert Klugbauer ◽  
Guy Droogmans ◽  
Bernd Nilius
Keyword(s):  
Voltage Dependence ◽  
Hek293 Cells ◽  
Voltage Sensitivity ◽  
Dependent Manner ◽  
Surface Charges ◽  
Extracellular Acidification ◽  
Activation Curve ◽  
Steady State Inactivation ◽  
Slope Factor ◽  
Ph Range

Since Ca2+ is a major competitor of protons for the modulation of high voltage–activated Ca2+ channels, we have studied the modulation by extracellular Ca2+ of the effects of proton on the T-type Ca2+ channel α1G (CaV3.1) expressed in HEK293 cells. At 2 mM extracellular Ca2+ concentration, extracellular acidification in the pH range from 9.1 to 6.2 induced a positive shift of the activation curve and increased its slope factor. Both effects were significantly reduced if the concentration was increased to 20 mM or enhanced in the absence of Ca2+. Extracellular protons shifted the voltage dependence of the time constant of activation and decreased its voltage sensitivity, which excludes a voltage-dependent open pore block by protons as the mechanism modifying the activation curve. Changes in the extracellular pH altered the voltage dependence of steady-state inactivation and deactivation kinetics in a Ca2+-dependent manner, but these effects were not strictly correlated with those on activation. Model simulations suggest that protons interact with intermediate closed states in the activation pathway, decreasing the gating charge and shifting the equilibrium between these states to less negative potentials, with these effects being inhibited by extracellular Ca2+. Extracellular acidification also induced an open pore block and a shift in selectivity toward monovalent cations, which were both modulated by extracellular Ca2+ and Na+. Mutation of the EEDD pore locus altered the Ca2+-dependent proton effects on channel selectivity and permeation. We conclude that Ca2+ modulates T-type channel function by competing with protons for binding to surface charges, by counteracting a proton-induced modification of channel activation and by competing with protons for binding to the selectivity filter of the channel.

scholarly journals Anti-arthralgic activity of the n-hexane extract (HTp) of yellow oleander seeds; Thevetia peruviana (Pers.) K. Schum

2021 ◽  
Author(s):  
Joy Ifunanya Odimegwu ◽  
Fatiha Oyebola Olabisi
Keyword(s):  
Scientific Evidence ◽  
Positive Control ◽  
Test Subject ◽  
Dependent Manner ◽  
Thevetia Peruviana ◽  
Relieve Pain ◽  
Pain Models ◽  
Hexane Extracts ◽  
Cardioactive Glycosides ◽  
Dose Dependent

Thevetia peruviana (Pers.) K.Schum. (Apocynaceae) seeds are known to possess cardioactive glycosides such as thevetin A, thevetin B, nerifolin etc. They are also used locally for general pain relief for which there is no scientific evidence to our knowledge. Arthralgia is regarded generally as pain without inflammation. It is endemic in the society and sufferers continue to imbibe pain relieving drugs in their tons all over the world. Analgesic activity test was carried out using the formalin-induced pain models, at 0.1g, 0.2g and 0.3g/kg doses of n-hexane extracts of Thevetia peruviana seeds (HTp) in Wistar mice. Diclofenac was used as positive control. Acute toxicity test was carried out at doses of 1000, 2500 and 5000 mg/kg weight of test subject. It was observed that HTp at concentrations of 0.1g, 0.2g and 0.3g/kg showed significant analgesic effect at compared to the control. The percentage inhibition observed was 29.60%, 44.80% and 50.72% for the early pain phase and 100% for the late pain phase respectively, indicating HTps NSAID-like property. HTp showed the highest percentage inhibition at 300 mg/kg (50.72 %) and significant; P < 0.005 pain reduction. HTp did not produce any toxicity up to a dose of 5000 mg/kg weight which is very interesting as the seeds are known for their toxicity due to the cardiac glycoside presence. The results of the study suggest that HTp does indeed relieve pain significantly in a dose dependent manner, thus justifying its use in management of arthralgia. Keywords: Arthralgia, Herbal medicine, Pain,Thevetia peruviana, yellow oleander

Differential Modulation of the Cardiac L- and T-type Calcium Channel Currents by Isoflurane

2001 ◽  
Vol 95 (2) ◽  
pp. 515-524 ◽  
Author(s):  
Amadou K. S. Camara ◽  
Zeljana Begic ◽  
Wai-Meng Kwok ◽  
Zeljko J. Bosnjak
Keyword(s):  
Steady State ◽  
Calcium Channels ◽  
Reversal Potential ◽  
Calcium Currents ◽  
Dependent Manner ◽  
Inotropic Effects ◽  
Phenotypic Differences ◽  
Steady State Inactivation ◽  
Dose Dependent ◽  
Hyperpolarizing Shift

