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Pamabrom is a diuretic that is effective in treating premenstrual syndrome and primary dysmenorrhea. The aim of this study was to examine the effect of metformin and modulators of the opioid receptor-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP)-[K.sup.+] channel pathway on the local antinociception induced by pamabrom. The rat paw 1% formalin test was used to assess the effects. Rats were treated with local administration of pamabrom (200-800 [micro]g/paw) or indomethacin (200800 [micro]g/paw). The antinociception of pamabrom or indomethacin was evaluated with and without the local pretreatment of the blockers. Local administration of pamabrom and indomethacin produced dose-dependent antinociception during the second phase of the test. Local pretreatment of the paws with naloxone (50 [micro]g/paw), L-nitro-arginine methyl ester (10-100 [micro]g/paw), or 1H-(1,2,4)-oxadiazolo[4,2-a]quinoxalin-1-one (10-100 [micro]g/paw) reverted the antinociception induced by local pamabrom, but not of indomethacin. Similarly, the [K.sup.+] channel blockers glibenclamide, glipizide, 4-aminopyridine, tetraethylammonium, charybdotoxin, or apamin reverted the pamabrom-induced antinociception, but not of indomethacin. Metformin significantly blocked the antinociception of pamabrom and indomethacin. Our data suggest that pamabrom could activate the opioid receptor-NO-cGMP-[K.sup.+] channel pathway to produce its peripheral antinociception in the formalin test. Likewise, a biguanide-dependent mechanism could be activated by pamabrom and indomethacin to generate antinociception. Key words: pamabrom, antinociception, nitric oxide, cGMP, opioid receptor, metformin, [K.sup.+] channels, Introduction Premenstrual syndrome (PMS) is a disorder of cyclic recurrence that encompasses a set of repetitive symptoms, which can occur a few days before menstruation and decrease or disappear with [...]

The objective of the present study was to scrutinize the effect of nitric oxide (NO), cyclic GMP (cGMP), potassium channel blockers, and metformin on the citral-produced peripheral antinociception. The rat paw 1% formalin test was used to assess nociception and antinociception. Rats were treated with local peripheral administration of citral (10- 100 [micro]g/paw). The antinociception of citral (100 [micro]g/paw) was evaluated with and without the local pretreatment of naloxone, NG-L-nitro-arginine methyl ester (L-NAME, a NO synthesis inhibitor), 1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ a soluble guanylyl cyclase inhibitor), metformin, opioid receptors antagonists, and [K.sup.+] channel blockers. Injection of citral in the rat paw significantly decreased the nociceptive effect of formalin administration during the two phases of the test. Local pretreatment of the paws with L-NAME and ODQ did not reduced the citral-induced antinociception. Glipizide or glibenclamide ([K.sub.ir]6.1-2; ATP-sensitive [K.sup.+] channel blockers), tetraethylammonium or 4-aminopyridine ([K.sub.V]; voltage-gated [K.sup.+] channel blockers), charybdotoxin ([K.sub.ca]1.1; big conductance calcium-activated [K.sup.+] channel blocker), apamin ([K.sub.ca]2.1- 3; small conductance [Ca.sup.2+]-activated [K.sup.+] channel antagonist), or metformin, but not the opioid antagonists, reduced the antinociception of citral. Citral produced peripheral antinociception during both phases of the formalin test. These effects were due to the activation of [K.sup.+] channels and a biguanide-dependent mechanism. Key words: antinociception, citral, nociception, [K.sup.