N-arachidonoyl glycine is an endogenous arachidonoyl amide that activates the orphan G protein-coupled receptor (GPCR) GPR18 in a pertussis toxin (PTX)-sensitive manner and produces antinociceptive and antiinflammatory effects. It is produced by direct conjugation of arachidonic acid to glycine and by oxidative metabolism of the endocannabinoid anandamide. Based on the presence of enzymes that conjugate fatty acids with glycine and the high abundance of palmitic acid in the brain, we hypothesized the endogenous formation of the saturated Nacyl amide N-palmitoyl glycine (PalGly). PalGly was partially purified from rat lipid extracts and identified using nanohigh-performance liquid chromatography/hybrid quadrupole time-of-flight mass spectrometry. Here, we show that PalGly is produced after cellular stimulation and that it occurs in high levels in rat skin and spinal cord. PalGly was up-regulated in fatty acid amide hydrolase knockout mice, suggesting a pathway for enzymatic regulation. PalGly potently inhibited heat-evoked firing of nociceptive neurons in rat dorsal horn. In addition, PalGly induced transient calcium influx in native adult dorsal root ganglion (DRG) cells and a DRG-like cell line (F-11). The effect of PalGly on the latter cells was characterized by strict structural requirements, PTX sensitivity, and dependence on the presence of extracellular calcium. PalGlyinduced calcium influx was blocked by the nonselective calcium channel blockers ruthenium red, 1-(␤-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl)-1H-

No abstract

BackgroundHealth professionals may advise women to either stop breastfeeding or drug treatment due to restrictive advice in drug monographs. Regional medicines information and pharmacovigilance centres in Norway (RELIS) provide free and industry-independent answers to questions about drugs and breastfeeding documented in a full-text, searchable database (RELIS database). We used the RELIS database to describe which health care practitioners sought information about medication safety in lactation, most common drugs involved, advice provided and which resources were used to provide the advice.MethodsA random selection of 100 question-answer pairs (QAPs) from the RELIS database indexed with “BREASTFEEDING” in the period from January 2011 to December 2015 was analysed. Inclusion criteria were queries from health professionals about drugs. Questions about herbal supplements and other exposures not classified as drugs were excluded. The QAPs were manually analysed for compatibility of one or several drugs with breastfeeding, health care profession and workplace of enquirer in addition to advice and search strategy used.ResultsIn the 100 QAPs there were enquires about 152 drugs. Seventy-four questions concerned a single drug, but the number of drugs evaluated varied between 1 and 16. Fifty-nine questions were from physicians, 34 from nurses or midwives, two from pharmacists and two from other health professionals. Questions from physicians contained 93 drug evaluations (61%), nurses or midwives 47 (31%) and pharmacists seven (5%). The most frequent categories of drugs were antidepressants, antiepileptics and immunosuppressants. The most asked about drugs were lamotrigine, codeine, quetiapine and escitalopram. Fifty-nine percent of the drugs were deemed safe while breastfeeding, 16% if precautions were taken and 12% not recommended. Thirty-nine percent of the drug evaluations used an advanced literature search strategy, and this was significantly (p < 0.05) more likely when the enquirer was a physician.ConclusionsThis analysis of questions to Norwegian medicines information centres about medicine use in breastfeeding indicates the need for communication about safety of drugs affecting the nervous system, primarily to medical doctors and midwives. In the majority of cases the medicine information centre can reassure about the safety of breastfeeding while taking a drug.Electronic supplementary materialThe online version of this article (10.1186/s13006-017-0143-8) contains supplementary material, which is available to authorized users.

The 5-hydroxytryptamine 2C (5-HT(2C)) receptor has a single nucleotide polymorphism (SNP) site at amino acid position 23 in its N-terminal tail. The polymorphism involves conversion of a cysteine to serine. The site, designated C23S, is located within a 32 amino acid long predicted signal peptide. The aim of the present study was to investigate whether the 5-HT(2C) receptor indeed has a functional cleavable signal peptide. For this purpose, ten N-terminally modified 5-HT(2C) receptors were constructed. Modifications included addition of the influenza virus hemagglutinin signal peptide, addition of a FLAG epitope, truncation of the N-terminal tail, and combinations of these changes. The receptors were transiently expressed in COS-7 cells. The relative amounts of receptors expressed at the membranes were quantified by [(3)H]-mesulergine radioligand binding. In one of the receptor constructs the FLAG epitope was inserted just after the endogenous putative signal peptide. Immunostaining with the M1 antibody, which recognizes the FLAG epitope only as free N-terminal entity, was used to detect whether the putative signal peptide preceding the FLAG epitope was cleaved off. The results suggest the following conclusions. The predicted signal peptide in the N-terminal tail of the 5-HT(2C) receptor acts as a cleavable signal peptide. Cleaving of the signal peptide is important for translocation of the wild type receptor to the plasma membrane. The two amino acids differentially encoded by the C23S SNP are likely absent from the mature 5-HT(2C) receptor.

No abstract