Jair Lozano-Cuenca

Center for Research and Advanced Studies of the National Polytechnic Institute, Irapuato, Guanajuato, Mexico

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Publications (21)49.87 Total impact

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    ABSTRACT: We have previously shown that 5-HT(1B) receptors inhibit prejunctionally the rat vasodepressor CGRPergic sensory outflow. Since 5-HT(1) receptors comprise 5-HT(1A), 5-HT(1B), 5-HT(1D) and 5-HT(1F) functional subtypes, this study has further investigated the role of 5-HT(1A), 5-HT(1D) and 5-HT(1F) receptor subtypes in the inhibition of the above vasodepressor sensory outflow. Pithed rats were pretreated with i.v. continuous infusions of hexamethonium and methoxamine, followed by 5-HT(1) receptor agonists. Then electrical spinal stimulation (T(9)-T(12)) or i.v. bolus injections of exogenous α-CGRP produced frequency-dependent or dose-dependent vasodepressor responses. The electrically-induced vasodepressor responses remained unchanged during infusions of the 5-HT(1A) receptor agonists 8-OH-DPAT and NN-DP-5-CT. In contrast, these responses were inhibited by the agonists sumatriptan (5-HT(1A/1B/1D/1F)), indorenate (5-HT(1A)), PNU-142633 (5-HT(1D)) or LY344864 (5-HT(1F)), which did not affect the vasodepressor responses to exogenous CGRP (implying a prejunctional sensory-inhibition). When analysing the effects of antagonists: (i) 310 μg/kg (but not 100 μg/kg) GR127935 (5-HT(1A/1B/1D/1F)) abolished the inhibition to sumatriptan, indorenate, PNU-142633 or LY344864; (ii) 310 μg/kg SB224289 (5-HT(1B)) or BRL15572 (5-HT(1D)) failed to block the inhibition to sumatriptan or PNU-142633, whereas SB224289+BRL15572 partly blocked the inhibition to sumatriptan; and (iii) 10 μg/kg WAY100635 (5-HT(1A)) failed to block the inhibition to indorenate. These results suggest that 5-HT(1F), but not 5-HT(1A) or 5-HT(1D), receptor subtypes inhibit the vasodepressor sensory CGRPergic outflow although, admittedly, no selective 5-HT(1F) receptor agonist is available yet. The pharmacological profile of these receptors resembles that shown in rat dorsal root ganglia by molecular biology techniques.
    European journal of pharmacology 06/2011; 659(2-3):233-43. · 2.59 Impact Factor
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    ABSTRACT: The importance of calcitonin gene-related peptide (CGRP) in the regulation of vascular tone has been widely documented. Indeed, stimulation of the perivascular sensory outflow in pithed rats results in vasodepressor responses, which are mediated by CGRP release. These vasodepressor responses are inhibited by clonidine via prejunctional alpha(2A/2C)-adrenoceptors, but no study has yet reported the role of prejunctional 5-hydroxytryptamine (5-HT) receptors in this experimental model. Since activation of prejunctional 5-HT(1) receptors results in inhibition of neurotransmitter release, this study sets out to investigate as an initial approach the role of 5-HT(1B) receptors in the inhibition of the vasodepressor sensory outflow in pithed rats. Male Wistar pithed rats were pretreated with hexamethonium (2mg/kg.min) followed by i.v. continuous infusions of methoxamine (20 microg/kg min), and then by saline (0.02 ml/min) or CP-93,129 (a rodent 5-HT(1B) receptor agonist; 0.1, 1 and 10 microg/kg min). Under these conditions, electrical stimulation (0.56-5.6 Hz; 50 V and 2 ms) of the spinal cord (T(9)-T(12)) resulted in frequency-dependent decreases in diastolic blood pressure. The infusions of CP-93,129, as compared to those of saline, inhibited the vasodepressor responses induced by electrical stimulation without affecting those to i.v. bolus injections of exogenous alpha-CGRP (0.1, 0.18, 0.31, 0.56 and 1 microg/kg). This inhibition by CP-93,129 was abolished by the antagonists GR127935 (5-HT(1B/1D)) or SB224289 (5-HT(1B)), but not by BRL15572 (5-HT(1D)). The above results suggest that CP-93,129-induced inhibition of the vasodepressor (perivascular) sensory outflow in pithed rats is mainly mediated by activation of prejunctional 5-HT(1B) receptors.
