Development of a predictive model for daughter pregnancy rate and standardization of voluntary waiting period in Murrah buffalo.

A predictive model for daughter pregnancy rate (DPR) in Indian Murrah buffaloes has been developed. The data pertaining to first lactation reproduction traits, viz., age at first calving (AFC), first service period (FSP), and number of services per first conception (NS/FCON) of 719 Murrah buffaloes calved from 1985 to 2010 at the National Dairy Research Institute (NDRI), Karnal (Haryana), India were adjusted against significant environmental influence. First lactation reproduction records of 474 Murrah buffaloes were used for determining voluntary waiting period (VWP) and estimating DPR. Seven simple and multiple regression models in each case were developed where the buffaloes had their first insemination after 63 days (DPR 63), 84 days (DPR 84), and 105 days (DPR 105) of first calving. Among the seven models (I to VII) for DPR 63, DPR 84, and DPR 105, model II, having only FSP as an independent reproduction variable, was found to be the best prediction model, based on the four statistical criterions (high coefficient of determination (R 2), low mean sum of squares due to error (MSSe), conceptual predictive (CP) value, and Bayesian information criterion (BIC)). Three linear equations were developed using model II, viz., DPR 63 = 0.0033 (274 − FSP), DPR 84 = 0.0027 (332 − FSP), and DPR 105 = 0.0027 (310 − FSP). The average errors for the prediction of DPR 63, DPR 84, and DPR 105 were 1, 13, and 8 %, respectively. Therefore, 63 days of VWP is the optimum period for getting the best DPR in Indian Murrah buffaloes.

Controlling Triboelectric Charge of MOFs by Leveraging Ligands Chemistry.

Metal-organic frameworks (MOFs) have emerged as promising materials for triboelectric nanogenerators (TENGs), but the effects of ligand choice on triboelectric charge remain underexplored. Hence, this paper demonstrates the effect of single, binary, and ternary ligands on TENG performance of cobalt/cerium-based (Co─Ce) bimetallic MOFs utilizing 2-methylimidazole (2Melm), terephthalic acid (BDC), and benzene tricarboxylic acid (BTC) as ligands. The detailed structural characterization revealed that varying ligand chemistries led to distinct MOF features affecting TENG performance. Single ligand bimetallic MOFs (designated as CoCe-2MeIm, CoCe-BDC, CoCe-BTC) has lower performance than binary ligand (designated as CoCe-2MeIm-BDC, CoCe-2MeIm-BTC, CoCe-BDC-BTC) and ternary ligand MOFs (designated as CoCe-2MeIm-BDC-BTC). Among all, the binary ligand MOF, CoCe-2MeIm-BTC, shows the best results (598 V, 26.7 µA) due to the combined effect of imidazole ring and (─COO─) groups. This is attributed to lone pairs on nitrogen atoms and a delocalized π-electron system in imidazole system in this material. CoCe-BTC has the lowest results (31 V, 3.2 µA) due to the bulkier nature of the electron-withdrawing (─COO─) groups and their impact on the π-electron system of the benzene ring. This study showcases the potential of ligand chemistry manipulation to control triboelectric charge and thereby enhance MOF-based TENG performance.

Triboelectric Energy Harvesting from Highly Conjugated Fused Aromatic Ladder Structure Under Extreme Environmental Conditions.

Practical application of triboelectric nanogenerators (TENGs) has been challenging, particularly, under harsh environmental conditions. This work proposes a novel 3D-fused aromatic ladder (FAL) structure as a tribo-positive material for TENGs, to address these challenges. The 3D-FAL offers a unique materials engineering platform for tailored properties, such as high specific surface area and porosity, good thermal and mechanical stability, and tunable electronic properties. The fabricated 3D-FAL-based TENG reaches a maximum peak power density of 451.2 µW cm-2 at 5 Hz frequency. More importantly, the 3D-FAL-based TENG maintains stable output performance under harsh operating environments, over wide temperature (-45-100 °C) and humidity ranges (8.3-96.7% RH), representing the development of novel FAL for sustainable energy generation under challenging environmental conditions. Furthermore, the 3D-FAL-based TENG proves to be a promising device for a speed monitoring system engaging reconstruction in virtual reality in a snowy environment.

