Mechanisms of Bv8-induced biphasic hyperalgesia: increased excitatory transmitter release and expression.

Bv8 is a pronociceptive peptide that binds to two G-protein coupled prokineticin receptors, PK-R1 and PK-R2. These receptors are localized in the dorsal horn of the spinal cord and dorsal root ganglia (DRG) of nociceptive neurons in rodents. Systemic administration of Bv8 elicits a biphasic reduction in nociceptive thresholds to thermal and mechanical stimuli.

Bv8/Prokineticins and their Receptors A New Pronociceptive System.

Bv8 is a small protein secreted by frog skin. Mammalian homologues of Bv8, the prokineticins PK1 and PK2, and their G-protein coupled receptors prokineticin receptor 1 (PKR1) and prokineticin receptor 2 (PKR2) have been identified and linked to several biological effects as gut motility, neurogenesis, angiogenesis, circadian rhythms, hematopoiesis, and nociception. Emerging evidences indicated that prokineticins are also associated with pathologies of the reproductive and nervous system, myocardial infarction, and tumorigenesis.

Triazine compounds as antagonists at Bv8-prokineticin receptors.

On the basis of a Janssen's patent, we approached a new synthesis of some 1,3,5-triazin-4,6-diones as potential non peptidic prokineticin receptor antagonists, containing the following substitutions: (N(1) and N(5) link a 4-methoxybenzyl and a 4-ethylbenzyl, respectively; C(2) can link an amino-ethyl-guanidine (reference compound 1) or an ethylendiamine (2) or an amino-ethyl-amino-2-imidazoline (3). New compounds were assessed for PKR1 and PKR2 affinity. Antagonist properties were evaluated as inhibition of 1 nM Bv8-induced intracellular Ca2+ mobilization.

The prokineticin receptor agonist Bv8 decreases IL-10 and IL-4 production in mice splenocytes by activating prokineticin receptor-1.

Background: Bv8, prokineticin-1, or endocrine gland-vascular endothelial growth factor, and prokineticin-2 are recently isolated peptide agonists of two G protein-coupled receptors, prokineticin receptor-1 (PROKR 1) and PROKR 2, and have been described as affecting a number of myeloid cell functions. We evaluated the impact of Bv8 on lymphoid cells by investigating its ability to modulate T cell cytokine balance in mouse.

Results: The production of T-helper1 cytokines (IL-2, IFN-gamma and IL-1beta), the T-helper 2 cytokine IL-4, and the anti-inflammatory cytokine IL-10 by mouse splenocytes was evaluated after polyclonal stimulation or immunisation with the keyhole limpet hemocyanin protein antigen by measuring cytokine levels.

Modulators of pain: Bv8 and prokineticins.

Bv8 is a small protein secreted by frog skin. Mammalian homologues of Bv8, the prokineticins PK1 and PK2, and their G-protein coupled receptors PKR1 and PKR2 have been identified and linked to several biological effects. Bv8 elicits a dose-dependent reduction in nociceptive threshold to thermal and mechanical stimuli applied to the skin of tail and paw of rats and mice and increases the sensitivity to nociceptive mediators as capsaicin and prostaglandins.

The prokineticin receptor agonist Bv8 increases GABA release in the periaqueductal grey and modifies RVM cell activities and thermoceptive reflexes in the rat.

The prokineticin Bv8, a small protein secreted by the skin of the Bombina variegata frog, is a potent agonist of both the identified prokineticin receptors, the G-protein-coupled PK-R1 and PK-R2. We found in this study that intraperiaqueductal grey (PAG) Bv8, 100 and 200 pmol per rat, exerted a pronociceptive action and caused opposite effects on the ongoing rostral ventromedial medulla (RVM) On- and Off-cell activities in rats. Bv8 increased and decreased the ongoing activity of RVM On and Off cells, respectively.

Bv8/Prokineticin proteins and their receptors.

The Bv8/Prokineticins (PKs) are a new family of peptides identified in frog, fish, reptiles and mammals that signal through two highly homologous G-protein coupled receptors, PKR1 and PKR2. Bv8/PK proteins possess a unique structural motif comprising five disulfide bonds and a completely conserved N-terminal hexapeptide sequence that is essential for the peptide's biological activities. Over the past few years, several biological functions of Bv8/PK proteins have been elucidated.