    European journal of pharmacology 04/2010; 637(1-3):131-7. · 2.59 Impact Factor
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    ABSTRACT: Serotonin (5-hydroxytryptamine; 5-HT) has been shown to produce vascular sympatho-inhibition in a wide variety of isolated blood vessels by activation of prejunctional 5-HT1 receptors. After considering the mechanisms involved in modulating neuroeffector transmission, the present review analyzes the experimental findings identifying the pharmacological profile of the 5-HT receptors that inhibit the sympathetically-induced vasopressor responses in pithed rats. Thus, 5-HT-induced sympatho-inhibition has been shown to be: (i) unaffected by physiological saline or by the selective antagonists ritanserin (5-HT2), MDL72222 (5-HT3) or tropisetron (5-HT3/4); (ii) blocked by methysergide, a non-selective 5-HT1/2 receptor antagonist; and (iii) potently mimicked by 5-carboxamidotryptamine (5-CT), a non-selective 5-HT1 receptor agonist, as well as by the selective agonists 8-OH-DPAT (5-HT1A), indorenate (5-HT1A), CP93,129 (5-HT1B), and sumatriptan (5-HT1B/1D). These findings show the involvement of prejunctional 5-HT1 receptors. With the use of selective antagonists, it has been shown subsequently that the sympatho-inhibition induced by indorenate, CP93, 129, and sumatriptan was selectively antagonized by WAY100635 (5-HT1A), cyanopindolol (5-HT1A/1B), and GR127935 (5-HT1B/1D), respectively. These results demonstrate that the 5-HT1 receptors mediating sympatho-inhibition on the systemic vasculature of pithed rats resemble the pharmacological profile of the 5-HT1A, 5-HT1B, and 5-HT1D subtypes.
    Archivos de cardiología de México 12/2009; 79 Suppl 2:83-94.
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    ABSTRACT: Serotonin (5–hydroxytryptamine; 5–HT) has been shown to produce vascular sympatho–inhibition in a wide variety of isolated blood vessels by activation of prejunctional 5–HT1 receptors. After considering the mechanisms involved in modulating neuroeffector transmission, the present review analyzes the experimental findings identifying the pharmacological profile of the 5–HT receptors that inhibit the sympathetically–induced vasopressor responses in pithed rats. Thus, 5–HT–induced sympatho–inhibition has been shown to be: (i) unaffected by physiological saline or by the selective antagonists ritanserin (5–HT2), MDL72222 (5–HT3) or tropisetron (5–HT3/4); (ii) blocked by methysergide, a non–selective 5–HT1/2 receptor antagonist; and (iii) potently mimicked by 5–carboxamidotryptamine (5–CT), a non–selective 5–HT1 receptor agonist, as well as by the selective agonists 8–OH–DPAT (5–HT1A) indorenate (5–HT1A), CP93,129 (5–HT1B), and sumatriptan (5–HT1B/1D). These findings show the involvement of prejunctional 5–HT1 receptors. With the use of selective antagonists, it has been shown subsequently that the sympathoinhibition induced by indorenate, CP93,129, and sumatriptan was selectively antagonized by WAY100635 (5–HT1A), cyanopindolol (5–HT1A/1B), and GR127935 (5–HT1B/1D), respectively,. These results demonstrate that the 5–HT1 receptors mediating sympatho–inhibition on the systemic vasculature of pithed rats resemble the pharmacological profile of the 5–HT1A, 5–HT1B, and 5–HT1D subtypes.
    Archivos de cardiología de México 12/2009; 79:83-94.
