[Show abstract][Hide abstract] ABSTRACT: The amount of epicardial adipose tissue (EAT) around the heart has been identified as an independent predictor of coronary artery disease (CAD), potentially through local release of inflammatory cytokines. Ethnic differences have been observed, but no studies have investigated this relationship in the Mexican population. The objective of the present study was to evaluate whether a relationship exist between EAT thickness assessed via echocardiography with CAD and adiponectin levels in a Mexican population.
[Show abstract][Hide abstract] ABSTRACT: The activation of GABAA receptor by γ-amino butyric acid (GABA) in primary afferent fibers produces depolarization. In normal conditions this depolarization causes a reduction in the release of neurotransmitters. Therefore, this depolarization remains inhibitory. However, previous studies have suggested that in inflammatory pain, GABA shifts its signaling from inhibition to excitation by an increased GABA-induced depolarization. The contribution of peripheral α5 subunit-containing GABAA receptors to the inflammatory pain is unknown. The purpose of this study was to investigate the possible pronociceptive role of peripheral α5 subunit-containing GABAA receptors in the formalin test. Formalin (0.5%) injection into the dorsum of the right hind paw produced flinching behavior in rats. Ipsilateral local peripheral pre-treatment (-10min) with exogenous GABA (0.003-0.03µg/paw) or common GABAA receptor agonists muscimol (0.003-0.03µg/paw), diazepam (0.017-0.056µg/paw) or phenobarbital (1-100µg/paw) significantly increased 0.5% formalin-induced nociceptive behavior. The pronociceptive effects of GABA (0.03µg/paw), muscimol (0.03µg/paw), diazepam (0.056µg/paw) and phenobarbital (100µg/paw) were prevented by either the GABAA receptor antagonist bicuculline (0.1-0.01µg/paw) or selective α5 subunit-containing GABAA receptor inverse agonist L-655,708 (0.17-0.017µg/paw). The α5 subunit-containing GABAA receptor protein was expressed in dorsal root ganglion (DRG) and dorsal spinal cord of naïve rats. Formalin injection did not modify α5 subunit-containing GABAA receptor expression. Overall, these results suggest that peripheral α5 subunit-containing GABAA receptors play a pronociceptive role in the rat formalin test.
European journal of pharmacology 04/2014; · 2.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Painful neuropathy is the most common and debilitating complication of diabetes and results in hyperalgesia and allodynia. Hyperglycemia clearly plays a key role in the development and progression of diabetic neuropathy. Current therapeutic approaches are only partially successful and they are only thought to reduce the pain associated with peripheral neuropathy. Some natural products offer combined antioxidant, anti-inflammatory and antinociceptive properties that may help to treat in a more integrative manner this condition. In this regard, the purpose of this study was to investigate the antineuropathic effect of 7-hydroxy-3,4-dihydrocadalin in streptozotocin-induced diabetic rats and mice without glucose control as well as the possible mechanism of action involved in this effect.
Rats and mice were injected with 50 or 200 mg/kg streptozotocin, respectively, to produce hyperglycemia. The formalin test and von Frey filaments were used to assess the nociceptive activity. Rota-rod was utilized to measure motor activity and malondialdehyde assay to determine anti-oxidative properties.
After 3 weeks of diabetes induction, chemical hyperalgesia was observed in streptozotocin-injected rats. Oral acute administration of 7-hydroxy-3,4-dihydrocadalin (0.3-30 mg/kg) decreased in a dose-dependent manner formalin-evoked hyperalgesia in diabetic rats. In addition, methiothepin (non-selective 5-HT receptor antagonist, 1 mg/kg, i.p.) and ODQ (guanylate cyclase inhibitor, 2 mg/kg, i.p.), but not naltrexone (opioid receptor antagonist, 1 mg/kg, s.c.), prevented 7-hydroxy-3,4-dihydrocadalin-induced antihyperalgesic effect. The anti-hyperalgesic effect of 7-hydroxy-3,4-dihydrocadalin was similar to that produced by pregabalin (10 mg/kg, p.o.). Furthermore, oral acute administration of 7-hydroxy-3,4-dihydrocadalin (30 mg/kg) reduced streptozotocin-induced changes in malondialdehyde concentration from plasma samples. Unlike pregabalin, 7-hydroxy-3,4-dihydrocadalin did not affect motor activity. Six weeks after diabetes induction, tactile allodynia was observed in the streptozotocin-injected rats. At this time, oral administration of 7-hydroxy-3,4-dihydrocadalin (30 mg/kg) or pregabalin (10 mg/kg) reduced in a similar way tactile allodynia in diabetic rats. Finally, chronic oral administration of 7-hydroxy-3,4-dihydrocadalin (30-300 mg/kg, 3 times/week, during 6 weeks), significantly prevented the development of mechanical hyperalgesia and allodynia in streptozotocin-induced diabetic mice.