Waste packaging polymeric foam for oil-water separation: An environmental remediation.

Nowadays, its urgent need to develop and fabricate efficient, low cost, eco-friendly, oil-water separation methodologies especially for variety of polluted water in the environments. To deals with serious oil spills and industrial organic pollutants, here in we have developed a highly efficient oil-water separation methodology by using waste material such as expanded polyethylene (EPE) polymeric foam which is most commonly used for packaging as a shock absorber and most abundantly available in the surroundings as waste. Oil-water separation setup was fabricated by using waste EPE polymeric foam without any pre-treatment. By simply scratching, special properties (wettability performance) such as hydrophobicity, leophilicity, and low water adhesion was imparted to the EPE polymeric foam. The different types of oil-water mixture used for the study and separation were achieved almost up to 78%. The oil absorption efficiency of the EPE polymeric foam was within range of 0.491-0.788 g/g. In addition to efficient oil-water separation, the modified EPE polymeric foam exhibited fast and continuous oil-water separation solely by gravity. The easy operation, chemical durability, and efficiency of the waste EPE polymeric foam give it high potential for use in industrial and consumer applications for large scale oil-water separation.

Analysis of interaction between etoricoxib and tramadol against mechanical hyperalgesia of spinal cord injury in rats.

Drug combinations have the potential advantage of greater analgesia over monotherapy. The present study was aimed to assess any possible interaction (additive or potentiation) in the antinociceptive effects of etoricoxib; a novel cyclooxygenase-2 inhibitor, and tramadol; a typical opioid agonist when administered in combination against mechanical hyperalgesia induced by spinal cord injury in rats. The nature of interaction was analyzed using surface of synergistic interaction (SSI) analysis and an isobolographic analysis. Etoricoxib or tramadol when administered alone to rats, exhibited different antihyperalgesic potencies (ED50 etoricoxib: 0.58+/-0.19 mg/kg, po; ED50 tramadol: 9.85+/-0.57 mg/kg, po). However, both the drugs were found to be long acting against this model of hyperalgesia. Further, etoricoxib and tramadol were co-administered in fixed ratios of ED50 fractions. One combination (0.29/4.79 mg/kg, po: etoricoxib/tramadol) exhibited additivity and other three combinations (0.15/2.39, 0.08/1.19, and 0.04/0.59 mg/kg, po: etoricoxib/tramadol) resulted in potentiation when analyzed by SSI. The SSI was calculated from the total antihyperalgesic effect produced by the combination after the subtraction of the antihyperalgesic effect produced by each of the individual drug. In the isobolographic analysis, the experimental ED50 was found to be far below the line of additivity also indicating a significant (P < 0.05) synergistic antihyperalgesic effect when etoricoxib and tramadol was co-administered to rats. The synergistic antihyperalgesic effect of etoricoxib and tramadol combination suggests that these combinations may have clinical utility in mechanical hyperalgesia associated with spinal injury.

Anti-inflammatory effect of licofelone against various inflammatory challenges.