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    ABSTRACT: This study analysed the inhibition produced by the agonists moxonidine (imidazoline I(1) receptors>alpha(2)-adrenoceptors) and agmatine (endogenous ligand of imidazoline I(1)/I(2) receptors), using B-HT 933 (6-ethyl-5,6,7,8-tetrahydro-4H-oxazolo[4,5-d]azepin-2-amine dihydrochloride; alpha(2)-adrenoceptors) for comparison, on the rat cardioaccelerator sympathetic outflow. Male Wistar rats were pithed and prepared to stimulate the cardiac sympathetic outflow or to receive i.v. bolus of exogenous noradrenaline. Sympathetic stimulation or noradrenaline produced, respectively, frequency-dependent and dose-dependent tachycardic responses. I.v. continuous infusions of moxonidine (3 and 10 microg/kg min), agmatine (1000 and 3000 microg/kg min) and B-HT 933 (30 and 100 microg/kg min) inhibited the tachycardic responses to sympathetic stimulation, but not those to noradrenaline. The cardiac sympatho-inhibition by either moxonidine (3 microg/kg min) or B-HT 933 (30 microg/kg min) was not modified by i.v. injections of saline or the antagonists AGN192403 [(+/-)-2-endo-Amino-3-exo-isopropylbicyclo[2.2.1]heptane hydrochloride; 3000microg/kg; imidazoline I(1) receptors] or BU224 (2-(4,5-dihydroimidazol-2-yl)quinoline hydrochloride; 300 microg/kg; imidazoline I(2) receptors) and abolished by rauwolscine (300 microg/kg; alpha(2)-adrenoceptors). At the same doses of these compounds, the sympatho-inhibition to moxonidine (10 microg/kg min) and agmatine (1000 microg/kg min) was: (1) not modified by saline, AGN192403 or BU224; (2) partially blocked by rauwolscine or the combination of rauwolscine plus BU224; and (3) abolished by the combination of rauwolscine plus AGN192403. These results demonstrate that the cardiac sympatho-inhibition to: (1) 3 microg/kg min moxonidine or 30 microg/kg min B-HT 933 involves alpha(2)-adrenoceptors; and (2) 10 microg/kg min moxonidine or 1000 microg/kg min agmatine involves alpha(2)-adrenoceptors and imidazoline I(1) receptors.
    European journal of pharmacology 07/2009; 616(1-3):175-82. · 2.59 Impact Factor
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    ABSTRACT: Migraine is a neurovascular disorder associated with trigeminal activation, vasodilatation and trigeminal release of calcitonin gene-related peptide (CGRP). The antimigraine properties of triptans may be due to: i) vasoconstriction of the carotid arterial bed via 5-HT(1B) receptors; and ii) inhibition of CGRP release from trigeminal nerves, via 5-HT(1B/1D) receptors. This study investigated the effects of intrathecally administered sumatriptan (a 5-HT(1B/1D) receptor agonist) and PNU-142633 (a 5-HT(1D) receptor agonist) on the canine external carotid vasodilator responses to capsaicin, alpha-CGRP and acetylcholine. For this purpose, 42 mongrel dogs were anaesthetised with sodium pentobarbitone and, subsequently, vagosympathectomized. The animals were prepared to measure arterial blood pressure, heart rate and external carotid blood flow; the thyroid artery was cannulated for infusion of agonists. 1-min intracarotid (i.c.) continuous infusions of capsaicin, alpha-CGRP and acetylcholine produced dose-dependent increases in external carotid blood flow without affecting arterial blood pressure or heart rate. These vasodilator responses remained unaffected after intrathecal (i.t.) administration of physiological saline (0.5 ml) or PNU-142633 (300-1000 microg); in contrast, i.t. sumatriptan (300-1000 microg) significantly inhibited the vasodilator responses to capsaicin, but not those to alpha-CGRP or acetylcholine. Furthermore, i.t. administration of SB224289 (a 5-HT(1B) receptor antagonist), but not of BRL15572 (a 5-HT(1D) receptor antagonist), abolished the above inhibition by sumatriptan. These results suggest that sumatriptan-induced inhibition of the external carotid vasodilatation to capsaicin involves a central mechanism mainly mediated by 5-HT(1B) receptors.
