Nitric Oxide and Opioids Involvement in Isobolographic Nsaids Antinociception

Drug Research ◽  
2019 ◽  
Vol 69 (12) ◽  
pp. 688-694
Author(s):  
Hugo F. Miranda ◽  
Viviana Noriega ◽  
Fernando Sierralta ◽  
Paula Poblete ◽  
Nicolás Aranda ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Mechanisms Of Action ◽  
Antinociceptive Activity ◽  
Tail Flick ◽  
Tail Flick Test ◽  
Pain Model ◽  
Isobolographic Analysis

AbstractDifferent NSAIDs are used as antinociceptive in various analgesic assays, among which should be mentioned: ibuprofen, ketorolac , ketoprofen, meloxicam , paracetamol and others. It has been shown that NSAIDs possess antinociceptive activity by blocking cyclooxygenase enzymes (COXs). The present study was designed to evaluate the possible involvement of the nitridergic pathway due to L-NAME and the opioidergic route by NTX in the antinoception induced by NSAIDs using a murine pain model the tail flick test in an automatic tail flick algesiometer. The antinociception was evaluated by means of isobolographic analysis. The interaction between the combination of NSAIDs, via i.p., on basis of their ED25, demonstrated that the coadministration of the drugs were synergistic with the exception of the lack of effect in combination of meloxicam with ibuprofen and with ketorolac, since the result was additive. These data validate that the NSAIDs administered alone or in combinations produce antinociception in which other mechanisms of action must be added to the simple inhibition of COXs. In addition, the pretreatment of the mice with L-NAME and NTX does not change previous isobolographic parameters of the mixture of NSAIDs.

Analgesia additive interaction between tadalafil and morphine in an experimental animal model

2020 ◽  
Vol 98 (11) ◽  
pp. 771-776
Author(s):  
Mohammed Mehanna ◽  
Souraya Domiati ◽  
Hania Nakkash Chmaisse ◽  
Ahmed El Mallah
Keyword(s):  
Central Nervous System ◽  
Side Effects ◽  
Tail Flick ◽  
Response Curves ◽  
Additive Interaction ◽  
Tail Flick Test ◽  
Isobolographic Analysis ◽  
Cgmp Pathway ◽  
The Central Nervous System ◽  
Total Fraction

Since both morphine and tadalafil have been proven to exert some of their analgesic activity through modulation of the NO–cGMP pathway, the aim of the current study is to evaluate the pharmacologic interaction between tadalafil and morphine to decrease the dose of morphine and subsequently its side effects. The assessment was carried out through isobolographic analysis relative to ED50s of both morphine and tadalafil obtained by tail-flick test on BALB/c mice. Morphine and tadalafil ED50s calculated from the dose–response curves were 8303 and 2080 μg/kg, respectively. The experimental ED50 values of morphine and tadalafil in their mixture were 4800 and 1210 μg/kg, respectively. Those results showed an additive interaction between morphine and tadalafil presented by a total fraction value for the mixture of 1160 μg/kg. This outcome can be interpreted by the fact that both drugs share common pathways, namely, NO–cGMP and opioid receptors. As a conclusion, the morphine and tadalafil combination showed an additive effect against acute pain, which is mediated through the central nervous system, thus providing a rationale for combining them to decrease morphine dose and thus minimizing its side effects.

scholarly journals Comparison of morphine, oxycodone and the biased MOR agonist SR-17018 for tolerance and efficacy in mouse models of pain

2020 ◽  
Author(s):  
Fani Pantouli ◽  
Travis W. Grim ◽  
Cullen L. Schmid ◽  
Agnes Acevedo-Canabal ◽  
Nicole M. Kennedy ◽  
...  
Keyword(s):  
Repeated Administration ◽  
Spinal Reflex ◽  
Tail Flick ◽  
Tail Flick Test ◽  
Pain Model ◽  
Thermal Nociception ◽  
Cellular Assays ◽  
Pain Models ◽  
Gtpγs Binding ◽  
Repeated Dosing

AbstractThe mu opioid receptor-selective agonist, SR-17018, preferentially activates GTPγS binding over βarrestin2 recruitment in cellular assays. In mice, SR-17018 stimulates GTPγS binding in brainstem and produces antinociception with potencies similar to morphine. However, it produces much less respiratory suppression and mice do not develop antinociceptive tolerance in the hot plate assay upon repeated dosing. Herein we evaluate the effects of acute and repeated dosing of SR-17018, oxycodone and morphine in additional models of pain-related behaviors. In the mouse warm water tail immersion assay, an assessment of spinal reflex to thermal nociception, repeated administration of SR-17018 produces tolerance as does morphine and oxycodone. SR-17018 retains efficacy in a formalin-induced inflammatory pain model upon repeated dosing, while oxycodone does not. In a chemotherapeutic-induced neuropathy pain model SR-17018 is more potent and efficacious than morphine or oxycodone, moreover, this efficacy is retained upon repeated dosing of SR-17018. These findings demonstrate that, with the exception of the tail flick test, SR-17018 retains efficacy upon chronic treatment across several pain models.