+] channels, metformin, formalin test, rat, peripheral effect. La presente etude avait pour objectif de scruter l'effet de l'oxyde nitrique (NO), du GMPc, de bloqueurs des canaux potassiques et de la metformine sur l'antinociception peripherique entrainee par le citral. Nous avons evalue la nociception et l'antinociception a l'aide du test a la formaline (1 %) sur la patte de rat. Nous avons procede a l'administration peripherique locale de citral (10-100 [micro]g/patte) chez les rats. Nous avons evalue le pouvoir antinociceptif du citral (100 [micro]g/patte) avec et sans administration locale prealable de naloxone, de L-NAME (pour << NG-L-nitro-arginine methyl ester >>, un inhibiteur de la synthese du NO), d'ODQ (pour << 1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one >>, un inhibiteur de la guanylyl cyclase soluble), de metformine, d'antagonistes des recepteurs des opiaces et de bloqueurs des canaux [K.sup.+]. L'injection de citral dans la patte des rats entrainait une diminution notable de l'effet nociceptif de l'administration de formaline au cours des deux phases du test. L'administration locale prealable de L-NAME et d'ODQ n'a pas entraine de diminution de l'antinociception entrainee par le citral. Le glipizide ou le glibenclamide ([K.sub.ir]6.1-2; des bloqueurs des canaux [K.sup.+] sensibles a l'ATP), le tetraethylammonium ou la 4-aminopyridine ([K.sub.V]; des bloqueurs des canaux [K.sup.+] dependants du voltage), la charybdotoxine ([K.sub.ca]1.1; un bloqueur des canaux [K.sup.+] a conductance elevee actives par le calcium) ou l'apamine ([K.sub.Ca]2.1-3; un antagoniste de canaux [K.sup.+] a faible conductance actives par les ions [Ca.sup.2+]), ou la metformine ont entraine une diminution de l'effet antinociceptif du citral, mais pas les antagonistes des recepteurs des opiaces. Le citral a entraine une antinociception peripherique au cours des deux phases du test a la formaline. Ces effets etaient lies a l'activation des canaux [K.sup.+] et a un mode d'action dependant des biguanides. [Traduit par la Redaction] Mots-cles : antinociception, citral, nociception, canaux [K.sup.+], metformine, test a la formaline, rat, effet peripherique., Introduction Citral, also known as geranial or neral, is an aromatic terpene derivative that can be found in different plants and citrus fruits. Citral is found as a clear yellowish [...]

The aim of this study was to examine if the peripheral antinociception of [alpha]-bisabolol involves the participation of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) synthesis followed by [K.sup.+] channel opening in the formalin test. Wistar rats were injected in the dorsal surface of the right hind paw with formalin (1%). Rats received a subcutaneous injection into the dorsal surface of the paw of vehicles or increasing doses of [alpha]-bisabolol (100-300 [micro]g/paw). To determine whether the peripheral antinociception induced by [alpha]-bisabolol was mediated by either the opioid receptors or the NO-cGMP-[K.sup.+] channels pathway, the effect of pretreatment (10 min before formalin injection) with the appropriate vehicles, naloxone, naltrexone, [N.sup.G]-nitro-L-arginine methyl ester (L-NAME), 1H-[1,2,4]-oxadiazolo[4,2-a]quinoxalin-1-one (ODQ), glibenclamide, glipizide, apamin, charybdotoxin, tetraethylammonium, or 4-aminopyridine on the antinociceptive effects induced by local peripheral [alpha]-bisabolol (300 [micro]g/paw) were assessed. [alpha]-Bisabolol produced antinociception during both phases of the formalin test. [alpha]-Bisabolol antinociception was blocked by L-NAME, ODQ, and all the [K.sup.+] channels blockers. The peripheral antinociceptive effect produced by [alpha]-bisabolol was not blocked by the opioid receptor inhibitors. [alpha]-Bisabolol was able to active the NO-cGMP-[K.sup.+] channels pathway to produce its antinoceptive effect. The participation of opioid receptors in the peripheral local antinociception induced by [alpha]-bisabolol is excluded. Key words: [alpha]-bisabolol, nociception, nitric oxide, cGMP, [K.sup.