The endogenous hydrogen sulfide producing enzyme cystathionine-β synthase contributes to visceral hypersensitivity in a rat model of irritable bowel syndrome

<p>Abstract</p> <p>Background</p> <p>The pathogenesis of visceral hypersensitivity, a characteristic pathophysiological feature of irritable bowel syndrome (IBS), remains elusive. Recent studies suggest a role for hydrogen sulfide (H₂S) in pain signaling but this has not been well studied in visceral models of hyperalgesia. We therefore determined the role for the endogenous H₂S producing enzyme cystathionine-β-synthetase (CBS) in a validated rat model of IBS-like chronic visceral hyperalgesia (CVH). CVH was induced by colonic injection of 0.5% acetic acid (AA) in 10-day-old rats and experiments were performed at 8–10 weeks of age. Dorsal root ganglion (DRG) neurons innervating the colon were labeled by injection of DiI (1,1'-dioleyl-3,3,3',3-tetramethylindocarbocyanine methanesulfonate) into the colon wall.</p> <p>Results</p> <p>In rat DRG, CBS-immunoreactivity was observed in approximately 85% of predominantly small- and medium-sized neurons. Colon specific DRG neurons revealed by retrograde labeling DiI were all CBS-positive. CBS-positive colon neurons co-expressed TRPV1 or P2X3 receptors. Western blotting analysis showed that CBS expression was significantly increased in colon DRGs 8 weeks after neonatal AA-treatment. Furthermore, the CBS inhibitor hydroxylamine markedly attenuated the abdominal withdrawal reflex scores in response to colorectal distention in rats with CVH. By contrast, the H₂S donor NaHS significantly enhanced the frequency of action potentials of colon specific DRG neurons evoked by 2 times rheobase electrical stimulation.</p> <p>Conclusion</p> <p>Our results suggest that upregulation of CBS expression in colonic DRG neurons and H₂S signaling may play an important role in developing CVH, thus identifying a specific neurobiological target for the treatment of CVH in functional bowel syndromes.</p

Direct intra-accumbal infusion of a beta-adrenergic receptor antagonist abolishes WIN 55,212-2-induced aversion

The cannabinoid system is known to interact with a variety of neuromodulators in the central nervous system and impacts diverse behaviors. Previous studies have demonstrated that limbic norepinephrine is a critical determinant in the behavioral expression of cannabinoid-induced aversion. The present study was carried out to define the adrenergic receptor subtype involved in mediating cannabinoid-induced behavioral responses. An acute microinjection of the 1-adrenergic receptor blocker, betaxolol, directly into the nucleus accumbens (Acb), was able to prevent WIN 55,212-2-induced aversion, but not lithium-induced aversion, as measured in a place conditioning paradigm. These results suggest that noradrenergic transmission in the Acb is important for cannabinoid-induced aversion and that beta-adrenergic antagonists may be effective in counteracting negative side effects of cannabinoid-based agents.This work was supported by PHS grant DA 020129. Ana Franky Carvalho was supported by the Portuguese Foundation for Science and Technology (SFRH/BD/33236/2007

Synedrella nodiflora extract depresses excitatory synaptic transmission and chemically-induced in vitro seizures in the rat hippocampus

Extracts of the tropical Cinderella plant Synedrella nodiflora are used traditionally to manage convulsive conditions in the West African sub-region. This study sought to determine the neuronal basis of the effectiveness of these plant extracts to suppress seizure activity. Using the hippocampal slice preparation from rats, the ability of the extract to depress excitatory synaptic transmission and in vitro seizure activity were investigated. Bath perfusion of the hydro-ethanolic extract of Synedrella nodiflora (SNE) caused a concentration-dependent depression of evoked field excitatory postsynaptic potentials (fEPSPs) recorded extracellularly in the CA1 region of the hippocampus with maximal depression of about 80% and an estimated IC50 of 0.06 mg/ml. The SNE-induced fEPSP depression was accompanied by an increase in paired pulse facilitation. The fEPSP depression only recovered partially after 20 min washing out. The effect of SNE was not stimulus dependent as it was present even in the absence of synaptic stimulation. Furthermore, it did not show desensitization as repeat application after 10 min washout produced the same level of fEPSP depression as the first application. The SNE effect on fEPSPs was not via adenosine release as it was neither blocked nor reversed by 8-CPT, an adenosine A1 receptor antagonist. In addition, SNE depressed in vitro seizures induced by zero Mg2+ and high K+ -containing artificial cerebrospinal fluid (aCSF) in a concentration-dependent manner. The results show that SNE depresses fEPSPs and spontaneous bursting activity in hippocampal neurons that may underlie its ability to abort convulsive activity in persons with epilepsy