scholarly journals Antinociceptive and Anti-Inflammatory Activities of the Ethanolic Extract fromSynadenium umbellatumPax. (Euphorbiaceae) Leaves and Its Fractions

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Rodrigo Borges ◽  
Marcus Vinícius Mariano Nascimento ◽  
Adryano Augustto Valladão de Carvalho ◽  
Marize Campos Valadares ◽  
José Realino de Paula ◽  
...  
Keyword(s):  
Acetic Acid ◽  
Ethanolic Extract ◽  
Inflammatory Activity ◽  
Antinociceptive Activity ◽  
Opioid System ◽  
Tail Flick ◽  
Tail Flick Test ◽  
Ear Edema ◽  
Croton Oil ◽  
Anti Inflammatory

Synadenium umbellatumPax., popularly known in Brazil as “cola-nota,” “avelós,” “cancerola,” and “milagrosa”, is a plant species used in folk medicine for the treatment of inflammation, pain, and several diseases. This study aimed to investigate the antinociceptive and anti-inflammatory activities of the ethanolic extract fromSynadenium umbellatumPax. leaves (EES) and its hexane (HF), chloroform (CF), and methanol/water (MF) fractions using the acetic acid-induced abdominal writhing test, formalin-induced paw licking test, tail flick test, croton oil-induced ear edema test, and carrageenan-induced peritonitis test. EES and MF reduced the number of acetic acid-induced abdominal writhes, while CF and HF did not. EES effect on acetic acid-induced abdominal writhing was reversed with a pretreatment with naloxone. EES reduced licking time in both phases of the formalin-induced paw licking test, but did not prolong the latency in the tail flick test. These results show that EES presented antinociceptive activity, probably involving the opioid system, anti-inflammatory activity in the croton oil-induced ear edema test, and leukocyte migration into the intraperitoneal cavity. MF also presented anti-inflammatory activity in the croton oil-induced ear edema test. In conclusion, EES and MF have antinociceptive activity involving the opioid system and anti-inflammatory activity.

scholarly journals Antinociceptive activity of methanolic extract of the leaves of Feronia limonia Linn

2014 ◽  
Vol 26 (1-2) ◽  
pp. 21-24
Author(s):  
Moni Rani Saha ◽  
Sheikh Zahir Raihan ◽  
Akm Shahidur Rahman
Keyword(s):  
Body Weight ◽  
Methanolic Extract ◽  
Diclofenac Sodium ◽  
Antinociceptive Activity ◽  
Tail Flick ◽  
Immersion Method ◽  
Tail Flick Test ◽  
Standard Drug ◽  
Swiss Albino Mice ◽  
Albino Mice

The antinociceptive activity of the methanolic extract of the leaves of Feronia limonia Linn. (Family Rutaceae) was investigated using acetic acid-induced writhing model and tail flick test in swiss albino mice. The extract produced about 26.01% ( p< 0.01), 39.88% ( p< 0.01) and 57.07% (p< 0.01) writhing inhibition at the dose of 100, 200 and 400 mg/kg of body weight respectively, which was comparable to the standard drug diclofenac sodium where the inhibition was about 63.58% (p< 0.01) at the dose of 25 mg/kg of body weight. All doses of extracts significantly (p<0.05) increased latency of flick tail in tail immersion method. The methanolic extract showed dose dependent antinociceptive activity in both type of test in swiss albino mice. Phytochemical investigations of the leaves extract indicate the presence of tannins, saponins, steroids, alkaloids and flavonoids. The preliminary study of the methanolic extract showed antinociceptive activity in both writhing and tail flick test in mice. http://dx.doi.org/10.3329/bjpp.v26i1-2.19962 Bangladesh J Physiol Pharmacol 2010; 26(1&2) : 21-24

scholarly journals TO STUDY THE ANTINOCICEPTIVE EFFECT OF CINNARIZINE ALONE AND IN COMBINATION WITH TRAMADOL IN ALBINO RATS BY TAIL FLICK METHOD

2020 ◽  
Vol 9 (1) ◽  
Author(s):  
Rajiv Kumar ◽  
Aasim Shakeel ◽  
Manju Gari ◽  
Uma Shankar Prasad Keshri
Keyword(s):  
Reaction Time ◽  
Opioid Analgesic ◽  
Antinociceptive Effect ◽  
Radiant Heat ◽  
Antinociceptive Activity ◽  
Albino Rats ◽  
Tail Flick ◽  
Withdrawal Time ◽  
Tail Flick Test ◽  
Standard Drug

