Insurmountable antagonism of human mu opioid receptors by buprenorphine is due to hemi-equilibrium.

Buprenorphine is an FDA approved drug for the treatment of opioid use disorder and is a long-lasting, low efficacy (partial) agonist of the μ opioid receptor. As a partial agonist, buprenorphine can act as either an agonist or an antagonist depending on the efficiency of the cellular signaling system. Here we investigated the antagonist properties of buprenorphine using a genetically-encoded biosensor to monitor cAMP levels in real time in HEK293 cells expressing a relatively low density of the human μ receptor.

14-3-3γ mediates the long-term inhibition of peripheral kappa opioid receptor antinociceptive signaling by norbinaltorphimine.

Long-term inhibition of kappa opioid receptor (KOR) signaling in peripheral pain-sensing neurons is a potential obstacle for development of peripherally-restricted KOR agonists that produce analgesia. Such a long-term inhibitory mechanism is invoked from activation of c-Jun N-terminal kinase (JNK) that follows a single injection of the KOR antagonist norbinaltorphimine (norBNI). This effect requires protein synthesis of an unknown mediator in peripheral pain-sensing neurons.

Age-related changes in peripheral nociceptor function.

Pain and pain management in the elderly population is a significant social and medical problem. Pain sensation is a complex phenomenon that typically involves activation of peripheral pain-sensing neurons (nociceptors) which send signals to the spinal cord and brain that are interpreted as pain, an unpleasant sensory experience. In this work, young (4-5 months) and aged (26-27 months) Fischer 344 x Brown Norway (F344xBN) rats were examined for nociceptor sensitivity to activation by thermal (cold and heat) and mechanical stimulation following treatment with inflammatory mediators and activators of transient receptor potential (TRP) channels.

Long-term antagonism and allosteric regulation of mu opioid receptors by the novel ligand, methocinnamox.

Opioid overdose is a leading cause of death in the United States. The only treatment available currently is the competitive antagonist, naloxone (Narcan ). Although naloxone is very effective and has saved many lives, as a competitive antagonist it has limitations.

Transition of microbial communities and degradation pathways in anaerobic digestion at decreasing retention time.

Tuning of operational variables is a common practice to control the anaerobic digestion process and, in advanced applications, to promote the accumulation of fermentation products. However, process variables are interrelated. In this study, the hydraulic retention time (HRT) was decoupled from the organic loading rate (OLR) in order to isolate the effect of HRT as a selective pressure on: process performance, metabolic rates (hydrolytic, acetogenic, and methanogenic) and the microbial community.

Organic waste biorefineries: Looking towards implementation.

The concept of biorefinery expands the possibilities to extract value from organic matter in form of either bespoke crops or organic waste. The viability of biorefinery schemes depends on the recovery of higher-value chemicals with potential for a wide distribution and an untapped marketability. The feasibility of biorefining organic waste is enhanced by the fact that the biorefinery will typically receive a waste management fee for accepting organic waste.

Influence of inoculum selection on the utilisation of volatile fatty acid and glucose in sulfate reducing reactors.

The capacity of three inocula (sewer biofilm, mangrove and estuary sediment) to utilise typical fermentation products of municipal solid waste for biological sulfate reduction was investigated. Each inoculum was used in two reactors, one fed a mixture of volatile fatty acids and another fed glucose to provide a suite of fermentation products via naturally occurring fermentation. Following 228 days of reactor operation, reactors inoculated with mangrove and estuary sediments exhibited higher sulfate reducing efficiencies (80-88%) compared to the biofilm-inoculated reactors (32-49%).

Signaling characteristics and functional regulation of delta opioid-kappa opioid receptor (DOP-KOP) heteromers in peripheral sensory neurons.

Receptor heteromers often display distinct pharmacological and functional properties compared to the individual receptor constituents. In this study, we compared the properties of the DOP-KOP heteromer agonist, 6'-guanidinonaltrindole (6'-GNTI), with agonists for DOP ([D-Pen2,5]-enkephalin [DPDPE]) and KOP (U50488) in peripheral sensory neurons in culture and in vivo. In primary cultures, all three agonists inhibited PGE-stimulated cAMP accumulation as well as activated extracellular signal-regulated kinase 1/2 (ERK) with similar efficacy.

Making Sense of Pharmacology: Inverse Agonism and Functional Selectivity.

Constitutive receptor activity/inverse agonism and functional selectivity/biased agonism are 2 concepts in contemporary pharmacology that have major implications for the use of drugs in medicine and research as well as for the processes of new drug development. Traditional receptor theory postulated that receptors in a population are quiescent unless activated by a ligand. Within this framework ligands could act as agonists with various degrees of intrinsic efficacy, or as antagonists with zero intrinsic efficacy.

