The role of central histaminergic system in the analgesic effect of morphine in mice

Amaç: Farelerde morfinin analjezik etkilerine aracılık eden histaminin kaynağının santral histaminerjik nöronlardan salınan histamin mi, yoksa mast hücrelerinin içerdiği histamin mi olduğu araştırıldı. Gereç ve Yöntem: Bu amaçla önce morfinin analjezik etkisi çalışıldı, daha sonra çalışmamızda kullanılan histamin H, ve H2 reseptör blokörlerinin ağrı üzerine ne tür etki yaptıkları ölçüldü. Analjezi ölçümü için hot plate analjezimetre kullanıldı. Bulgular: Dinletinden, feniramin (histamin H1 reseptör blokörleri) ve ranitidinin (H2 reseptör blokörü) analjezik etkilerinin olmadığı istatistiksel olarak gösterildi. Morfin ile histamin antagonistlerinin aralarında etkileşim olup olmadığını anlamak için histamin antagonistlerinin uygulanan tüm dozları, morfin (10 ve 30 mg/kg) ile kombine verilerek hot plate ölçümleri yapıldı. Dimetinden ve feniramin morfinin etkisinde anlamlı bir değişiklik meydana getirmedi, ancak dimetindenin (100 mg/kg) kullanılan dozlarının en yükseğinde morfinin etkisini potansiyalize ettiği görüldü. Ranitidin ise hem i.p. hem de i.c.v. uygulandığında morfinin (10 ve 30 mg/kg, i.p.) analjezik etkisini antagonize etti. Bu sonuçlara göre morfinin analjezik etkisine histamin H2 reseptörleri aracılık etmektedir. Morfinin analjezik etkisinde histaminin kaynağını belirlemek için hem i.p. hem de i.c.v. olarak 48/80 maddesi kullanıldı. Bu şekilde mast hücreleri degranüle edildikten sonra morfin uygulandığında elde edilen sonuçlar mast hücresi sağlam farelerden alman sonuçlar ile karşılaştırıldığında, mast hücreleri degranüle edilmiş farelerde morfinin analjezik etkisinin devam etmesine karşın, istatistiksel olarak azaldığı belirlendi. Sonuç: Çalışmamız morfinin analjezik etkisine histamin H2 reseptörlerinin aracılık ettiğini ve bu etkide nöronal histamine ek olarak mast hücrelerinin de rolü olabileceğini göstermektedir.Purpose: We investigated the source of histamine contributing to the analgesic effect of morphine in mice; whether it is secreted from histaminergic neurons or mast cells. Methods: First, we studied the analgesic effect of morphine, then evaluated the effects H1, and H2 receptor blockers on pain. To measure analgesia, we used hot plate analgesimeter. Results: With these tests we demonstrated that H1 (dinethindene and pheniramine) and H2 receptor blockers (ranitidine) had no statistically significant analgesic effects. In order to determine whether there is an interaction between histamine antagonists and morphine, hot plate measurements were performed, combining morphine (10 and 30 mg/kg) with histamine antagonists, Dimethindene and pheniramine didn't make any significant change in the effect of morphine; however dimethindene (100 mg/kg), with its highest dose, augmented the analgesic effect of morphine. On the other hand, both i.p. and i.c.v. administrations of ranitidine antagonized the analgesic effect of morphine. We concluded that histamine H2 receptors mediate the analgesic effect of morphine. In order to determine the source of histamine in the analgesic effect of morphine, compound 48/80, a selective mast cell degranulator was administered i.p. and i.c.v. After mast cells were degranulated, control measurements were taken and then morphine was applied (10 and 30 mg/kg). When these results were compared with the results obtained from mice which had intact mast cells, the analgesic effect of morphine was found to be attenuated in mice whose mast cells were degranulated. Conclusion: These results show that the analgesic effect of morphine is mediated by histamine H2 receptors; moreover, besides central histaminergic system, mast cells' histamine content might also play role in the analgesic effect of morphine

Effects of melatonin and dexpanthenol on antioxidant parameters when combined with estrogen treatment in ovariectomized rats