Impaired nociception and inflammatory pain sensation in mice lacking the prokineticin receptor PKR1: focus on interaction between PKR1 and the capsaicin receptor TRPV1 in pain behavior.

Bv8, prokineticin-1 or EG-VEGF (endocrine gland-derived vascular endothelial growth factor), and prokineticin-2, are naturally occurring peptide agonists of two G-protein-coupled receptors (GPCRs), prokineticin receptor 1 (PKR1) and PKR2. PKRs are expressed in neurons in the CNS and peripheral nervous system and many dorsal root ganglion (DRG) cells expressing PKRs also express transient receptor potential vanilloid receptor-1 (TRPV1). Mice lacking the pkr1 gene were generated to explore the role of the PKR1 receptor in nociceptive signaling and in nociceptor sensitization.

Sensitization of transient receptor potential vanilloid 1 by the prokineticin receptor agonist Bv8.

Small mammalian proteins called the prokineticins [prokineticin 1 (PK1) and PK2] and two corresponding G-protein-coupled receptors [prokineticin receptor 1 (PKR1) and PKR2] have been identified recently, but the physiological role of the PK/PKR system remains mostly unexplored. Bv8, a protein extracted from frog skin, is a convenient and potent agonist for both PKR1 and PKR2, and injection of Bv8 in vivo causes a potent and long-lasting hyperalgesia. Here, we investigate the cellular basis of hyperalgesia caused by activation of PKRs.

Bv8, the amphibian homologue of the mammalian prokineticins, induces a proinflammatory phenotype of mouse macrophages.

1.--The small protein Bv8, isolated from the amphibian skin, belongs to a novel family of secreted proteins linked to several biological effects. We describe the expression of Bv8/prokineticins and their receptors in mouse macrophages, and characterize their proinflammatory activities.

Biological activities of Bv8 analogues.

1 The small protein Bv8, secreted by the skin of the frog Bombina variegata, belongs to a novel family of secreted proteins whose orthologues have been identified in snakes (MIT) and in mammals (prokineticins (PKs)). A characteristic feature of this protein family is the same N-terminal sequence, AVITGA, and the presence of 10 cysteines with identical spacing in the C-terminal domain. Two closely related G protein-coupled receptors that mediate signal transduction of Bv8/PKs have been cloned (PK-R1 and PK-R2).

Bv8, the amphibian homologue of the mammalian prokineticins, modulates ingestive behaviour in rats.

1. The small protein Bv8, secreted by the skin of the frog Bombina variegata, belongs to a novel family of secreted proteins whose mammalian orthologues have been identified and named prokineticins (PK-1 and PK-2). 2.

Nociceptive sensitization by the secretory protein Bv8.

1 The small protein Bv8, isolated from amphibian skin, belongs to a novel family of secretory proteins (Bv8-Prokineticin family, SWISS-PROT: Q9PW66) whose orthologues have been conserved throughout evolution, from invertebrates to humans. 2 When injected intravenously or subcutaneously (from 0.06 to 500 pmol kg(-1)) or intrathecally (from 6 fmol to 250 pmol) in rats, Bv8 produced an intense systemic nociceptive sensitization to mechanical and thermal stimuli applied to the tail and paws.

Activity of mu- and delta-opioid agonists in vas deferens from mice deficient in MOR gene.

1. Mice lacking the mu-opioid receptor have been recently generated. Centrally mediated responses of mu-opioid agonists are suppressed whereas some of the delta-opioid responses are preserved in these mutant mice.

Pharmacology of amphibian opiate peptides.

In 1980 the skin of certain frogs belonging to the genus Phyllomedusinae was found to contain two new peptides that proved to be selective mu-opioid agonists, and named dermorphins. Since 1987 deltorphins, a family of highly selective delta-opioid peptides were identified either by cloning of the cDNA from frog skins or isolation of the peptides. The distinctive feature of opioid peptides is the presence of a naturally occurring D-enantiomer at the second position in their common N-terminal sequence, Tyr-D-Xaa-Phe.

Effects of antisense oligonucleotides on brain delta-opioid receptor density and on SNC80-induced locomotor stimulation and colonic transit inhibition in rats.