We investigated the pharmacological profile of licofelone [6-(4-chlorophenyl)-2,3-dihydro-2,2-dimethyl-7-phenyl-1H-pyrrolizine-5-acetic acid] against different inflammogens. The anti-inflammatory and anti-hyperalgesic effect of licofelone (2, 30 and 100 mg/kg, p.o.) against all the challenges was statistically significant (P < 0.05) when compared with control and indomethacin (10 mg/kg, p.o.). The ED(50) value of 19.1 mg/kg (onset by 2 h, duration: short), 13.0 mg/kg and 16.8 mg/kg (onset by 1 h, duration: long) was observed for licofelone against carrageenan-, arachidonic acid- and bradykinin-induced paw oedema, respectively. Similarly, licofelone showed ED(50) value of 47.6 mg/kg (onset by 1 h, duration: long), 92.2 mg/kg (onset by 1 h, duration: medium), and 78.6 mg/kg (onset by 2 h, duration: medium) against carrageenan-, arachidonic acid- and bradykinin-induced mechanical hyperalgesia, respectively. The rank order of potency based on percent inhibition and percent reversal against inflammation and mechanical hyperalgesia, respectively, was found to be licofelone > indomethacin. Moreover, licofelone (10-100 mg/kg, p.o.) significantly (P < 0.05) and dose-dependently prevented the Freund's adjuvant-induced increased vascularity in mice (vascularity index; 10 mg/kg: 0.059 +/- 0.015; 20 mg/kg: 0.048 +/- 0.004; 30 mg/kg: 0.039 +/- 0.012; 100 mg/kg: 0.025 +/- 0.015 vs. control: 0.0285 +/- 0.003). Furthermore, the results suggested that dual inhibitors of cyclooxygenase and lipoxygenase like licofelone provide an effective control of inflammation and hyperalgesia against acute inflammation/hyperalgesia in rats and mice.

Modulatory effect of sildenafil in diabetes and electroconvulsive shock-induced cognitive dysfunction in rats.

The nitric oxide/guanylyl cyclase, cyclic guanosine monophosphate/phosphodiesterase 5 (NO/cGMP/PDE5) pathways play a key role in physiological and pathological situations, such as synaptic plasticity, learning and memory formation, diabetic gastropathy and neuropathy, long-term potentiation (LTP), epilepsy, cerebral ischemia, and neurodegenerative diseases. Several studies have demonstrated the alteration of NO-cGMP pathway in cognitive impairment. The present study was aimed to study the effect of sildenafil, a PDE5 inhibitor on diabetes and electroconvulsive shock (ECS)-induced cognitive dysfunction in rat using one-trial step-through type of passive avoidance and elevated plus-maze task. Diabetic and ECS-treated rats showed poor learning performance in step-through passive avoidance and plus-maze task. Acute administration of sildenafil significantly reversed the diabetes and ECS-induced retention deficits in both the test paradigms. Sildenafil also significantly improved the cognitive performance in young rats in both the paradigms. Furthermore, L-NAME, a non-selective NOS inhibitor and methylene blue, a guanylate cyclase inhibitor blocked the effect of sildenafil. The results thus suggest that cognitive impairment might be due to the modulatory effect of nNOS or PDE5 enzyme on cGMP levels. Moreover, sildenafil-induced reversal of cognitive impairment suggests the protective role of PDE5 inhibitors in neurodegenerative disorders.

Differential effect of zileuton, a 5-lipoxygenase inhibitor, against nociceptive paradigms in mice and rats.

Pain is commonly associated with inflammation. Several mediators including prostaglandins have been implicated in pain and inflammation. However, the recent reports indicated the role of leukotrienes as signaling molecules in pain. The present study was aimed to evaluate the effect of 5-LOX inhibitor, zileuton in nociceptive paradigms including inflammatory pain. Acetic acid-induced writhing, tail flick and hot plate tests to assess pain response were used. The effect on carrageenan-induced mechanical hyperalgesia, and acetic acid-induced vascular permeability was also determined. Zileuton (ED50=31.81 mg/kg p.o.), zafirlukast (ED50=6.19 mg/kg p.o.), montelukast (ED50=7.17 mg/kg p.o.) inhibited acetic acid-induced writhing in mice. Further, zileuton and ZK 158252, leukotriene B4 receptor antagonist did not alter basal response against tail flick and hot plate assays. Acetic acid-induced vascular permeability was significantly inhibited by zileuton. Oral administration of zileuton showed efficacy against carrageenan-induced mechanical hyperalgesia and also reversed histological changes in paw biopsies. These data suggest that zileuton, a 5-LOX inhibitor, exhibited antinociceptive effect in paradigms of inflammatory pain.

Effect of licofelone against mechanical hyperalgesia and cold allodynia in the rat model of incisional pain.