    European journal of pharmacology 06/2009; 615(1-3):133-8. · 2.59 Impact Factor
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    ABSTRACT: The present study set out to analyse the pharmacological profile of the inhibitory responses induced by the antimigraine agents dihydroergotamine (DHE) and methysergide on the tachycardic responses to preganglionic sympathetic stimulation in pithed rats. For this purpose, 132 male Wistar normotensive rats were pithed and prepared to: (i) selectively stimulate the preganglionic (C(7)-T(1)) cardiac sympathetic outflow; or (ii) receive intravenous (i.v.) bolus injections of exogenous noradrenaline. Electrical sympathetic stimulation or exogenous noradrenaline produced, respectively, frequency-dependent and dose-dependent tachycardic responses. Moreover, i.v. continuous infusions of DHE (1.8, 3.1 and 5.6 microg/kg x min) or methysergide (100, 300 and 1000 microg/kg x min) dose-dependently inhibited the tachycardic responses to sympathetic stimulation, but not those to exogenous noradrenaline. Using physiological saline or antagonists (given as i.v. bolus injections), the cardiac sympatho-inhibition induced by either DHE (3.1 microg/kg x min) or methysergide (300 microg/kg x min) was: (1) unaffected by saline (1 ml/kg); (2) partially blocked by the antagonists rauwolscine (300 microg/kg; alpha(2)) or N-[4-methoxy-3-(4-methyl-1-piperazinyl) phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl) [1,1,-biphenyl]-4-carboxamide hydrochloride monohydrate (GR127935, 300 microg/kg; 5-HT(1B/1D)); and (3) completely antagonised by the combination rauwolscine plus GR127935. These antagonists, at doses high enough to completely block their respective receptors, failed to modify the sympathetically-induced tachycardic responses per se. The above results, taken together, suggest that the cardiac sympatho-inhibition induced by DHE (3.1 microg/kg x min) and methysergide (300 microg/kg x min) may be mainly mediated by stimulation of both alpha(2)-adrenoceptors and 5-HT(1B/1D) receptors.
    European journal of pharmacology 05/2009; 612(1-3):80-6. · 2.59 Impact Factor
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    ABSTRACT: This study analyzed in pithed rats the effect of several acute and prophylactic antimigraine drugs on the CGRPergic vasodepressor sensory outflow, in an attempt to investigate systemic cardiovascular effects in a model unrelated to migraine. Male Wistar pithed rats were pretreated with continuous i.v. infusions of hexamethonium (2 microg/kg.min; to block autonomic outflow) and methoxamine (15-20 microg/kg.min; to maintain diastolic blood pressure at around 130 mmHg). Under these conditions, the effect of both electrical stimulation (0.56-5.6 Hz; 50 V and 2 ms) of the spinal cord (T(9)-T(12)) or i.v. bolus injections of exogenous alpha-CGRP (0.1-1 microg/kg) were studied in animals pretreated with continuous i.v. infusions of sumatriptan (1-100 microg/kg.min), ergotamine (0.18-0.56 microg/kg.min), dihydroergotamine (1-10 microg/kg.min), magnesium valproate (1000-1800 microg/kg.min), propranolol (100-300 microg/kg.min) or their respective vehicles. Electrical stimulation of the spinal cord and i.v. bolus injections of exogenous alpha-CGRP resulted in, respectively, frequency- and dose-dependent decreases in diastolic blood pressure without affecting heart rate. Moreover, the infusions of sumatriptan, ergotamine and dihydroergotamine, but not of magnesium valproate, propranolol or their respective vehicles, dose-dependently inhibited the vasodepressor responses to electrical stimulation. In contrast, sumatriptan (10 microg/kg.min), ergotamine (0.31 microg/kg.min) and dihydroergotamine (3 microg/kg.min) failed to inhibit the vasodepressor responses to exogenous alpha-CGRP. The above findings suggest that the acute (rather than the prophylactic) antimigraine drugs attenuate the vasodepressor sensory outflow mainly by prejunctional mechanisms. This may be of particular relevance when considering potential cardiovascular adverse effects by acute antimigraine drugs.