Background: Pain is the most common reason for physician consultation in most countries. It is a major symptom in many medical conditions, and can interfere with a person's quality of life and general functioning. Acute pain is usually managed with medications such as analgesics and anesthetics. Cinnarizine is a piperazine derivative and Tramadol is an opioid analgesic. Cinnarizine is also a calcium channel blocker. So, in the present study an attempt has been made to access the antinociceptive activity of Cinnarizine alone & in combination with standard drug Tramadol with the hope of pharmacological synergism and better relief from pain. Material & Methods: 4 rats in 6 groups were weighed & colour coded. Basal reaction time to radiant heat was taken. Tail withdrawal time was recorded as the end point. Reaction time was taken at 0, 30 & 60 minutes on day 0, 7, 14, 21 & 28. Result: All observation were done by the ANOVA followed by post hoc Tukey’s. It is seen that Cinnarizine alone (in both doses) has antinociceptive activity but that is not statistically significant. But when it is given along with Tramadol it potentiates antinociceptive activity of Tramadol which is statistically significant. Conclusion: The result of this study conclude that Cinnarizine alone has antinociceptive activity in both doses (i.e 2.5mg/kg & 5mg/kg) but it is statistically not significant. Tramadol shows higher antinociception with Cinnarizine in dose of 5mg/kg than with 2.5mg/kg. Keywords: Antinociception, Cinnarizine, Tramadol, Tail flick test, Albino rats

Lactoferrin enhances opioid-mediated analgesia via nitric oxide in the rat spinal cord

2003 ◽  
Vol 285 (2) ◽  
pp. R306-R312 ◽  
Author(s):  
Ken-ichiro Hayashida ◽  
Takashi Takeuchi ◽  
Hirohiko Shimizu ◽  
Kunio Ando ◽  
Etsumori Harada
Keyword(s):  
Nitric Oxide ◽  
Spinal Cord ◽  
Methyl Ester ◽  
Opioid Receptor ◽  
Formalin Test ◽  
Biological Fluids ◽  
Bovine Milk ◽  
Tail Flick ◽  
Tail Flick Test ◽  
Μ Opioid Receptor

Lactoferrin (LF) is a multifunctional protein that is found in milk, neutrophils, and other biological fluids, and its receptors have also been identified in the central nervous system. Recently, we found that bovine milk-derived LF (BLF) produced analgesia via a μ-opioid receptor-mediated response in the spinal cord. However, the precise mechanism of this analgesic effect remains unclear. In this study, spinally applied BLF produced analgesia that was reversed by coadministration with a nitric oxide (NO) synthase inhibitor, NG-nitro-l-arginine methyl ester, during phases 1 and 2 in the formalin test. Spinal coadministration of a μ-opioid receptor agonist, morphine, with a subeffective dose of BLF produced a much more highly potentiated analgesia than that produced by morphine alone during phases 1 and 2 in the formalin test. This potentiated analgesia by morphine with BLF was reversed by a μ-opioid receptor antagonist, d-Phe-Cys-Tyr-d-Trp-Orn-Thr-NH2, or by NG-nitro-l-arginine methyl ester. In the tail-flick test, continuous spinal infusion of morphine via an osmotic minipump over 6 days resulted in development of tolerance by day 4, but no tolerance of BLF was observed throughout the experiment. These results suggest that BLF acts as an enhancer of the spinal opioidergic system via an NO-mediated mechanism.

scholarly journals A study of antinociceptive effect of venlafaxine in albino mice

2016 ◽  
Vol 6 (1) ◽  
pp. 184
Author(s):  
Santhosh Ramakrishna ◽  
Shivashankaramurthy K. Gurusiddappa ◽  
Kiran L. Jambulingappa
Keyword(s):  
Normal Saline ◽  
Antinociceptive Effect ◽  
Antinociceptive Activity ◽  
Tail Flick ◽  
Hot Plate Test ◽  
Tail Flick Test ◽  
Group 4 ◽  
Group 3 ◽  
Albino Mice ◽  
Group 2