Hyperalgesia from an incisional pain is evoked by noxious stimuli (mechanical and cold). The present study was aimed to examine the effect of licofelone, a dual inhibitor of cyclooxygenases (COX-1/COX-2) and 5-lipoxygenase (5-LOX) against mechanical hyperalgesia and cold allodynia in the rat model of incisional pain. Mechanical hyperalgesia and cold allodynia was assessed employing Randall and Sellitto analgesymeter and cold water maintained at 10 degrees C, respectively. Zileuton (25-100 mg/kg, po), a 5-LOX inhibitor, indomethacin (1-30 mg/kg, po), a non-selective COX inhibitor, and licofelone (10-100 mg/kg, po) a dual inhibitor, significantly reversed the mechanical hyperalgesia and also caused an increase in cold allodynia threshold with different pharmacologic profile. The rank order of potency based on ED50 values in both the paradigms was found to be licofelone > indomethacin > zileuton. The results of the present study are indicative of the role of leukotrienes along with prostaglandins in the rat model of incisional pain (a paradigm of postoperative pain). The results suggested that dual inhibition approach of simultaneous inhibition of COX and LOX pathways might prove beneficial in combating hyperalgesia of postoperative pain.

Effect of licofelone against NSAIDs-induced gastrointestinal ulceration and inflammation.

The present study was aimed to evaluate the effect of licofelone, a dual inhibitor of cycloxygenase1/2-5-lipoxygenase against indomethacin-induced gastric damage in rats and mice in order to assess the role of leukotrienes if any, in non-steroidal anti-inflammatory drugs (NSAIDs)-induced gastrointestinal inflammation. Acute pretreatment with licofelone reversed the indomethacin-induced gastric ulceration, neutrophil adhesion in mesentery venules, neutrophil count in blood, lipid peroxides and vascularity in the stomachs of mice and rats. Further, chronic pretreatment of licofelone also prevented indomethacin-induced gastric morphological changes and cellular infiltration in mesentery venules. Moreover, acute administration of indomethacin elevated leukotriene B4 levels in gastric mucosa, which was reversed by pretreatment with licofelone The results suggest that licofelone offered gastroprotection against NSAIDs-induced gastropathy through its effect on leukotrienes and by inhibiting extravasation of neutrophils.

Effect of 5-lipoxygenase inhibitor against lipopolysaccharide-induced hypothermia in mice.

Bacterial endotoxin produces sepsis associated with alterations in body temperature (fever or hypothermia). The intraperitoneal administration of bacterial endotoxin, lipopolysaccharide (LPS; 50 microg/mouse) led to a decrease in colonic temperature starting 1 hr after the injection. The hypothermic effect was accompanied by a significant increase in hypothalamic leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) levels. 5-lipoxygenase inhibitor, zileuton (200 and 400 mg/kg, po) administered 30 min before LPS challenge significantly prevented hypothermia. However, non-selective cyclooxygenase inhibitor, indomethacin (10, 20 mg/kg, po) did not reverse the hypothermic response. Further, pretreatment of mice with zileuton prevented LPS-stimulated increase in hypothalamic LTB4 levels and caused a relatively small increase in PGE2 levels. Indomethacin had no effect on LTB4 levels but it reduced PGE2 levels. These results suggest a possible involvement of leukotrienes in LPS-induced hypothermia and the potential protective role of 5-lipoxygenase inhibitors in endotoxemia.

Inhibitory effect of sildenafil on gastrointestinal smooth muscle: role of NO-cGMP transduction pathway.