    Life Sciences 12/2008; 84(5-6):125-31. · 2.56 Impact Factor
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    ABSTRACT: Ergotamine inhibits the sympathetically-induced tachycardia in pithed rats. The present study identified the pharmacological profile of this response. Male Wistar rats were pithed and prepared to stimulate the preganglionic (C(7)-T(1)) cardiac sympathetic outflow. Intravenous continuous infusions of ergotamine dose-dependently inhibited the tachycardic responses to sympathetic stimulation, but not those to exogenous noradrenaline. Using several antagonists, the sympatho-inhibition to ergotamine was: (1) partially blocked by rauwolscine (alpha(2)), haloperidol (D(1/2)-like) or rauwolscine plus GR127935 (5-HT(1B/1D)); (2) abolished by rauwolscine plus haloperidol; and (3) unaffected by either saline or GR127935. In animals systematically pretreated with haloperidol, this sympatho-inhibition was: (1) unaffected by BRL44408 (alpha(2A)), partially antagonized by MK912 (alpha(2C)); and (3) abolished by BRL44408 plus MK912. These antagonists failed to modify the sympathetically induced tachycardic responses per se. Thus, the cardiac sympatho-inhibition by ergotamine may be mainly mediated by alpha(2A)/alpha(2C)-adrenoceptors, D(2)-like receptors and, to a lesser extent, by 5-HT(1B/1D) receptors.
    Archiv für Experimentelle Pathologie und Pharmakologie 10/2008; 379(2):137-48. · 2.15 Impact Factor
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    ABSTRACT: British Journal of Pharmacology (2008) 154, 1160; doi:10.1038/bjp.2008.250
    British Journal of Pharmacology 08/2008; 154(5):1160. · 5.07 Impact Factor
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    ABSTRACT: Resistance blood vessels are innervated by sympathetic and primary sensory nerves, which modulate vascular tone through the release of noradrenaline and calcitonin gene-related peptide (CGRP), respectively. Moreover, electrical stimulation of the perivascular sensory outflow in pithed rats results in vasodepressor responses which are mainly mediated by CGRP release. The present study has investigated the role of alpha(2)-adrenoceptors in the inhibition of these vasodepressor responses. 144 pithed male Wistar rats were pretreated with hexamethonium (2 mg kg(-1) min(-1)) followed by i.v. continuous infusions of either methoxamine (15 and 30 microg kg(-1) min(-1)) or clonidine (3, 10 and 30 microg kg(-1) min(-1)). Under these conditions, electrical stimulation (0.56-5.6 Hz; 50 V and 2 ms) of the spinal cord (T(9)-T(12)) resulted in frequency-dependent decreases in diastolic blood pressure. The infusion of clonidine (10 microg kg(-1) min(-1)), as compared to those of methoxamine (15 or 30 microg kg(-1) min(-1)), inhibited the vasodepressor responses to electrical stimulation without affecting those to i.v. bolus injections of alpha-CGRP (0.1-1 microg kg(-1)). This inhibition by clonidine was: (i) antagonized by 300 microg kg(-1) rauwolscine (alpha(2A/2B/2C)), 300 and 1000 microg kg(-1) BRL44408 (alpha(2A)), or 10 and 30 microg kg(-1) MK912 (alpha(2C)); and (ii) unaffected by 1 ml kg(-1) saline, 100 microg kg(-1) BRL44408, 3000 and 10,000 microg kg(-1) imiloxan (alpha(2B)) or 3 microg kg(-1) MK912. The inhibition produced by 10 microg kg(-1) min(-1) clonidine on the vasodepressor (perivascular) sensory outflow in rats may be mainly mediated by prejunctional alpha(2A)/alpha(2C)-adrenoceptors.
    British Journal of Pharmacology 06/2008; 154(1):51-9. · 5.07 Impact Factor
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    ABSTRACT: It has been proposed that the antinociception of systemic diclofenac is the outcome of peripheral and central actions. Hence, our purpose was to examine if systemic diclofenac is able to achieve effective concentrations at local and spinal sites and to characterize the interaction between its local and spinal actions. Pain was produced in the rat using the formalin test. Oral diclofenac (1–10 mg/kg) reduced formalin-induced pain. The antinociceptive effect of oral diclofenac (10 mg/kg) was abolished by local or spinal administration of either L-NAME (1–100 µg and 1–50 µg) or glibenclamide (12.5–100 µg and 25–75 µg). These results suggest that oral diclofenac achieves effective concentrations producing an antinociceptive effect involving participation of the NO–potassium channel pathway at both, the local and spinal levels. In an additional experimental series, diclofenac was administered either locally (25–200 μg) or spinally (12.5–100 μg), yielding an antinociceptive effect by both routes. Then, diclofenac was given simultaneously by these two routes in a fixed-ratio, and antinociception was assayed. Isobolographic analysis revealed an additive interaction between the local and spinal effects of diclofenac. Hence, our results provide evidence that the overall antinociceptive effect induced by systemic diclofenac is the outcome of central and peripheral mechanisms.