Methodology to determine the extent of anaerobic digestion, composting and CH oxidation in a landfill environment.

An examination of the processes contributing to the production of landfill greenhouse gas (GHG) emissions is required, as the actual level to which waste degrades anaerobically and aerobically beneath covers has not been differentiated. This paper presents a methodology to distinguish between the rate of anaerobic digestion (r), composting (r) and CH oxidation (r) in a landfill environment, by means of a system of mass balances developed for molecular species (CH, CO) and stable carbon isotopes (δC-CO and δC-CH). The technique was applied at two sampling locations on a sloped area of landfill.

Allosterism within Opioid- Opioid Receptor Heteromers in Peripheral Sensory Neurons: Regulation of Opioid Agonist Efficacy.

There is abundant evidence for formation of G protein-coupled receptor heteromers in heterologous expression systems, but little is known of the function of heteromers in native systems. Heteromers of and opioid receptors (DOR-KOR heteromers) have been identified in native systems. We previously reported that activation of DOR-KOR heteromers expressed by rat pain-sensing neurons (nociceptors) produces robust, peripherally mediated antinociception.

Pilot scale evaluation of a model to distinguish the rates of simultaneous anaerobic digestion, composting and methane oxidation in static waste beds.

The aim of this paper was to apply and validate a model for measuring the rate and extent of anaerobic digestion, composting and CH oxidation in laboratory scale beds. Degradation studies were performed in four reactors each packed with shredded unsorted municipal solid waste, with one bed covered with a 100 mm layer of soil. The rates of production of CH, CO, C-CO and the rate of consumption of O were measured and used as inputs to a mass balance expressions for these components to calculate the rates of anaerobic digestion, composting and CH oxidation.

Pharmacological augmentation of nicotinamide phosphoribosyltransferase (NAMPT) protects against paclitaxel-induced peripheral neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) arises from collateral damage to peripheral afferent sensory neurons by anticancer pharmacotherapy, leading to debilitating neuropathic pain. No effective treatment for CIPN exists, short of dose-reduction which worsens cancer prognosis. Here, we report that stimulation of nicotinamide phosphoribosyltransferase (NAMPT) produced robust neuroprotection in an aggressive CIPN model utilizing the frontline anticancer drug, paclitaxel (PTX).

A mass balance model to estimate the rate of composting, methane oxidation and anaerobic digestion in soil covers and shallow waste layers.

Although CH oxidation in landfill soil covers is widely studied, the extent of composting and CH oxidation in underlying waste layers has been speculated but not measured. The objective of this study was to develop and validate a mass balance model to estimate the simultaneous rates of anaerobic digestion (r), CH oxidation (r) and composting (r) in environments where O penetration is variable and zones of aerobic and anaerobic activity are intermingled. The modelled domain could include, as an example, a soil cover and the underlying shallow waste to a nominated depth.

Constitutive Desensitization of Opioid Receptors in Peripheral Sensory Neurons.

Opioid receptors expressed by peripheral pain-sensing neurons are functionally inactive for antinociceptive signaling under most basal conditions; however, tissue damage or exposure to inflammatory mediators (e.g., bradykinin) converts these receptors from a nonresponsive state to a functionally competent state.

Long-Term Reduction of Kappa Opioid Receptor Function by the Biased Ligand, Norbinaltorphimine, Requires c-Jun N-Terminal Kinase Activity and New Protein Synthesis in Peripheral Sensory Neurons.

A single administration of the κ opioid receptor (KOR) antagonist, norbinaltorphimine (norBNI), produces long-term reduction in KOR function in heterologous expression systems and brain that is mediated by activation of c-Jun N-terminal kinase (JNK). In this study, we examined the long-term effects of norBNI on adult rat peripheral sensory neurons in vivo and ex vivo. Following a single intraplantar (i.

Critical analysis of hydrogen production from mixed culture fermentation under thermophilic condition (60 °C).

Bio-hydrogen production from mixed culture fermentation (MCF) of glucose was studied by conducting a comprehensive product measurement and detailed mass balance analysis of their contributions to the final H2 yield. The culture used in this study was enriched on glucose at 60 °C through a sequential batch operation consisting of daily glucose feeds, headspace purging and medium replacement every third day in serum bottles for over 2 years. 2-Bromoethanesulfonate (BES) was only required during the first three 3-day cycles to permanently eliminate methanogenic activity.

The use of food waste as a carbon source for on-site treatment of nutrient-rich blackwater from an office block.