Nitric oxide (NO) is an important neurotransmitter in the gut and has been demonstrated to be a key physiological mediator of non-adrenergic non-cholinergic (NANC) relaxation of gastrointestinal smooth muscle. In the present study the effect of PDE 5 inhibitor sildenafil on the gastrointestinal function (gastric emptying and intestinal transit) has been demonstrated in mice. Sildenafil (0.5-2 mg/kg, po) did not alter the percent gastric emptying however, in higher doses (5, 10 and 30 mg/kg, po) it inhibited the gastric emptying. On acute administration (0.5-5 mg/kg, po) it did not alter the intestinal transit but in higher doses (10 and 30 mg/kg, p.o.) delayed the intestinal transit. Further, the inhibitory effect of sildenafil was significantly blocked by L-NAME (10 mg/kg, ip), a non-selective NOS inhibitor and methylene blue (1 mg/kg, ip), a guanylate cyclase inhibitor. These findings suggest the participation of NO-cGMP transduction pathway in the inhibitory effect of sildenafil (higher doses) on the gastrointestinal smooth muscles and its potential application in patients with nutcracker oesophagus, hypertensive lower oesophageal sphincter (LOS), achalsia and diabetic gastroparesis or colitis where there is a loss of nNOS.

Effect of nimesulide on acetic acid- and leukotriene-induced inflammatory bowel disease in rats.

Inflammatory bowel disease (IBD) is a relapsing inflammation of intestine, which is mediated by release of inflammatory mediators. Both cyclo-oxygenase product prostaglandin (PGE2) and lipo-oxygenase product leukotriene (LTB4), may contribute to the pathogenesis of the inflammatory response. Nimesulide, a preferential COX-2 inhibitor was evaluated for its efficacy against experimental colitis in two different models (acetic acid- and LTB4-induced IBD) in rats. Inflammatory response was induced by intrarectal single administration of acetic acid or LTB4. Nimesulide (9 and 18 mg/kg, p.o.) significantly prevented development of inflammatory changes, decreased myeloperoxidase (MPO) activity, and also restored the altered contractility response of the isolated colon segment to KCl. The results suggested the involvement of both cyclo-oxygenase (COX) and lipo-oxygenase-mediated proinflammatory agents in colonic inflammatory process associated with IBD. Further, this study suggests that such therapeutic interventions may be of value in the treatment of IBD.

Modulatory effect of diclofenac on antispasmodic effect of pitofenone in cholinergic spasm.

Biliary, ureteric and intestinal colic are extremely common clinical conditions associated with smooth muscle spasm. In the present study, antispasmodic activity was carried out against acetylcholine (10-640 ng/ml)-induced contractions on guinea pig ileum. Acetylcholine (10-640 ng/ml) induced concentration-dependent contraction of smooth muscle. Diclofenac, in varying concentration (9.4 x 10(-5) mol/l and 14.1 x 10(-5) mol/l) shifted the concentration response curve of acetylcholine to the right without suppressing the maximal response. However, in higher concentration diclofenac (18.9 x 10(-5) mol/l) blocked the response in an unsurmountable fashion. Further, analgin (11.09 x 10(-5), 16.63 x 10(-5) and 22.18 x 10(-5) mol/l) in equimolar concentrations did not alter the concentration response curve of acetylcholine, but in higher concentration analgin (44.36 x 10(-5) mol/l) also blocked the response in an unsurmountable fashion. Pitofenone (2.5 x 10(-6) mol/l) also, shifted the concentration response curve of acetylcholine to right in a parallel fashion with no change in maximal response. The present study confirms the potent antispasmodic activity of diclofenac-pitofenone combination in comparison to analgin-pitofenone in molar equivalent concentration (in comparison to diclofenac) against acetylcholine-induced contractions of guinea pig ileum.

Effect of 5-lipoxygenase inhibition on events associated with inflammatory bowel disease in rats.

Leukotrienes play a part in inflammatory response. The unique role of the enzyme 5-lipoxygenase (5-LOX) in the production of leukotrienes makes it a likely therapeutic target for inflammatory conditions like asthma, rheumatoid arthritis, psoriasis, and inflammatory bowel disease (IBD). The aim of the present study was to evaluate the effect of zileuton, an orally active selective 5-LOX inhibitor against the events associated with dextran sodium sulphate-induced colitis in a rat model of IBD. The animals were administered simultaneously zileuton (100mg/kg) or sulphasalazine (100mg/kg) orally for 7 days. On day eight, rats were sacrificed, and distal colon isolated to determine myeloperoxidase activity, in vivo superoxide dismutase activity, prostaglandin E2 levels and histological examination. Both zileuton and sulphasalazine significantly prevented the development of inflammatory events associated with colitis. The effect of zileuton was more pronounced towards reducing myeloperoxidase activity and increasing PGE2 levels in distal colon. The results show that chemotactic leukotrienes are responsible for inflammatory surge in damaged colon and, zileuton, significantly improved healing by inhibition of neutrophil recruitment and indirectly through increase in prostaglandins at the site of inflammation. It is suggested that inhibitors of 5-LOX enzyme may have useful therapeutic role in the treatment of chronic intestinal inflammation.