Data suggests that 7-hydroxy-3,4-dihydrocadalin has acute and chronic effects in painful diabetic neuropathy. This effect seems to involve antioxidant properties as well as activation of 5-HT receptors and inhibition of guanylate cyclase enzyme.
BMC Complementary and Alternative Medicine 04/2014; 14(1):129. · 1.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hydrogen sulfide (H2S) is a gasotransmitter endogenously generated from the metabolism of L-cysteine by action of two main enzymes called cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE). This gas has been involved in the pain processing and insulin resistance produced during diabetes development. However, there is no evidence about its participation in the peripheral neuropathy induced by this metabolic disorder. Experimental diabetes was induced by streptozotocin (50 mg/kg, i.p.) in female Wistar rats. Streptozotocin injection increased formalin-evoked flinching in diabetic rats as compared to non-diabetic rats after 2 weeks. Peripheral administration of NaHS (an exogenous donor of H2S) and L-cysteine (an endogenous donor of H2S) dose-dependently increased flinching behavior in diabetic and non-diabetic rats. Contrariwise, hydroxylamine (HA, a CBS inhibitor) and DL-propargylglycine (PPG, a CSE inhibitor) decreased formalin-induced nociceptive behavior in both experimental groups. In addition, an ineffective dose of HA and PPG partially prevented the L-cysteine-induced hyperalgesia in diabetic and non-diabetic rats. Interestingly, HA and PPG were three order of magnitude more potent in diabetic rats respect to non-diabetic rats, whereas NaHS was ten times more potent in the streptozotocin-diabetic group. Nine to 11 weeks after diabetes induction, tactile allodynia was observed in the streptozotocin-injected rats. On this condition, intraperitoneal administration of PPG or HA reduced tactile allodynia in diabetic rats. Paradoxically, H2S levels were decreased in nerve sciatic, dorsal root ganglion and spinal cord, but not blood plasma, during diabetes-associated peripheral neuropathy development. Collectively, results suggest that H2S synthetized by CBS and CSE participate in formalin-induced nociception in diabetic and non-diabetic rats, as well as; in tactile allodynia in streptozotocin-injected rats. In addition, data seems to indicate that diabetic rats are more sensible to H2S-induced hyperalgesia than normoglycemic rats.
[Show abstract][Hide abstract] ABSTRACT: Background: Combinations of non-steroidal anti-inflammatory drugs with opioids are frequently used to reduce opioid doses required in the clinical management of acute pain. The present study was designed to evaluate the possible antinociceptive interaction between morphine and diclofenac at peripheral level in male rats. Methods: Drugs were chosen based on their efficacy in the treatment of this kind of pain and as representative drugs of their respective analgesic groups. For the formalin test, 50 μ of 1% formalin solution was injected subcutaneously into the right hind paw. The interaction between morphine and diclofenac was evaluated by using isobolographic analysis and interaction index. Drug interaction was examined by administering fixed-ratio combinations of morphine-diclofenac (1 : 1 and 3 : 1) of their respective ED30 fractions. Results: Diclofenac and morphine reduced flinching behavior in a dose-dependent manner during phase 2 but not phase 1 of the formalin test. Isobolographic analysis showed a synergistic interaction for the combination of morphine and diclofenac after local peripheral administration. Conclusions: Data suggest that the combination of morphine with diclofenac at the site of injury is synergistic and could be useful in the treatment of wounds, bruises, rheumatisms and other painful peripheral conditions associated with an inflammatory process.