    Pharmacology Biochemistry and Behavior 01/2008; · 2.82 Impact Factor
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    ABSTRACT: Capsaicin, a pungent constituent from red chilli peppers, activates sensory nerve fibres via transient receptor potential vanilloid receptors type 1 (TRPV1) to release neuropeptides like calcitonin gene-related peptide (CGRP) and substance P. Capsaicin-sensitive nerves are widely distributed in human and porcine vasculature. In this study, we examined the mechanism of capsaicin-induced relaxations, with special emphasis on the role of CGRP, using various pharmacological tools. Segments of human and porcine proximal and distal coronary arteries, as well as cranial arteries, were mounted in organ baths. Concentration response curves to capsaicin were constructed in the absence or presence of the CGRP receptor antagonist olcegepant (BIBN4096BS, 1 microM), the neurokinin NK1 receptor antagonist L-733060 (0.5 microM), the voltage-sensitive calcium channel blocker ruthenium red (100 microM), the TRPV1 receptor antagonist capsazepine (5 microM), the nitric oxide synthetase inhibitor Nomega-nitro-L-arginine methyl ester HCl (L-NAME; 100 microM), the gap junction blocker 18alpha-glycyrrhetinic acid (10 microM), as well as the RhoA kinase inhibitor Y-27632 (1 microM). Further, we also used the K+ channel inhibitors 4-aminopyridine (1 mM), charybdotoxin (0.5 microM) + apamin (0.1 microM) and iberiotoxin (0.5 microM) + apamin (0.1 microM). The role of the endothelium was assessed by endothelial denudation in distal coronary artery segments. In distal coronary artery segments, we also measured levels of cyclic adenosine monophosphate (cAMP) after exposure to capsaicin, and in human segments, we also assessed the amount of CGRP released in the organ bath fluid after exposure to capsaicin. Capsaicin evoked concentration-dependent relaxant responses in precontracted arteries, but none of the above-mentioned inhibitors did affect these relaxations. There was no increase in the cAMP levels after exposure to capsaicin, unlike after (exogenously administered) alpha-CGRP. Interestingly, there were significant increases in CGRP levels after exposure to vehicle (ethanol) as well as capsaicin, although this did not induce relaxant responses. In conclusion, the capsaicin-induced relaxations of the human and porcine distal coronary arteries are not mediated by CGRP, NK1, NO, vanilloid receptors, voltage-sensitive calcium channels, K+ channels or cAMP-mediated mechanisms. Therefore, these relaxant responses to capsaicin are likely to be attributed to a non-specific, CGRP-independent mechanism.
    Archiv für Experimentelle Pathologie und Pharmakologie 04/2007; 375(1):29-38. · 2.15 Impact Factor
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    ABSTRACT: Combinations of NSAIDs and opioids are currently employed for the treatment of moderate-to-severe pain in order to obtain an increased analgesic esponse, allowing the use of low doses of each agent, hence limiting side effects. There is active interest in developing combinations for oral adminstration. Therefore, we examined the antinociceptive activity of oral indomethacin and codeine, alone and incombination, in the formalin test in the rat. Both codeine and indomethacin, when given alone, produced a dose-dependent antinociceptive effect. ED30 values were 5.0 +/- 0.31 and 54.8 +/- 5.8 mg/kg for codeine and indomethacin respectively. Codeine-indomethacin combinations also produced a dose-dependent antinociceptive effect. The interaction between these two agents was characterized by isobolographic analysis using a fixed-ratio dosing strategy. Accordingly, the theoretical ED30 of the combination for a pure additive interaction, (i.e., that the combined effect is the result of the sum of the effects of the individual components), was 29.9 +/- 2.9 mg/kg. The observed ED30 for the codeine-indomethacin combination was 21.7 +/- 2.34 mg/kg. Comparison by the Student "t" test showed that there is no statistically significant difference (p > 0.05) between the observed and the theoretical DE30 values and thus a synergistic interaction is ruled out. We conclude that the indomethacin-codeine interaction is additive and does not result in analgesic synergism, unlike other combinations such as codeine-diclofenac. Our results show that, since not all the opioid-NSAID associations result in synergism, the individual components of a combination should be carefully selected, and that mechanisms of synergy may suggest actions of the NSAID partner not previously known.