Suppression of Ca2+ syntillas increases spontaneous exocytosis in mouse adrenal chromaffin cells

A central concept in the physiology of neurosecretion is that a rise in cytosolic [Ca2+] in the vicinity of plasmalemmal Ca2+ channels due to Ca2+ influx elicits exocytosis. Here, we examine the effect on spontaneous exocytosis of a rise in focal cytosolic [Ca2+] in the vicinity of ryanodine receptors (RYRs) due to release from internal stores in the form of Ca2+ syntillas. Ca2+ syntillas are focal cytosolic transients mediated by RYRs, which we first found in hypothalamic magnocellular neuronal terminals. (scintilla, Latin for spark; found in nerve terminals, normally synaptic structures.) We have also observed Ca2+ syntillas in mouse adrenal chromaffin cells. Here, we examine the effect of Ca2+ syntillas on exocytosis in chromaffin cells. In such a study on elicited exocytosis, there are two sources of Ca2+: one due to influx from the cell exterior through voltage-gated Ca2+ channels, and that due to release from intracellular stores. To eliminate complications arising from Ca2+ influx, we have examined spontaneous exocytosis where influx is not activated. We report here that decreasing syntillas leads to an increase in spontaneous exocytosis measured amperometrically. Two independent lines of experimentation each lead to this conclusion. In one case, release from stores was blocked by ryanodine; in another, stores were partially emptied using thapsigargin plus caffeine, after which syntillas were decreased. We conclude that Ca2+ syntillas act to inhibit spontaneous exocytosis, and we propose a simple model to account quantitatively for this action of syntillas

Nanomolar oxytocin synergizes with weak electrical afferent stimulation to activate the locomotor CPG of the rat spinal cord in vitro.

Synergizing the effect of afferent fibre stimulation with pharmacological interventions is a desirable goal to trigger spinal locomotor activity, especially after injury. Thus, to better understand the mechanisms to optimize this process, we studied the role of the neuropeptide oxytocin (previously shown to stimulate locomotor networks) on network and motoneuron properties using the isolated neonatal rat spinal cord. On motoneurons oxytocin (1 nM-1 \u3bcM) generated sporadic bursts with superimposed firing and dose-dependent depolarization. No desensitization was observed despite repeated applications. Tetrodotoxin completely blocked the effects of oxytocin, demonstrating the network origin of the responses. Recording motoneuron pool activity from lumbar ventral roots showed oxytocin mediated depolarization with synchronous bursts, and depression of reflex responses in a stimulus and peptide-concentration dependent fashion. Disinhibited bursting caused by strychnine and bicuculline was accelerated by oxytocin whose action was blocked by the oxytocin antagonist atosiban. Fictive locomotion appeared when subthreshold concentrations of NMDA plus 5HT were coapplied with oxytocin, an effect prevented after 24 h incubation with the inhibitor of 5HT synthesis, PCPA. When fictive locomotion was fully manifested, oxytocin did not change periodicity, although cycle amplitude became smaller. A novel protocol of electrical stimulation based on noisy waveforms and applied to one dorsal root evoked stereotypic fictive locomotion. Whenever the stimulus intensity was subthreshold, low doses of oxytocin triggered fictive locomotion although oxytocin per se did not affect primary afferent depolarization evoked by dorsal root pulses. Among the several functional targets for the action of oxytocin at lumbar spinal cord level, the present results highlight how small concentrations of this peptide could bring spinal networks to threshold for fictive locomotion in combination with other protocols, and delineate the use of oxytocin to strengthen the efficiency of electrical stimulation to activate locomotor circuits