+] channels. Cette etude visait a evaluer si les effets de la synthese d'oxyde nitrique (NO) et de guanosine monophosphate cyclique (GMPc) suivie de l'ouverture des canaux [K.sup.+] participent aux effets antinociceptifs peripheriques de l'[alpha]-bisabolol dans le test a la formaline. Nous avons injecte de la formaline (1 %) dans la face dorsale de la patte posterieure droite de rats Wistar. Nous avons injecte par voie sous- cutanee les vehicules ou de l'[alpha]-bisabolol a doses croissantes dans la face dorsale de la patte des rats (100-300 [micro]g/patte). En vue d'etablir si l'antinociception peripherique engendree par l'[alpha]-bisabolol etait mediee par les recepteurs aux opiaces ou par la voie de signalisation NO-cGMP--canaux [K.sup.+], nous avons evalue l'effet de l'administration prealable (10 min avant l'injection de formaline) des vehicules appropries, de naloxone, de naltrexone, de L-NAME, d'ODQ de glibenclamide, de glipizide, d'apamine, de charybdotoxine, de tetraethylammonium ou de 4-aminopyridine sur les effets antinociceptifs engendres par l'administration locale d'[alpha]-bisabolol en peripherie (300 [micro]g/patte). L'[alpha]-bisabolol entrainait une antinociception aux cours des deux phases du test a la formaline. Nous avons inhibe l'antinociception par l'[alpha]-bisabolol a l'aide de L-NAME, d'ODQ et de tous les bloqueurs des canaux [K.sup.+]. L'effet antinociceptif peripherique produit par l'[alpha]-bisabolol n'etait pas inhibe par les inhibiteurs des recepteurs aux opiaces. L'[alpha]-bisabolol permettait d'activer la voie de signalisation NO-cGMP--canaux [K.sup.+] pour produire son effet antinociceptif. Nous excluons la participation des recepteurs aux opiaces dans l'antinociception peripherique locale engendree par l'[alpha]- bisabolol. [Traduit par la Redaction] Mots-cles: [alpha]-bisabolol, nociception, oxyde nitrique, GMPc, canaux [K.sup.+]., Introduction [alpha]-Bisabolol (IUPAC name: (2 R)-6-methyl-2-[(1 R)-4-methylcyclohex3-en-1- yl] hept-5-en-2-ol) is a plant-derived, natural, unsaturated, monocyclic sesquiterpene alcohol. [alpha]-Bisabolol is the primary constituent from several aromatic plants such as German chamomile [...]

The aim of this study was to examine if the peripheral antinociceptive effects of the opioid agonist/antagonist nalbuphine and buprenorphine involve the sequential participation of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) synthesis followed by [K.sup.+] channel opening in the formalin test. Wistar rats (180-220 g) were injected in the dorsal surface of the right hind paw with formalin (1%). Rats received a subcutaneous (s.c.) injection into the dorsal surface of the paw of vehicles or increasing doses of nalbuphine (50-200 [micro]g/paw) or buprenorphine (1-5 [micro]g/paw) 20 min before formalin injection into the paw. Nalbuphine antinociception was reversed by the s.c. injection into the paw of the inhibitor of NO synthesis ([N.sup.G]-nitro-L-arginine methyl ester (L-NAME)), by the inhibitor of guanylyl cyclase (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ)), by the [K.sub.ir]6.1-2, ATP-sensitive [K.sup.+] channel inhibitors (glibenclamide and glipizide), by the [K.sub.Ca]2.1-3, small conductance [Ca.sup.2+]-activated [K.sup.+] channel blocker (apamin), by the [K.sub.Ca]1.1, large conductance [Ca.sup.2+]-activated [K.sup.+] channel blocker (charybdotoxin), and by the KV, voltage-dependent [K.sup.+] channel inhibitors (4-aminopyridine (4-AP) and tetraethylammonium chloride (TEA)). The antinociceptive effect produced by buprenorphine was blocked by the s.c. injection of 4-AP and TEA but not by L-NAME, ODQ, glibenclamide, glipizide, apamin, or charybdotoxin. The present results provide evidence for differences in peripheral mechanisms of action between these opioid drugs. Key words: opioids, potassium channels, nitric oxide, nociception, rat formalin test. Cette etude portait sur les effets antinociceptifs peripheriques d'opiaces agoniste et antagoniste, la nalbuphine et la buprenorphine, jouant un role dans la participation sequentielle de la synthese d'oxyde nitrique (NO) et de la guanosine monophosphate cyclique (GMPc), suivie de l'ouverture des canaux [K.sup.