Isolating and characterizing three alternatively spliced mu opioid receptor variants: mMOR-1A, mMOR-1O, and mMOR-1P.

Extensive alternative pre-mRNA splicing of the mu opioid receptor gene, OPRM1, has demonstrated an array of splice variants in mice, rats and humans. Three classes of splice variants have been identified: full-length seven transmembrane (TM) domain variants with C-terminal splicing, truncated 6TM variants and single TM variants. The current studies isolates and characterizes an additional three full-length C-terminal splice variants generated from the mouse OPRM1 gene: mMOR-1A, mMOR-1O, and mMOR-1P.

The anti-apoptotic effect of leukotriene B4 in neutrophils: a role for phosphatidylinositol 3-kinase, extracellular signal-regulated kinase and Mcl-1.

The constitutive commitment of neutrophils to apoptosis is a key process for the control and resolution of inflammation and it can be delayed by various inflammatory mediators including leukotriene B4 (LTB4). The mechanisms by which LTB4 contributes to neutrophil survival are still unclear and the present work aims at identifying intracellular pathways underlying this effect. Inhibition of human neutrophil apoptosis by LTB4 was abrogated by the phosphatidylinositol 3-kinase (PI3-K) inhibitor wortmannin and by the specific MEK inhibitor PD98059.

Pharmacological characterization of dihydromorphine, 6-acetyldihydromorphine and dihydroheroin analgesia and their differentiation from morphine.

The present study examined the pharmacology of dihydromorphine, 6-acetyldihydromorphine and dihydroheroin (3,6-diacetyldihydromorphine). Like morphine, dihydromorphine and its acetylated derivatives all were highly selective mu-opioids in receptor binding assays. All the compounds were potent mu-selective analgesics, as shown by their sensitivity towards the mu-selective opioid receptor antagonists naloxonazine and beta-funaltrexamine.

Histogranin-like antinociceptive and anti-inflammatory derivatives of o-phenylenediamine and benzimidazole.

Histogranin (HN)-like nonpeptides were designed and synthesized using benzimidazole (compound 1) and o-phenylenediamine (compounds 2-7) as scaffolds for the attachment of phenolic hydroxyl and basic guanidino pharmacophoric elements present in HN. The benzimidazole derivative N-5-guanidinopentanamide-(2R)-yl-2-(p-hydroxybenzyl)-5-carboxybenzimidazole (1) and the o-phenylenediamine derivative N-5-guanidinopentanamide-(2S)-yl-2-N-(p-hydroxyphenylacetyl) phenylenediamine (2) were more potent analgesics than HN in both the mouse writhing (5.5 and 3.

Bioactive peptidic analogues and cyclostereoisomers of the minimal antinociceptive histogranin fragment-(7-10).

Novel analogues of the minimal antinociceptive histogranin (HN) fragment Gly(7)-Gln-Gly-Arg(10), in which amino acids in positions 8, 9, and 10 were replaced by lipophilic amino acids and corresponding d-amino acid residues in combination with N- to C-terminal cyclization, were synthesized and tested in various animal models of pain. All synthetic compounds were potent and efficacious analgesics in the mouse writhing test. Cyclic [-Gly-Ala-Tyr-d-Arg-] (9) and cyclic [-Gly p-Cl-Phe-Tyr-d-Arg-] (10) were the most potent analgesics, being 17 and 135 times as potent as HN, respectively (AD(50) of 1.

Identification and characterization of two new human mu opioid receptor splice variants, hMOR-1O and hMOR-1X.

The mouse gene encoding the mu opioid receptor, Oprm, undergoes extensive alternatively splicing, with 14 variants having been identified. However, only one variant of human mu opioid receptor gene (Oprm), MOR-1A, has been described. We now report two novel splice variants of the human Oprm gene, hMOR-1O and hMOR-1X.

The role of descending fibers from the rostral ventromedial medulla in opioid analgesia in rats.

There has been controversy as to whether the contribution of descending fibers from the rostral ventromedial medulla to opioid analgesia depends on the nature of the noxious stimulus eliciting pain. In the present study, inactivation of descending fibers by microinjection of muscimol (50 ng) in the rostral ventromedial medulla abolished morphine analgesia in the tail immersion and hot plate tests but decreased morphine analgesia by 60% in the formalin test. Analysis of the dose-response relation for morphine after inactivation of descending fibers revealed that, except for the tail immersion test, high doses of morphine could not overcome the block induced by muscimol.