Background Volatile anesthetics exert their negative chronotropic and inotropic effects, in part by depressing the L- and T-type calcium channels. This study examines and compares the dose-dependent effects of isoflurane on atrial L- and T-type calcium currents (I(Ca,L) and I(Ca,T)) and ventricular I(Ca,L). Methods Whole cell I(Ca) was recorded from enzymatically isolated guinea pig cardiomyocytes. Current-voltage relations for atrial and ventricular I(Ca,L) was obtained from holding potentials of -90 and -50 mV to test a potential of +60 mV in 10-mV increments. Atrial I(Ca,T) was determined by subtraction of currents obtained from holding potentials of -50 and -90 mV. Steady state inactivation was determined using standard two-pulse protocols, and data were fitted with the Boltzmann equation. Results Isoflurane depressed I(Ca) in a dose-dependent manner, with Kd values of 0.23+/-0.03, 0.34+/-0.03, and 0.71+/-0.02 mM of anesthetic for atrial I(Ca,T) and I(Ca,L) and ventricular (ICa,L), respectively, and caused a significant (P &lt; 0.05) hyperpolarizing shift in steady state inactivation. At 1.2 and 1.6 mm, isoflurane caused a significant (P &lt; 0.05) depolarizing shift in the steady state activation in ventricular I(Ca,L) but not in atrial I(Ca,L) or I(Ca,T). In addition to the depression of I(Ca,L), isoflurane also induced a hyperpolarizing shift in the reversal potential of I(Ca) for both atrial and ventricular L-type calcium channels. Conclusion The results show that atrial I(Ca,T) is more sensitive to isoflurane than atrial I(Ca,L), and ventricular I(Ca,L) was the least responsive to the anesthetic. These differential sensitivities of the calcium channels in the atrial and ventricular chambers might reflect phenotypic differences in the calcium channels or differences in modulation by the anesthetic.

scholarly journals Nongenomic Action of Progesterone Inhibits Oxytocin-Induced Phosphoinositide Hydrolysis and Prostaglandin F2α Secretion in the Ovine Endometrium

Endocrinology ◽  
2006 ◽  
Vol 147 (2) ◽  
pp. 937-942 ◽  
Author(s):  
Cecily V. Bishop ◽  
Fredrick Stormshak
Keyword(s):  
Prostaglandin F2α ◽  
Detectable Effect ◽  
Dependent Manner ◽  
Dose Response Relationship ◽  
Nongenomic Action ◽  
The Media ◽  
Relationship Of ◽  
Nongenomic Effects ◽  
Dose Dependent ◽  
Stimulation Of

Experiments were conducted to characterize the nongenomic effects of progesterone (P4) on binding of oxytocin (OT) to its receptor and signal transduction in the ovine endometrium. The dose-response relationship of P4 to OT binding was examined. Membranes from endometrial tissue of ovariectomized hormone-treated ewes were preincubated in the presence of P4 for 1 h followed by OT receptor analysis. P4 interfered with the binding of OT in a dose-dependent manner. Endometrium was then recovered from cyclic ewes and divided into explants. Treatment consisted of two dosages of P4 and two dosages of OT. Explants were analyzed for total inositol monophosphate, bisphosphate (IP2), and trisphosphate (IP3) content. Preincubation with P4 for 10 min significantly interfered with OT stimulation of IP2 and IP3 synthesis. Oxytocin increased monophosphate production, but there was no detectable effect of P4. In the next experiment, endometrial explants were cultured in the absence or the presence of arachidonic acid. Explants were then exposed for 1 h to medium containing vehicle or P4. After incubation, explants were challenged with OT and the media were collected and analyzed for 13,14 dihydro-15-keto prostaglandin F2α by RIA. Treatment of explants with AA increased PGF2α content compared with that of controls. Brief exposure to P4 significantly decreased OT-induced PGF2α secretion from explants previously exposed to medium or AA. Collectively, these data are interpreted to indicate that the observed reduction in OT-induced IP2 and IP3 production and OT-induced PGF2α secretion was due to P4 inhibition of OT binding to its receptor.

scholarly journals Evaluation of antinociceptive and antipyretic effect of Pupalia lappacea Juss

2013 ◽  
Vol 2 (2) ◽  
pp. 23-28 ◽  
Author(s):  
Vajrala Neeharika ◽  
Humaira Fatima ◽  
Bommineni Madhava Reddy
Keyword(s):  
Acetic Acid ◽  
Antinociceptive Effect ◽  
Ethanolic Extract ◽  
Pharmaceutical Journal ◽  
Dependent Manner ◽  
Hot Plate ◽  
Hot Plate Test ◽  
Antipyretic Activity ◽  
Cns Depressant ◽  
Dose Dependent

Pupalia lappacea Juss (Family: Amaranthaceae) is claimed to be useful in treatment of bone fracture, wounds, boils, cough, toothache, fever and malaria. The study was aimed to evaluate the 80% aqueous ethanolic extract of aerial parts of P. lappacea for antinociceptive and antipyretic activities to verify the traditional claim. The extract was orally administered at doses of 200, 400 and 600 mg/kg. The extract has significantly (P<0.01) reduced the nociception induced by acetic acid. The effect produced was in dose dependent manner. The antinociceptive effect was not reversed by pretreatment with naloxone in acetic acid induced writhing test. In hot plate method, the extract has significantly increased the latency time of jump. The naloxone has partially antagonised the antinociception of extract in hot plate test indicating P. lappacea has morphinomimetic properties. In the study of the CNS-depressant effects, the extract was found to produce significant reduction in head pokes and locomotion in mice by using hole board and locomotor activity test respectively. The extract has significantly reduced the rectal temperature in yeast induced pyrexia in rats at 600 mg/kg. The activity produced by extract was in dose dependent manner. Phytochemical investigation of ethanolic extract of P. lappacea revealed the presence of steroids and/or triterpenoids, flavonoids and phenolic compounds which may be responsible for antinociceptive and antipyretic activity of P. lappacea.DOI: http://dx.doi.org/10.3329/icpj.v2i2.13193 International Current Pharmaceutical Journal 2013, 2(2): 23-28

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