Tiwari, Prafulla/0000-0001-7913-5386WOS: 000326100600017PubMed: 23471492The purpose of the study was to assess whether it is possible to reduce the oxidative damage using antioxidant agents combined with hormone replacement therapy after menopause. In this prospective experimental study, 50 mature female Wistar albino rats weighing 270-310 g were used. Rats were divided into the following six groups: (1) Ovx group (n = 7): the animals underwent bilateral ovariectomy. No drug was administered following bilateral ovariectomy. (2) Ovx + E (2) group (n = 7): bilateral ovariectomy + 17 beta-estradiol (100 mu g/kg/day); (3) Ovx + E (2) + MT5 group (n = 7): bilateral ovariectomy + 17 beta-estradiol (100 mu g/kg/day) + melatonin (5 mg/kg/day); (4) Ovx + E (2) + MT20 group (n = 7): bilateral ovariectomy + 17 beta-estradiol (100 mu g/kg/day) + melatonin (20 mg/kg/day); (5) Ovx + E (2) + Dxp250 group (n = 7): bilateral ovariectomy + 17 beta-estradiol (100 mu g/kg/day) + dexpanthenol (250 mg/kg/day); (6) Ovx + E (2) + Dxp500 group (n = 7): bilateral ovariectomy + 17 beta-estradiol (100 mu g/kg/day) + dexpanthenol (500 mg/kg/day), and the activity of these antioxidative enzymes and oxidative stress products were measured. Enzymatic activity levels of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase(GSH-Px), and glutathione reductase and levels of free radicals (malondialdehyde (MDA) and nitric oxide) were both analyzed. We observed an increase in the level of GSH activity, but no significant differences in levels of CAT, SOD, and GSH-Px enzymatic activity and in levels of free radical MDA following 17 beta-estradiol or additional antioxidant treatment (melatonin or dexpanthenol). Despite the present study indicating that the addition of melatonin and dexpanthenol into the hormone replacement therapy regimen may contribute to the antioxidant effect of estrogen, the existence of limited data in this field indicates that further studies are warranted

Drug exposure in early pregnancy might be related to the effects of increased maternal progesterone in implantation period

Aim: This short communication aims to evaluate the relation in between drug exposure time and early pregnancy regarding gestational weeks. Methods: The study covers the referrals made to the Department of Pharmacology for a teratogenic consultation in a 3-year period. From the recordings of pregnant women, the last menstrual period and the starting date of medication were used to determine the time of prescription with regard to gestational weeks. Results: In all of the three years, potentially teratogenic medication was prescribed more frequently in the 3rd, 4th and 5th gestational weeks (in between 15–35 days of pregnancy). Approximately 75% of the pregnant women in the study were prescribed with drugs, most frequently with analgesics, antibiotics, gastrointestinal drugs and antidepressants, in these gestational weeks. Conclusions: The timing of prescriptions in early pregnancy frequently coincides with the increased levels of maternal progesterone in implantation period. Progesterone may lead to negative mood symptoms of an increased pain perception, anxiety, irritability and aggression in some of the pregnant women and therefore causes an increased stress condition which in turn may result in pain, infection and inflammation in the individual. Taking the frequently used medications into consideration, the reason for prescriptions in this period might be related to the symptoms originating from the effects of progesterone. Future studies are needed to better demonstrate this association of drug exposure and effects of maternal progesterone in early pregnancy

Infarct limitation by a protein kinase G activator at reperfusion in rabbit hearts is dependent on sensitizing the heart to A2b agonists by protein kinase C

PKG activator 8-(4-chlorophenylthio)-guanosine 3′,5′-cyclic monophosphate (CPT) at reperfusion protects ischemic hearts, but the mechanism is unknown. We recently proposed that in preconditioned hearts PKC lowers the threshold for adenosine to initiate signaling from low-affinity A2b receptors during early reperfusion thus allowing endogenous adenosine to activate survival kinases phosphatidylinositol 3-kinase (PI3K) and ERK. We tested whether CPT might also sensitize A2b receptors to adenosine. CPT (10 μM) during the first minutes of reperfusion markedly reduced infarction in isolated rabbit hearts undergoing 30-min regional ischemia/2-h reperfusion, and salvage was blocked by MRS 1754, an A2b-selective antagonist. Coadministration of wortmannin (PI3K inhibitor) or PD-98059 (MEK1/2 and therefore ERK1/2 inhibitor) also blocked protection. In nonischemic hearts, 10-min infusion of CPT did not change phosphorylation of Akt or ERK1/2. Neither did a subthreshold dose (2.5 nM) of the nonselective but A2b-potent receptor agonist 5′-(N-ethylcarboxamido)adenosine (NECA). However, when 2.5 nM NECA was combined with 10 μM CPT, both phospho-Akt and phospho-ERK1/2 significantly increased, indicating CPT had lowered the threshold for A2b-dependent signaling. The PKC antagonist chelerythrine blocked this phosphorylation induced by CPT + NECA. Chelerythrine also blocked the anti-infarct effect of CPT as did nonselective (glibenclamide) and mitochondrial-selective (5-hydroxydecanoate) KATP channel blockers. A free radical scavenger, N-(2-mercaptopropionyl)glycine, also blocked CPT protection. We propose CPT targets PKG, which activates PKC through mitochondrial KATP channel (mitoKATP)-dependent redox signaling, a sequence mimicking that already documented in preconditioning. Activated PKC then augments sensitivity of normally low-affinity cardiac adenosine A2b receptors so endogenous adenosine can protect by activating Akt and ERK