Metabotropic Glutamate Receptors as Novel Therapeutic Targets on Visceral Sensory Pathways

Metabotropic glutamate receptors (mGluR) have a diverse range of structures and molecular coupling mechanisms. There are eight mGluR subtypes divided into three major groups. Group I (mGluR1 and 5) is excitatory; groups II (mGluR2 and 3) and III (mGluR 4, 6, and 7) are inhibitory. All mGluR are found in the mammalian nervous system but some are absent from sensory neurons. The focus here is on mGluR in sensory pathways from the viscera, where they have been explored as therapeutic targets. Group I mGluR are activated by endogenous glutamate or constitutively active without agonist. Constitutive activity can be exploited by inverse agonists to reduce neuronal excitability without synaptic input. This is promising for reducing activation of nociceptive afferents and pain using mGluR5 negative allosteric modulators. Many inhibitory mGluR are also expressed in visceral afferents, many of which markedly reduce excitability. Their role in visceral pain remains to be determined, but they have shown promise in inhibition of the triggering of gastro-esophageal reflux, via an action on mechanosensory gastric afferents. The extent of reflux inhibition is limited, however, and may not reach a clinically useful level. On the other hand, negative modulation of mGluR5 has very potent actions on reflux inhibition, which has produced the most likely candidates so far as therapeutic drugs. These act probably outside the central nervous system, and may therefore provide a generous therapeutic window. There are many unanswered questions about mGluR along visceral afferent pathways, the answers to which may reveal many more therapeutic candidates

Seed production of barnyardgrass (Echinochloa crus-galli) in response to time of emergence in cotton and rice

The spread of herbicide resistance in barnyardgrass (Echinochloa crus-galli (L.) Beauv.) poses a serious threat to crop production in the southern United States. A thorough knowledge of the biology of barnyardgrass is fundamental for designing effective resistance-management programmes. In the present study, seed production of barnyardgrass in response to time of emergence was investigated in cotton and rice, respectively, in Fayetteville and Rohwer, Arkansas, over a 2-year period (2008–09). Barnyardgrass seed production was greater when seedlings emerged with the crop, but some seed production was observed even if seedlings emerged several weeks after crop emergence. Moreover, barnyardgrass seed production was highly variable across environments. When emerging with the crop (0 weeks after crop emergence (WAE)), barnyardgrass produced c. 35 500 and 16 500 seeds/plant in cotton, and c. 39 000 and 2900 seeds/plant in rice, in 2008 and 2009, respectively. Seed production was observed when seedlings emerged up to 5 WAE (2008) or 7 WAE (2009) in cotton and up to 5 WAE (2008, 2009) in rice; corresponding seed production was c. 2500 and 1500 seeds/plant in cotton, and c. 14 700 and 110 seeds/plant in rice, in 2008 and 2009, respectively. The results suggest that cultural approaches that delay the emergence of barnyardgrass or approaches that make the associated crop more competitive will be useful in integrated management programmes. In the context of herbicide resistance management, it may be valuable to prevent seed return to the seedbank, irrespective of cohorts. The findings are vital for parameterizing herbicide resistance simulation models for barnyardgrass

TRP channels: new targets for visceral pain

L A Blackshaw, S M Brierley, P A Hughe

Infographic. All health professionals should talk about physical activity with patients

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MicroSAGE is Highly Representative and Reproducible but Reveals Major Differences in Gene Expression Among Samples Obtained from Similar Tissues

Background: Serial analysis of gene expression using small amounts of starting material (microSAGE) has not yet been conclusively shown to be representative, reproducible or accurate. Results: We show that microSAGE is highly representative, reproducible and accurate, but that pronounced differences in gene expression are seen between tissue samples taken from different individuals. Conclusions: MicroSAGE is a reliable method of comprehensively profiling differences in gene expression among samples, but care should be taken in generalizing results obtained from libraries constructed from tissue obtained from different individuals and/or processed or stored differently

Simultaneous measurement of gastric emptying of a soup test meal using MRI and gamma scintigraphy

Measurement of gastric emptying is of clinical value for a range of conditions. Gamma scintigraphy (GS) has an established role, but the use of magnetic resonance imaging (MRI) has recently increased. Previous comparison studies between MRI and GS showed good correlation, but were performed on separate study days. In this study, the modalities were alternated rapidly allowing direct comparison with no intra-individual variability confounds. Twelve healthy participants consumed 400 g of Technetium-99m (99mTc)-labelled soup test meal (204 kcal) and were imaged at intervals for 150 min, alternating between MRI and GS. The time to empty half of the stomach contents (T1/2) and retention rate (RR) were calculated and data correlated. The average T1/2 was similar for MRI (44 ± 6 min) and GS (35 ± 4 min) with a moderate but significant difference between the two modalities (p ≤0.004). The individual T1/2 values were measured, and MRI and GS showed a good positive correlation (r = 0.95, p ≤ 0.0001), as well as all the RRs at each time point up to 120 min. Gastric emptying was measured for the first time by MRI and GS on the same day. This may help with translating the use of this simple meal, known to elicit reliable, physiological, and pathological gastrointestinal motor, peptide, and appetite response

Nasal Administration and Plasma Pharmacokinetics of Parathyroid Hormone Peptide PTH 1-34 for the Treatment of Osteoporosis

Nasal delivery of large peptides such as parathyroid 1-34 (PTH 1-34) can benefit from a permeation enhancer to promote absorption across the nasal mucosa into the bloodstream. Previously, we have published an encouraging bioavailability (78%), relative to subbcutaneous injection in a small animal preclinical model, for a liquid nasal spray formulation containing the permeation enhancer polyethylene glycol (15)-hydroxystearate (Solutol® HS15). We report here the plasma pharmacokinetics of PTH 1-34 in healthy human volunteers receiving the liquid nasal spray formulation containing Solutol® HS15. For comparison, data for a commercially manufactured teriparatide formulation delivered via subcutaneous injection pen are also presented. Tc-99m-DTPA gamma scintigraphy monitored the deposition of the nasal spray in the nasal cavity and clearance via the inferior meatus and nasopharynx. The 50% clearance time was 17.8 min (minimum 10.9, maximum 74.3 min). For PTH 1-34, mean plasma Cmax of 5 pg/mL and 253 pg/mL were obtained for the nasal spray and subcutaneous injection respectively; relative bioavailability of the nasal spray was 1%. Subsequently, we investigated the pharmacokinetics of the liquid nasal spray formulation as well as a dry powder nasal formulation also containing Solutol® HS15 in a crossover study in an established ovine model. In this preclinical model, the relative bioavailability of liquid and powder nasal formulations was 1.4% and 1.0% respectively. The absolute bioavailability of subcutaneously administered PTH 1-34 (mean 77%, range 55–108%) in sheep was in agreement with published human data for teriparatide (up to 95%). These findings have important implications in the search for alternative routes of administration of peptides for the treatment of osteoporosis, and in terms of improving translation from animal models to humans

Mechanisms of activation of mouse and human enteroendocrine cells by nutrients

AstraZeneca, Wellcome Trust, Bowel and Cancer Research, Barts and the London Charity