Cholinergic-NO-cGMP mediation of sildenafil-induced antinociception.

Acetylcholine and cholinomimetic agents with predominant muscarinic action are known to increase the concentration of cGMP by activation of nitric oxide signaling pathway in the nociceptive conditions. The present study was aimed to investigate the NO-cGMP-PDE5 pathway in nociceptive conditions in the experimental animals. Nociceptive threshold was assessed by acetic acid-induced writhing assay (chemonociception) or carrageenan-induced hyperalgesia. Sildenafil [1-5 mg/kg, ip, 50-200 microg/paw, intraplantar (ipl)] produced dose dependent antinociception in both the tested models. Coadministration of acetylcholine (50 mcg/paw, ipl) or cholinomimetic agent, neostigmine (0.1 mcg/kg, ip and 25 ng/paw, ipl) augmented the peripheral antinociceptive effect of sildenafil. This effect was sensitive to blockade by L-NAME (20 mg/kg, ip, 100 microg/paw, ipl), a non-selective NOS inhibitor and methylene blue (1 mg/kg, ip), a guanylate cyclase inhibitor, which per se had little or no effect in both the models of nociception. Further, the per se analgesic effect of acetylcholine and neostigmine was blocked by both L-NAME and methylene blue in the models of nociception, suggesting the activation of NO-cGMP pathway. Also, both L-NAME and methylene blue blocked the per se analgesic effect of sildenafil. These results indicate the peripheral accumulation of cGMP may be responsible for antinociceptive effect, and a possible interaction between cholinergic agents and PDE5 system in models of nociception.

Peripheral and central activation of nitric oxide-cyclic GMP pathway by sildenafil.

Experimental studies have indicated the importance of cAMP and cGMP in modulation of peripheral sensory neurons leading to hyperalgesic response. The concentration of both depends upon the activity of phosphodiesterase, which is responsible for their degradation. The aim of the present study was to evaluate the effect of the PDE-5 inhibitor sildenafil on central or peripheral administration in formalin-induced hyperalgesia in rats. Sildenafil dose-dependently and significantly attenuated both the early and late phase of formalin-induced hyperalgesia on central administration. However, sildenafil on peripheral administration inhibited only the late phase of formalin-induced hyperalgesia in rats. The anti-nociceptive effect of sildenafil was blocked by L-NAME, a non-selective NOS inhibitor, and methylene blue (MB), a guanylate cyclase inhibitor, but sildenafil itself had little or no effect on the first phase of the formalin test in rats. The results from the present study indicates that sildenafil, besides peripheral actions, has a central anti-nociceptive effect, which may be due to activation of the NO-cGMP pathway, as this effect was blocked by L-NAME and MB. PDE-5 inhibitors could be considered as a new class of anti-nociceptive agents for future drug development.

Effect of zileuton in radicular pain induced by herniated nucleus pulposus in rats.