Background: Serotonin and norepinephrine are important neurotransmitters involved in pain inhibition in descending pain inhibitory tracts. Venlafaxine being an antidepressant exerts its mechanism mainly by inhibiting reuptake of serotonin and norepinephrine like Tramadol. The objectives were to study the antinociceptive activity of Venlafaxine and its comparison with Pethidine.Methods: A total of 32 Swiss albino mice were divided into 4 groups with 8 animals in each group. Group 1 received normal saline as control in dose of 5ml/kg i.p, Group 2 received Pethidine as standard in dose of 30mg/kg s.c, Group 3 received Venlafaxine as in dose of 10mg/kg i.p and Group 4 received Venlafaxine in dose of 22.5mg/kg. Tail flick test and hot plate test were used for evaluating antinociceptive activity. All animals were subjected to the above mentioned tests before and 30 minutes after the administration of the drugs. Results were subjected to suitable statistical analysis.Results: The results from the above mentioned tests showed that Venlafaxine in dose of 10mg/kg showed significant antinociceptive activity as compared to normal saline (p <0.05) but was not comparable to Pethidine (p >0.05). Venlafaxine in dose of 22.5mg/kg showed significant antinociceptive activity as compared to normal saline (p <0.05) and activity was comparable to Pethidine.Conclusions: Venlafaxine in both the doses showed significant antinociceptive activity in acute models of pain in animals.

Interaction of Intrathecally Infused Morphine and Lidocaine in Rats (Part I) 

1998 ◽  
Vol 89 (6) ◽  
pp. 1455-1463 ◽  
Author(s):  
Yoji Saito ◽  
Megumi Kaneko ◽  
Yumiko Kirihara ◽  
Shinichi Sakura ◽  
Yoshihiro Kosaka
Keyword(s):  
Motor Function ◽  
Motor Impairment ◽  
Tail Flick ◽  
Tail Flick Test ◽  
Colorectal Distension ◽  
Isobolographic Analysis ◽  
Constant Rate ◽  
Antinociceptive Effects ◽  
Dose Dependent

Background Synergistic antinociception of opioids and local anesthetics has been established in bolus injections but not in long-term use. The somatic and visceral antinociceptive effects of intrathecally infused morphine or lidocaine were characterized, and the nature of the interaction of those agents in rats was evaluated. Methods Intrathecal catheters were implanted in rats. Morphine (0.3 to 10 microg x kg(-1) x h(-1)), lidocaine (30-1,000 microg x kg(-1) x h(-1)), a combination of those, or saline was infused intrathecally at a constant rate of 1 microl/h for 6 days. The tail flick and colorectal distension tests were used to measure the somatic and visceral antinociceptive effects, respectively. Nociceptive tests and motor function tests were repeated on days 1, 2, 3, 4, and 6. Isobolographic analysis was performed on the results of the tail flick test to determine the magnitude of the interaction. Results Intrathecally infused morphine produced dose-dependent antinociceptive effects in both the tail flick and the colorectal distension tests. Morphine showed a lower peak percentage maximum possible effect (%MPE) in the colorectal distension test than in the tail flick test. Intrathecal lidocaine also produced dose-dependent antinociceptive effects. Lidocaine infusion at 1,000 microg x kg(-1) x h(-1) caused motor impairment. Coinfusion of morphine 0.3 microg x kg(-1) x h(-1) and lidocaine 200 microg x kg(-1) x h(-1), which had no effects by themselves, significantly increased the percentage maximum possible effects (P &lt; 0.01). Coinfused lidocaine potentiated the duration and the magnitude of morphine antinociception. Isobolographic analysis of the tail flick test on day 1 showed a synergistic interaction between morphine and lidocaine. Conclusions Morphine and lidocaine intrathecally coadministered synergistically potentiated the antinociceptive effects of each other. That coinfusion dramatically potentiated visceral antinociception, whereas the infusion of morphine alone showed little visceral antinociception.

scholarly journals Nitroaromatic Antibiotics as Nitrogen Oxide Sources

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 267
Author(s):  
Allison M. Rice ◽  
Yueming Long ◽  
S. Bruce King
Keyword(s):  
Nitric Oxide ◽  
Nitrogen Oxide ◽  
Reactive Nitrogen Species ◽  
Human African Trypanosomiasis ◽  
Anaerobic Bacteria ◽  
Mechanisms Of Action ◽  
Disease Treatment ◽  
Therapeutic Development ◽  
New Treatments ◽  
Reductive Metabolism

Nitroaromatic antibiotics show activity against anaerobic bacteria and parasites, finding use in the treatment of Heliobacter pylori infections, tuberculosis, trichomoniasis, human African trypanosomiasis, Chagas disease and leishmaniasis. Despite this activity and a clear need for the development of new treatments for these conditions, the associated toxicity and lack of clear mechanisms of action have limited their therapeutic development. Nitroaromatic antibiotics require reductive bioactivation for activity and this reductive metabolism can convert the nitro group to nitric oxide (NO) or a related reactive nitrogen species (RNS). As nitric oxide plays important roles in the defensive immune response to bacterial infection through both signaling and redox-mediated pathways, defining controlled NO generation pathways from these antibiotics would allow the design of new therapeutics. This review focuses on the release of nitrogen oxide species from various nitroaromatic antibiotics to portend the increased ability for these compounds to positively impact infectious disease treatment.

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