1. To reduce the density of delta-opioid receptor protein, five antisense phosphorothioate oligodeoxynucleotides (aODN), targeting the three exons of rat delta-opioid receptor mRNA (DOR), were injected twice daily for 4 days or continuously infused for 7 days into brain lateral ventricles (i.c.

Bv8, a small protein from frog skin and its homologue from snake venom induce hyperalgesia in rats.

From skin secretions of Bombina variegata and Bombina bombina, we isolated a small protein termed Bv8. The sequence of its 77 amino acids was established by peptide analysis and by cDNA cloning of the Bv8 precursor. Bv8 stimulates the contraction of the guinea-pig ileum at nanomolar concentrations.

Respiratory and cardiovascular effects of the mu-opioid receptor agonist [Lys7]dermorphin in awake rats.

1. Changes in respiratory variables, arterial blood pressure and heart rate were studied in awake rats after injection of the opioid peptide [Lys7]dermorphin and its main metabolites, [1-5]dermorphin and [1-4]dermorphin. 2.

Postnatal development of delta-opioid receptor subtypes in mice.

1. The density and affinity of binding sites for the delta-selective opioid ligands [3H]-[D-Ala2, Asp4]deltorphin (DELT-I), [3H]-[D-Ala2Glu4]-deltorphin (DELT-II), [3H]-[D-Pen2,D-Pen5]enkephalin (DPDPE), and [3H]-naltrindole (NTI) were determined in whole brain from 10, 15, 25 and 60 day-old C57BL mice. 2.

The dermorphin peptide family.

1. In 1980, the skin of certain frogs belonging to the genus Phyllomedusinae was found to contain two new peptides that proved to be selective mu-opioid agonists. Given the name dermorphins, these were the first members of a peptide family that in the past 15 years has grown to reach a total of seven naturally occurring peptides and nearly 30 synthetic analogs.

Opioid receptor affinity and analgesic activity of O- and C-glycosylated opioid peptides.

O- and C-glycosylation of the mu-agonist dermorphin reduced neither its mu receptor affinity in binding assay nor its agonist potency in guinea-pig ileum assay (GPI). O- and C-glycosylation of the delta-agonist deltorphin reduced its delta-receptor affinity and its agonist potency in mouse vas deferens assay (MVD). O- and C-glycosylated dermorphin, administered i.

Interaction between the mu-agonist dermorphin and the delta-agonist [D-Ala2, Glu4]deltorphin in supraspinal antinociception and delta-opioid receptor binding.

1. In rats, the interaction between the mu-opioid agonist dermorphin and the delta-opioid agonist [D-Ala2, Glu4]deltorphin was studied in binding experiments to delta-opioid receptors and in the antinociceptive test to radiant heat. 2.

Development of delta-opioid receptor subtypes and the regulatory role of weaning: radioligand binding, autoradiography and in situ hybridization studies.

Evidence from behavioral studies suggests that the process of weaning activates the development of a delta-opioid receptor subtype. We now report the influence of weaning on the development of delta receptors in the central nervous system assessed by membrane homogenate binding and autoradiography with selective delta radioligands and by in situ hybridization using a cRNA probe for the delta receptor. Binding was carried out by using [3H][D-Ala2]deltorphin I (DELT I), [3H]IIe5,6-deltorphin II (IIe5,6-DELT II) and [3H]naltrindole (NTI).

Production of antinociception by peripheral administration of [Lys7]dermorphin, a naturally occurring peptide with high affinity for mu-opioid receptors.

1. The opioid activity of the amphibian peptide, [Lys7]dermorphin, was studied in rats and mice. When administered intracerebroventricularly (i.

A crystal-state, solution and theoretical study of the preferred conformation of linear C alpha, alpha-diphenylglycine derivatives and dipeptides with potential anticonvulsant activity.

Several linear molecules containing the C alpha, alpha-diphenylglycine residue were prepared as potential anticonvulsants. The conformational preferences of the C alpha, alpha-diphenylglycine residue were assessed in these synthetic derivatives and dipeptides by X-ray diffraction, FTIR absorption and 1H NMR techniques, and by conformational energy computations. Five (out of six) derivatives adopt the fully extended C5 conformation in the crystal state.