Arachidonic acid metabolites, prostaglandins and leukotrienes are detected in clinical cases of herniated nucleus pulposus. However, little is known about their role in the associated symptoms like radicular pain. The aim of the present study was to examine the role of leukotrienes in an animal model of hyperalgesia induced by application of autologus nucleus pulposus to sciatic nerve in rats. Hyperalgesia was assessed employing noxious mechanical and thermal stimuli. Zileuton, a 5-lipoxygenase inhibitor, dose dependently (25-100 mg/kg, p.o.), and indomethacin (2 mg/kg, p.o.), a non-selective cyclooxygenase inhibitor, significantly (P > 0.05) decreased mechanical as well as thermal hyperalgesia on postoperative days 3, 5 and 7 as compared to the nucleus pulposus group. Further, co-administration of zileuton (25 mg/kg, p.o.) with indomethacin (2 mg/kg, p.o.) showed enhanced anti-hyperalgesic effect in both the paradigms as compared to effect per se. The present study, thus, suggested that leukotrienes as well as prostaglandins might play a significant role in hyperalgesia induced by autologus nucleus pulposus in rats. The results suggested that dual inhibition approach of 5-lipoxygenase and cyclooxygenase enzymes may prove beneficial in such conditions.

Modulatory effect of cyclooxygenase inhibitors on sildenafil-induced antinociception.

Peripheral activation of the NO-cGMP pathway has been implicated in various nociceptive conditions. The antinociceptive effect of the PDE-5 inhibitor, sildenafil, alone or in combination with cyclooxygenase inhibitor diclofenac and nimesulide, was assessed in the different animal models of peripheral nociception. In the present study we investigated the possible interaction between cyclooxygenase and NO-cGMP pathway in writhing assay and carrageenan-induced hyperalgesia in mice and rats, respectively. Sildenafil [1-2 mg/kg, i.p. or 50-100 microg/paw, intraplantar (i.pl.)], nimesulide (1-2 mg/kg, i.p. or 25-50 microg/paw, i.pl.) and diclofenac (1-2 mg/kg, i.p. or 25-50 microg/paw, i.pl.) exhibited an antinociceptive effect in both the models. When ineffective doses of sildenafil (0.5 mg/kg, i.p and 25 microg/paw, i.pl.) were co-administered with ineffective doses of nimesulide (0.5 mg/kg, i.p. and 10 microg/paw, i.pl.) and diclofenac (0.5 mg/kg, i.p. and 10 microg/paw, i.pl.), there was a significant increase in the antinociceptive effect in both the models of peripheral nociception. Further, the potentiation of the effect was blocked by L-NAME (20 mg/kg, i.p., 100 microg/paw, i.pl.), a non-selective NOS inhibitor and methylene blue (1 mg/kg, i.p.), a guanylate cyclase inhibitor. L-NAME or methylene blue itself had little or no effect on both the models of hyperalgesia. These results suggest that cyclooxygenase, NO and cGMP are relevant in the combination-induced antinociception. In conclusion, sildenafil induced antinociception, and its potentiation of the effect of the cyclooxygenase inhibitors nimesulide and diclofenac was probably mediated through the activation of the NO-cGMP pathway and inhibition of cyclic GMP degradation.

Modulatory effect of the PDE-5 inhibitor sildenafil in diabetic neuropathy.

Diabetic neuropathy is one of the most frequent peripheral neuropathies associated with hyperalgesia and hyperesthesia. Besides alteration in the levels of neurotransmitter, alteration in the neuronal nitric oxide synthase (nNOS) is a key factor in the pathogenesis of diabetic neuropathy. The present study was aimed at evaluating the role of PDE-5 inhibitor on nociception in streptozotocin-induced diabetes in animal models of nociception (writhing assay in mice and paw hyperalgesia test in rats). Diabetic animals showed a significant decrease in pain threshold as compared to non-diabetic animals in both tests, indicating diabetes induced hyperalgesia in mice and rats. The PDE-5 inhibitor, sildenafil, significantly increased the pain threshold in both diabetic and non-diabetic animals. However, L-NAME, a non-specific NOS inhibitor and methylene blue (MB), a guanylate cyclase inhibitor blocked the antinociceptive effect. The per se administration of L-NAME or MB augmented the hyperalgesic response in diabetic animals with little or no effect in non-diabetic animals, indicating the alteration of NO-cGMP pathway in diabetes. The results in the present study demonstrate that the decreased nNOS-cGMP system may play a crucial role in the pathogenesis of diabetic neuropathy.