[Show abstract][Hide abstract] ABSTRACT: Intracellular pH is a fundamental parameter to cell function that requires tight homeostasis. In the absence of any regulation, excessive acidification of the cytosol would have the tendency to produce cellular damage. Mammalian Na(+)/H(+) exchangers (NHEs) are electroneutral Na(+)-dependent proteins that exchange extracellular Na(+) for intracellular H(+). To date, there are 9 identified NHE isoforms where NHE1 is the most ubiquitous member, known as the housekeeping exchanger. NHE1 seems to have a protective role in the ischemia-reperfusion injury and other inflammatory diseases. In nociception, NHE1 is found in neurons along nociceptive pathways, and its pharmacological inhibition increases nociceptive behavior in acute pain models at peripheral and central levels. Electrophysiological studies also show that NHE modulates electrical activity of primary nociceptive terminals. However, its role in neuropathic pain still remains controversial. In humans, NHE1 may be responsible for inflammatory bowel diseases since its expression is reduced in Crohn's disease and ulcerative colitis. The purpose of this work is to provide a review of the evidence about participation of NHE1 in the nociceptive processing.
Pain research and treatment. 01/2013; 2013:217864.
[Show abstract][Hide abstract] ABSTRACT: The macronutrient component of diets is critical for metabolic control and insulin action. The aim of this study was to compare the effects of high fat diets (HFDs) vs. high carbohydrate diets (HCDs) on metabolic control and insulin resistance in Wistar rats. Thirty animals divided into five groups (n = 6) were fed: (1) Control diet (CD); (2) High-saturated fat diet (HSFD); (3) High-unsaturated fat diet (HUFD); (4) High-digestible starch diet, (HDSD); and (5) High-resistant starch diet (HRSD) during eight weeks. HFDs and HCDs reduced weight gain in comparison with CD, however no statistical significance was reached. Calorie intake was similar in both HFDs and CD, but rats receiving HCDs showed higher calorie consumption than other groups, (p < 0.01). HRSD showed the lowest levels of serum and hepatic lipids. The HUFD induced the lowest fasting glycemia levels and HOMA-IR values. The HDSD group exhibited the highest insulin resistance and hepatic cholesterol content. In conclusion, HUFD exhibited the most beneficial effects on glycemic control meanwhile HRSD induced the highest reduction on lipid content and did not modify insulin sensitivity. In both groups, HFDs and HCDs, the diet constituents were more important factors than caloric intake for metabolic disturbance and insulin resistance.
International Journal of Environmental Research and Public Health 05/2012; 9(5):1663-76. · 1.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: mRNA and protein presence of Na+/H+ exchanger (NHE) 1 (NHE1) and 5 (NHE5) in dorsal root ganglion (DRG) and dorsal spinal cord as well as its possible role in three inflammatory nociception tests were determined. Local peripheral ipsilateral, but not contralateral, administration of NHE inhibitors 5-(N,N-dimethyl)amiloride hydrochloride (DMA, 0.3-30 microM/paw), 5-(N-ethyl-N-isopropyl)amiloride (EIPA, 0.3-30 microM/paw) and amiloride (0.1-10 microM/paw) significantly increased flinching but not licking behavior in the capsaicin and 5-HT tests. Moreover, DMA and EIPA (0.03-30 microM/paw) as well as amiloride (0.1-1 microM/paw) augmented, in a dose-dependent manner, 0.5% formalin-induced flinching behavior during phase II but not during phase I. Reverse transcription-polymerase chain reaction showed the expression of NHE1 and NHE5 in DRG and dorsal spinal cord. Western blot analysis confirmed the presence of NHE1 in DRG and spinal cord. Moreover, NHE5 was expressed in dorsal spinal cord, but not in DRG where a 45 kDa truncated isoform of NHE5 was identified. Collectively, these data suggest that NHE1, but not NHE5, plays an important role reducing inflammatory pain in rats.
[Show abstract][Hide abstract] ABSTRACT: The pharmacokinetics of meloxicam, a potent analgesic and antiinflammatory drug used in several rheumatic diseases, has been studied in rats that received oral doses of 3.2, 5.6 or 10 mg/kg of meloxicam. Blood samples were obtained at selected times during 24 h after administration, and meloxicam concentrations were determined by a validated high-performance liquid chromatography (HPLC) method, using micro-whole-blood samples, developed in our laboratory. After administration of meloxicam, blood concentrations increased reaching a dose-dependent maximal concentration in about 2 h. Then, concentrations decayed with a half-life of 9 h. An increase in C(max) and AUC as a function of the dose was observed, and no statistically significant difference was observed in AUC/dose or C(max)/dose between doses. However, linearity could not be concluded because of the wide variability observed.