    Proceedings of the Western Pharmacology Society 02/2007; 50:78-81.
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    ABSTRACT: It has been suggested that the alpha(2)-adrenoceptors mediating cardiac sympatho-inhibition in pithed rats closely resemble the pharmacological profile of the alpha(2A)-adrenoceptor subtype. However, several lines of evidence suggest that more than one subtype may be involved. Thus, the present study has pharmacologically re-evaluated the receptor subtype(s) involved in the inhibitory effect of the alpha(2)-adrenoceptor agonist, B-HT 933, on the tachycardic responses elicited by selective cardiac sympathetic stimulation (0.03, 0.1, 0.3, 1 and 3 Hz) in desipramine-pretreated pithed rats. I.v. continuous infusions of B-HT 933 (30 microg/kg min), which failed to modify the tachycardic responses to exogenous noradrenaline, inhibited those induced by preganglionic (C(7)-T(1)) stimulation of the cardiac sympathetic outflow at all frequencies of stimulation (0.03-3 Hz). This cardiac sympatho-inhibitory response to B-HT 933 was: (1) unaltered by saline (1 ml/kg) or the antagonists BRL44408 (100 microg/kg; alpha(2A)) or imiloxan (3000 and 10,000 microg/kg; alpha(2B)); (2) partially antagonized by BRL44408 (300 microg/kg) or MK912 (10 microg/kg; alpha(2C)) given separately; and (3) completely antagonized by rauwolscine (300 microg/kg; alpha(2)), MK912 (30 microg/kg) or the combination of BRL44408 (300 microg/kg) plus MK912 (10 microg/kg). Moreover, the above doses of antagonists, which are high enough to block their respective receptors, failed to block per se the tachycardic responses to sympathetic stimulation. These results suggest that the cardiac sympatho-inhibition induced by B-HT 933 in pithed rats is mainly mediated by stimulation of alpha(2A)- and alpha(2C)-adrenoceptors.
    European Journal of Pharmacology 02/2007; 554(2-3):205-11. · 2.59 Impact Factor
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    ABSTRACT: It has been suggested that during a migraine attack capsaicin-sensitive trigeminal sensory nerves release calcitonin gene-related peptide (CGRP), resulting in cranial vasodilatation and central nociception; hence, trigeminal inhibition may prevent this vasodilatation and abort migraine headache. This study investigated the effects of the agonists sumatriptan (5-HT(1B/1D) water-soluble), donitriptan (5-HT(1B/1D) lipid-soluble), PNU-142633 (5-HT(1D) water-soluble) and PNU-109291 (5-HT(1D) lipid-soluble) on vasodilator responses to capsaicin, alpha-CGRP and acetylcholine in dog external carotid artery. 59 vagosympathectomized dogs were anaesthetized with sodium pentobarbitone. Blood pressure and heart rate were recorded with a pressure transducer, connected to a cannula inserted into a femoral artery. A precalibrated flow probe was placed around the common carotid artery, with ligation of the internal carotid and occipital branches, and connected to an ultrasonic flowmeter. The thyroid artery was cannulated for infusion of agonists. Intracarotid infusions of capsaicin, alpha-CGRP and acetylcholine dose-dependently increased blood flow through the carotid artery. These responses remained unaffected after intravenous (i.v.) infusions of sumatriptan, PNU-142633, PNU-109291 or physiological saline; in contrast, donitriptan significantly attenuated the vasodilator responses to capsaicin, but not those to alpha-CGRP or acetylcholine. Only sumatriptan and donitriptan dose-dependently decreased the carotid blood flow. Interestingly, i.v. administration of the antagonist, SB224289 (5-HT(1B)), but not of BRL15572 (5-HT(1D)), abolished the inhibition by donitriptan. Our results suggest that the inhibition produced by donitriptan of capsaicin-induced external carotid vasodilatation is mainly mediated by 5-HT(1B), rather than 5-HT(1D), receptors, probably by a central mechanism.