Dendritic release of neurotransmitters

Release of neuroactive substances by exocytosis from dendrites is surprisingly widespread and is not confined to a particular class of transmitters: it occurs in multiple brain regions, and includes a range of neuropeptides, classical neurotransmitters and signaling molecules such as nitric oxide, carbon monoxide, ATP and arachidonic acid. This review is focused on hypothalamic neuroendocrine cells that release vasopressin and oxytocin and midbrain neurons that release dopamine. For these two model systems, the stimuli, mechanisms and physiological functions of dendritic release have been explored in greater detail than is yet available for other neurons and neuroactive substances

Fighting poverty with micro-credit. Experiences from Micro-Finance and small-loan center (MASLOC) in Savelugu/Nanton District of Northern Ghana

The concept of government getting herself directly involved in direct disbursement of microfinance is a novelty in Ghana. In 2006, the Government of Ghana established the MASLOC with seed money of fifty million United State dollars, directly under the Office of the President with following objective: To undertake sound and judicious administration, on fiduciary basis, of government and/or development partner funds for micro and small scale credit programmes. The rationale behind this bold government initiate is to make microfinance accessible to people in the micro and small enterprises who are found in the informal sector dominated by women, the poor and marginalized. This study examined micro-credit as a poverty reduction tool using the experiences of MASLOC scheme in the Savelugu/Nanton district in the northern region of Ghana. The study through the use of open ended questions based on key informant interviews discovered that most clients of MASLOC scheme were satisfied with the scheme. The study found out that there are marked improvement in household economic variables such as increased level of incomes, saving, expenditures on consumption and acquisition of assets. MASLOC have also organized financial training for their clients on financial management. The study reveals that female clients pay back their loan more their male counterparts. Despite the enhanced and visible improvements in the lives of clients, there were some operational problems with the MASLOC scheme: political interference, inadequate credit to clients, and lack of education among others. In the light of this, the study made the following recommendations towards improvement of the MASLOC scheme: MASLOC scheme, which is directly under the Office of the President, should be separated in order not to give the scheme political tag, the establishment of a complete audit department at MASLOC, extension of the scheme more rural communities to reach the poor people

Education and girl-child empowerment : the case of Bunkpurugu/Yunyoo district in Northern Ghana

Education is a human right. It is guaranteed under the United Nations Convention on the rights of the child. This convention is the most widely ratified international treaty in the world today. Ghana has ratified the Convention on the Rights of a child and makes education a Constitutional right. The 1992 Constitution of Ghana guarantees Free and Compulsory Basic Education to every child of school going age irrespective of gender, religion, ethnicity or geographical location. Yet, ‘Basic Education for All’ is still very far from being a reality for many children, particularly the girl-child. This study emphasizes that a major barrier to girl-child access and participation in formal education is the cultural and traditional values and the daily realities of poverty stand between girls and their prospects for educational opportunities. Traditional beliefs, practices and sayings perpetuate gender imbalance in terms of educational attainments. This paper argues that the education of girl-child would improve their life chances, and also enhance the welfare of their households, thus its resultant benefit of the girl-child being empowered. In the light of these challenges in the girl-child education, this paper further brings to the fore the efforts of a growing number of NGOs and international agencies complementing the government’s efforts in the Bunkpurugu/Yunyoo in promoting greater participation towards girl-child education. This study shows that early marriage is somewhat a reality among many of the target girls for this study. Girls are also more likely to drop out of school because of their domestic responsibilities. The study also shows that girls are often discriminated against when it comes to parents’ decision to fund their wards education. In the light of this, the study makes the following recommendation towards improving girl-child education: Educating parents on girls’ education, Abolition of schools fees and other related at the Junior High School level, enforcement of laws on early marriages, enforcement of laws on child labor, expansion school feeding programme and Engagement of men and civic groups as advocates for girls' education