Methods and Findings in Experimental and Clinical Pharmacology 12/2007; 29(9):587-91. · 0.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The effects of cholecystokinin (CCK-8) and the CCK receptor antagonist proglumide, on antinociception induced by local peripheral (subcutaneous) injected morphine in non-diabetic (ND) and streptozotocin-induced diabetic (D) rats, were examined by means of the formalin test. Morphine induced dose-dependent antinociception both in ND and D rats. However, in D rats, antinociceptive morphine potency was about twofold less than in ND rats. Pre-treatment with CCK-8 abolished the antinociceptive effect of morphine in a dose-dependent manner in both groups of rats. Additionally, proglumide enhanced the antinociceptive effect induced by all doses of morphine tested. Both CCK-8 and proglumide had no effect on flinching behaviour when given alone to ND rats. Unlike ND rats, in D rats proglumide produced dose-dependent antinociception and CCK-8 enhanced formalin-evoked flinches, as observed during the second phase of the test. In conclusion, our data show a decrease in peripheral antinociceptive potency of morphine when diabetes was present. Additionally, peripheral CCK plays an antagonic role to the peripheral antinociceptive effect of morphine, additional to the well known CCK/morphine interaction at spinal and supraspinal level.
[Show abstract][Hide abstract] ABSTRACT: The possible pronociceptive role of peripheral cholecystokinin (CCK-8) as well as CCK(A) and CCK(B) receptors in diabetic rats was assessed. Subcutaneous injection of 0.5% formalin induced a greater nociceptive behavior in diabetic than in non-diabetic rats. Moreover, local peripheral injection of CCK-8 (0.1-100 microg) significantly increased 0.5% formalin-induced nociceptive activity in diabetic, but not in non-diabetic, rats. This effect was restricted to the formalin-injected paw as administration of CCK-8 into the contralateral paw was ineffective. Local peripheral administration of CCK-8, in the absence of formalin injection, produced a low level of, but significant increase in, flinching behavior in diabetic compared to non-diabetic rats. In addition, local peripheral administration of the non-selective CCK receptor antagonist proglumide (1-100 microg), CCK(A) receptor antagonist lorglumide (0.1-100 microg) or CCK(B) receptor antagonist CR-2945 (0.1-100 microg), but not vehicle or contralateral administration of CCK receptor antagonists, significantly reduced 0.5% formalin-induced flinching in diabetic rats. CR-2945 was the most effective drug in this condition. These effects were not observed in non-diabetic rats. The local peripheral pronociceptive effect of CCK-8 (100 microg) was significantly reduced by proglumide (100 microg), lorglumide (100 microg), and CR-2945 (100 microg). Results suggest that diabetes-induced peripheral sensitization could be due to a local peripheral release of CCK-8, which in turn would act on CCK(B), mainly but also in CCK(A), receptors located on the primary afferent neurons.
[Show abstract][Hide abstract] ABSTRACT: The local peripheral (subcutaneous) injection of phosphodiesterase 3 inhibitor trequinsin dose-dependently enhanced formalin-evoked flinching during late second phase of this test. Treatment with the nitric oxide synthase inhibitor N-L-nitro-arginine methyl ester or guanylyl cyclase inhibitor 1-H-[1,2,4,]oxadiazolo[4,3-a]quinoxalin-1-one significantly reversed trequinsin-induced pronociceptive effect. Results suggest that the peripheral phosphodiesterase 3 may play an important physiologic role on inflammatory pain by controlling cyclic AMP levels and therefore the nociceptor threshold.
European Journal of Pharmacology 10/2005; 519(1-2):75-9. · 2.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Lamotrigine inhibits glutamate release through the preferential blockade of voltage-dependent Na+ channels. In contrast, morphine reduces release of excitatory amino acids through the activation of opioid receptors and also inhibits tetrodotoxin-resistant Na+ channels on peripheral afferent neurons. The current study was designed to investigate the antinociceptive effects of locally administered morphine and lamotrigine. The interaction between morphine and lamotrigine at the periphery was also examined.
Morphine, lamotrigine, or a combination of morphine and lamotrigine was administered locally to female Wistar rats, and the antinociceptive effect was determined in the formalin test. Isobolographic analyses were used to define the nature of the functional interactions between morphine and lamotrigine.
Peripheral administration of either morphine or lamotrigine produced a dose-related antinociceptive effect. Isobolographic analyses revealed that peripheral morphine and lamotrigine interacted synergistically in the formalin test.
The study shows a functional interaction between lamotrigine and morphine at the peripheral level.