    British Journal of Pharmacology 10/2006; 149(1):82-91. · 5.07 Impact Factor
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    ABSTRACT: Migraine is a disorder associated with increased plasma concentrations of calcitonin gene-related peptide (CGRP). CGRP, a neuropeptide released from activated trigeminal sensory nerves, dilates cranial blood vessels and transmits vascular nociception. Moreover, several antimigraine drugs inhibit the dural neurogenic vasodilatation to trigeminal stimulation. Hence, this study investigated in anaesthetized dogs the effects of the alpha(2)-adrenoceptor agonist, clonidine, on the external carotid vasodilator responses to capsaicin, alpha-CGRP and acetylcholine. 1-min intracarotid infusions of capsaicin (10, 18, 30 and 56 microg/min), alpha-CGRP (0.1, 0.3, 1 and 3 microg/min) and acetylcholine (0.01, 0.03, 0.1 and 0.3 microg/min) produced dose-dependent increases in external carotid conductance without affecting blood pressure or heart rate. Interestingly, the carotid vasodilator responses to capsaicin, but not those to alpha-CGRP or acetylcholine, were partially inhibited after clonidine (total dose: 24.4 microg/kg, i.v.); in contrast, equivalent volumes of saline did not affect the responses to capsaicin, alpha-CGRP or acetylcholine. The inhibitory responses to clonidine were antagonized by i.v. administration of the alpha(2)-adrenoceptor antagonists rauwolscine (alpha(2A/2B/2C); 300 microg/kg), BRL44408 (alpha(2A); 1000 microg/kg) or MK912 (alpha(2C); 100 and 300 microg/kg), but not by imiloxan (alpha(2B); 1000 microg/kg). These results suggest that clonidine inhibits the external carotid vasodilator responses to capsaicin by peripheral trigeminovascular and/or central mechanisms; this inhibitory response to clonidine seems to be predominantly mediated by alpha(2A)-adrenoceptors and, to a much lesser extent, by alpha(2C)-adrenoceptors.
    European Journal of Pharmacology 09/2006; 543(1-3):68-76. · 2.59 Impact Factor
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    ABSTRACT: The possible participation of the nitric oxide (NO)-cyclic GMP-K(+) channel pathway, serotonergic or opioidergic system on lumiracoxib-induced local or intrathecal antinociception was assessed in the formalin test. Local or intrathecal administration of lumiracoxib dose-dependently produced antinociception in the second phase of the test. Moreover, local or intrathecal pretreatment with N(G)-L-nitro-arginine methyl ester (L-NAME, NO synthesis inhibitor), 1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ, guanylyl cyclase inhibitor), glibenclamide (ATP-sensitive K(+) channel blocker), charybdotoxin and apamin (large- and small-conductance Ca(2+)-activated-K(+) channel blockers, respectively) or margatoxin (voltage-dependent K(+) channel blocker), but not N(G)-D-nitro-arginine methyl ester (D-NAME) or vehicle, significantly prevented lumiracoxib-induced antinociception. The intrathecal injection of methiothepin (serotonin receptor antagonist) reduced lumiracoxib-induced intrathecal antinociception. Local peripheral or intrathecal naloxone did not modify either local or intrathecal lumiracoxib-induced antinociception. Results suggest that lumiracoxib activates the NO-cyclic GMP-K(+) channels to produce local and intrathecal antinociception. Data also suggest that lumiracoxib activates the intrathecal serotonergic system, but not opioid receptors either at peripheral or spinal sites.
    European Journal of Pharmacology 05/2005; 513(1-2):81-91. · 2.59 Impact Factor