+] a l'aide du test a la formaline. Nous avons injecte de la formaline (1 %) dans la face dorsale de la patte posterieure de rats Wistar (180-220 g). Les rats ont recu dans la face dorsale de la patte une injection par voie sous-cutanee (s.-c.) de vehicule ou de nalbuphine (50-200 [micro]g/patte) ou de buprenorphine (1-5 [micro]g/patte) a doses croissantes 20 min avant l'injection de formaline dans la patte. L'antinociception par la nalbuphine s'inversait avec l'injection par voie s.-c. de l'inhibiteur de la synthese de NO (methyl ester de [N.sup.G]-nitro-L-arginine (L-NAME)), d'un inhibiteur de la guanylyl cyclase (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ)), d'inhibiteurs des canaux [K.sup.+] sensibles a l'ATP, [K.sub.ir]6.1-2 (glibenclamide et glipizide), d'un inhibiteur des canaux [K.sup.+] actives par le [Ca.sup.2+] de faible conductance [K.sub.Ca]2.1-3 (apamine), d'un inhibiteur des canaux [K.sup.+] actives par le [Ca.sup.2+]de forte conductance, [K.sub.Ca]1.1 (charybdotoxine) et d'inhibiteurs des canaux [K.sup.+] dependants du voltage, KV (4-aminopyridine (4-AP) et chlorure de tetraethylammonium (TEA)). L'effet antinociceptif produit par la buprenorphine etait inhibe par l'injection par voie s.-c. de 4-AP et de TEA, mais pas avec le L-NAME, l'ODQ, le glibenclamide, le glipizide, l'apamine ou la charybdotoxine. Les presents resultats apportent des donnees probantes quant aux differences entre ces opiaces selon leurs modes d'action peripheriques. [Traduit par la Redaction] Mots-cles : opiaces, canaux potassiques, oxyde nitrique, nociception, test a la formaline chez le rat., Introduction The opioid system modulates several physiological processes, including analgesia, stress responses, and neuroendocrine function. Opioid drugs are some of the most efficacious analgesics used in humans (Ballantyne and Sullivan [...]

Despite considerable progress in our understanding of systemic lupus erythematosus (SLE) pathophysiology, patient diagnosis is often deficient and late, and this has an impact on disease progression. The aim of this study was to analyze non-coding RNA (ncRNA) packaged into exosomes by next-generation sequencing to assess the molecular profile associated with renal damage, one of the most serious complications of SLE, to identify new potential targets to improve disease diagnosis and management using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The plasma exosomes had a specific ncRNA profile associated with lupus nephritis (LN). The three ncRNA types with the highest number of differentially expressed transcripts were microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and piwi-interacting RNAs (piRNAs). We identified an exosomal 29-ncRNA molecular signature, of which 15 were associated only with LN presence; piRNAs were the most representative, followed by lncRNAs and miRNAs. The transcriptional regulatory network showed a significant role for four lncRNAs (LINC01015, LINC01986, AC087257.1 and AC022596.1) and two miRNAs (miR-16-5p and miR-101-3p) in network organization, targeting critical pathways implicated in inflammation, fibrosis, epithelial–mesenchymal transition and actin cytoskeleton. From these, a handful of potential targets, such as transforming growth factor-β (TGF-β) superfamily binding proteins (activin-A, TGFB receptors, etc.), WNT/β-catenin and fibroblast growth factors (FGFs) have been identified for use as therapeutic targets of renal damage in SLE. [ABSTRACT FROM AUTHOR]