Wastewater from office blocks is typically dominated by blackwater and is therefore concentrated and nutrient-rich. A pilot plant was operated for 260 days, receiving 300 L d(-1) of wastewater directly from an office building to determine whether nutrient removal could be achieved using food waste (FW) as a supplemental carbon source. The pilot plant consisted of a 600 L prefermenter and a 600 L membrane bioreactor that was operated as a sequential batch reactor in order to cycle through anoxic, anaerobic and aerobic phases.

Rapid digestion of shredded MSW by sequentially flooding and draining small landfill cells.

This paper compares the digestion of a packed bed of shredded municipal waste using a flood and drain regime against a control digestion of similarly prepared material using a trickle flow regime. All trials were performed on shallow (2m) beds of the sub-8cm fraction of shredded mixed MSW, encapsulated in a polyethylene bladder. The control cell (Cell 1) was loaded with 1974 tonnes shredded municipal waste and produced 76±9m(3) CH4dryt(-1) (45±2m(3) CH4 'as received't(-1)) over 200days in response to a daily recirculation of the leachate inventory which was maintained at 60m(3).

Functional selectivity of kappa opioid receptor agonists in peripheral sensory neurons.

Activation of kappa opioid receptors (KORs) expressed by peripheral sensory neurons that respond to noxious stimuli (nociceptors) can reduce neurotransmission of pain stimuli from the periphery to the central nervous system. We have previously shown that the antinociception dose-response curve for peripherally restricted doses of the KOR agonist (-)-(trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide (U50488) has an inverted U shape. Here, we found that the downward phase of the U50488 dose-response curve was blocked by an inhibitor of extracellular signal-regulated kinase (ERK) activation U0126.

Atypical antipsychotics and inverse agonism at 5-HT2 receptors.

It is now well accepted that receptors can regulate cellular signaling pathways in the absence of a stimulating ligand, and inverse agonists can reduce this ligand-independent or "constitutive" receptor activity. Both the serotonin 5-HT2A and 5-HT2C receptors have demonstrated constitutive receptor activity in vitro and in vivo. Each has been identified as a target for treatment of schizophrenia.

Dual regulation of δ-opioid receptor function by arachidonic acid metabolites in rat peripheral sensory neurons.

The regulation of opioid receptor system function in peripheral sensory neurons is not well understood. Opioid agonist efficacy to inhibit nociceptor function and to promote antinociception is generally weak under basal conditions and frequently no response occurs. However, in response to a cyclooxygenase-dependent metabolite of arachidonic acid (AA) after exposure to inflammatory mediators, such as bradykinin (BK) or exogenous AA, peripheral opioid receptor systems become much more responsive to opioid agonists.

Changes in glucose fermentation pathways by an enriched bacterial culture in response to regulated dissolved H2 concentrations.

It is well established that metabolic pathways in the fermentation of organic waste are primarily controlled by dissolved H2 concentrations, but there is no reported study that compares observed and predicted shifts in fermentation pathways induced by manipulating the dissolved H2 concentration. A perfusion system is presented that was developed to control dissolved H2 concentrations in the continuous fermentation of glucose by a culture highly enriched towards Thermoanaerobacterium thermosaccharolyticum (86 ± 9% relative abundance) from an originally diverse consortia in the leachate of a laboratory digester fed with municipal solid waste. Media from a 2.

G protein-coupled receptor 30 (GPR30) forms a plasma membrane complex with membrane-associated guanylate kinases (MAGUKs) and protein kinase A-anchoring protein 5 (AKAP5) that constitutively inhibits cAMP production.

GPR30, or G protein-coupled estrogen receptor, is a G protein-coupled receptor reported to bind 17β-estradiol (E2), couple to the G proteins Gs and Gi/o, and mediate non-genomic estrogenic responses. However, controversies exist regarding the receptor pharmacological profile, effector coupling, and subcellular localization. We addressed the role of the type I PDZ motif at the receptor C terminus in receptor trafficking and coupling to cAMP production in HEK293 cells and CHO cells ectopically expressing the receptor and in Madin-Darby canine kidney cells expressing the native receptor.

Activation of estrogen receptor α enhances bradykinin signaling in peripheral sensory neurons of female rats.

Numerous studies have demonstrated that females have a higher risk of experiencing several pain disorders with either greater frequency or severity than males. Although the mechanisms that underlie this sex disparity remain unclear, several studies have shown an important role for sex steroids, such as estrogen, in the modulation of nociception. Receptors for estrogen are present in primary afferent neurons in the trigeminal and dorsal root ganglia, and brief exposure to estrogen increases responses to the inflammatory mediator bradykinin (BK).