[Show abstract][Hide abstract] ABSTRACT: The involvement of K(+) channels in the antinociceptive action of diclofenac was assessed in the formalin test. Local administration of diclofenac produced a dose-dependent antinociceptive effect due to a local action because drug administration in the contralateral paw was ineffective. Pretreatment of the injured paw with glibenclamide and tolbutamide (ATP-sensitive K(+) channel inhibitors), charybdotoxin and apamin (large- and small-conductance Ca(2+)-activated K(+) channel blockers, respectively), 4-aminopyridine or tetraethylammonium (voltage-dependent K(+) channel inhibitors) prevented diclofenac-induced antinociception. Given alone, K(+) channel inhibitors did not modify formalin-induced nociceptive behavior. Pinacidil (an ATP-sensitive K(+) channel opener) also produced antinociception which was blocked by glibenclamide. The peripheral antinociceptive effect of morphine (positive control) was blocked by glibenclamide and 4-aminopyridine but not by charybdotoxin or apamin. The results suggest that the peripheral antinociceptive effect of diclofenac may result from the activation of several types of K(+) channels, which may cause hyperpolarization of peripheral terminals of primary afferents.
European Journal of Pharmacology 04/2002; 438(1-2):85-91. · 2.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The peripheral antinociceptive effect of the selective COX-2 inhibitor celecoxib in the formalin-induced inflammatory pain was compared with that of resveratrol (COX-1 inhibitor) and diclofenac (non-selective COX inhibitor). Rats received local pretreatment with saline, celecoxib, diclofenac or resveratrol followed by 50 microl of either 1% or 5% formalin. Peripheral administration of celecoxib did not produce antinociception at either formalin concentration. In contrast, diclofenac and resveratrol produced a dose-dependent antinociceptive effect in the second phase of both 1% and 5% formalin test. The peripheral antinociception produced by diclofenac or resveratrol was due to a local action, as drug administration in the contralateral paw was ineffective. Results indicate that the selective COX-2 inhibitor celecoxib does not produce peripheral antinociception in formalin-induced inflammatory pain. In contrast, selective COX-1 and non-selective COX inhibitors (resveratrol and diclofenac, respectively) are effective drugs in this model of pain.
Life Sciences 03/2002; 70(14):1669-76. · 2.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The involvement of nitric oxide (NO), cyclic GMP and ATP-sensitive K(+) channels in the antinociceptive effect of ketorolac was assessed using the formalin test in the rat. Local administration of ketorolac in a formalin-injured paw produced a dose-dependent antinociceptive effect due to a local action, as drug administration in the contralateral paw was ineffective. Pretreatment of the injured paw with N(G)-L-nitro-arginine methyl ester (L-NAME, an NO synthesis inhibitor), 1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ, a soluble guanylyl cyclase inhibitor) or glibenclamide (an ATP-sensitive K(+) channel blocker) prevented ketorolac-induced antinociception. However, pretreatment with saline or N(G)-D-nitro-arginine methyl ester (D-NAME) did not block antinociception. Local administration of S-nitroso-N-acetylpenicillamine (SNAP, an NO donor) was inactive by itself, but increased the effect of ketorolac. The present results suggest that the antinociceptive effect of ketorolac involves activation of the NO-cyclic GMP pathway, followed by an opening of ATP-sensitive K(+) channels at the peripheral level.
European Journal of Pharmacology 09/2001; 426(1-2):39-44. · 2.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The antinociceptive activity of an inhibitor of phosphodiesterase 5, alone or combined with diclofenac, was assessed in the formalin test. Local administration of diclofenac produced a significant antinociception in both phases of the formalin test in female Wistar rats. In contrast, 1-[4-ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [3,4-d]pyrimidin-5-yl)phenylsulfonyl]-4-methyl piperazine (sildenafil, an inhibitor of phosphodiesterase 5) produced significant antinociception, only during the second phase of the formalin test. Non-effective doses of sildenafil (25-100 microg/paw) significantly increased the antinociceptive effect of an inactive dose of diclofenac (25 microg) in both phases of the test. The antinociception produced by the drugs alone or the combination was due to a local action, as its administration in the contralateral paw was ineffective. Since sildenafil is a potent and selective inhibitor of phosphodiesterase 5, our results suggest that this drug produced its antinociceptive activity, and increased that of diclofenac, probably through the inhibition of cyclic GMP degradation.
European Journal of Pharmacology 05/2001; 418(3):195-200. · 2.68 Impact Factor