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At least 343 records · Page 19Linked to original sources
PubMed1997

Mast cell-mediated induction of ICAM-1, VCAM-1 and E-selectin in endothelial cells in vitro: constitutive release of inducing mediators but no effect of degranulation.

Mast cell (MC)-mediated induction of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and of E-selectin was studied in cultures of rat heart endothelial cells (EC) and human umbilical vein EC (HUVEC) respectively. MC induced VCAM-1 and E-selectin, but hardly any ICAM-1 in EC. Induction was not dependent on MC degranulation, but seemed to be provoked by constitutively released substances, other than histamine, from MC. Co-incubation of MC and EC, allowing for direct contact between the two cell types, was more potent in induction than MC co-incubated separately from EC using a permeable membrane. MC were less potent in induction than exogenous added cytokines or LPS. Induction of cell adhesion molecules in rat heart EC was MC-specific, since EC incubations with either rat cardiomyocytes or heart fibroblasts had no effect. The data show that rat MC, independent of degranulation, secrete mediators relevant for the induction of a specific set of EC adhesion molecules in vitro. This suggests a (supportive) role for MC in cell-adhesion molecule induction in the endothelium in settings of early or mild inflammation. The results are discussed in the context of inflammatory processes in the heart in vivo.

Animals↗
PubMed1985

Regulation of C4 photosynthesis: purification and properties of the protein catalyzing ADP-mediated inactivation and Pi-mediated activation of pyruvate,Pi dikinase.

Pyruvate,Pi dikinase regulatory protein (PDRP) has been highly purified from maize leaves, and its role in catalyzing both ADP-mediated inactivation (due to phosphorylation of a threonine residue) and Pi-mediated activation (due to dephosphorylation by phosphorolysis) of pyruvate,Pi dikinase has been confirmed. These reactions account for the dark/light-mediated regulation of pyruvate,Pi dikinase observed in the leaves of C4 plants. During purification to apparent homogeneity the ratio of these two activities remained constant. The molecular weight of the native PDRP was about 180,000 at pH 8.3 and 90,000 at pH 7.5. Its monomeric molecular weight was 45,000. It was confirmed that inactive pyruvate,Pi dikinase free of a phosphate group on a catalytic histidine was the preferred substrate for activation. Michaelis constants for orthophosphate and the above form of active pyruvate,Pi dikinase were determined, as well as the mechanism of inhibition of the PDRP-catalyzed reaction by ATP, ADP, AMP, and PPi. For the inactivation reaction, Km values were 1.2 microM for the active pyruvate,Pi dikinase and 52 microM for ADP. CDP and GDP but not UDP could substitute for ADP. The inactivation reaction is inhibited by inactive pyruvate,Pi dikinase competitively with respect to both active pyruvate,Pi dikinase and ADP. Both the activation and inactivation reactions catalyzed by PDRP have a broad pH optimum between 7.8 and 8.3. The results are discussed in terms of the likely mechanism of dark/light regulation of pyruvate,Pi dikinase in vivo.

Adenosine Diphosphate↗
PubMed1992

Characterization of opioid receptor-mediated regulation of incertohypothalamic dopamine neurons: lack of evidence for a role of 5-hydroxytryptaminergic neurons in mediating the stimulatory effects of morphine.

The purpose of the present study was to characterize opioid receptor-mediated regulation of incertohypothalamic dopaminergic (DA) neurons in the rat brain by examining the acute effects of selective mu or kappa opioid receptor agonists and antagonists on concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) in the medial zona incerta (MZI) and the dorsomedial hypothalamic nucleus (DMN) which contain cell bodies and terminals, respectively, of these neurons. Morphine caused a dose- and time-related increase in concentrations of DOPAC in MZI and DMN; this stimulatory effect was blocked by the mu opioid receptor antagonist naltrexone. In contrast, activation or blockade of kappa opioid receptors following administration of U-50,488 or nor-binaltorphimine, respectively, had no effect on DOPAC concentrations in either the MZI or DMN. The basal activity of incertohypothalamic DA neurons and their response to morphine was similar in male and female rats. Morphine also increased the concentrations of 5-hydroxyindoleacetic acid in MZI and DMN, indicating that morphine increases the activity of 5-hydroxytryptamine (5HT) neurons projecting to these regions. This might suggest that morphine-induced activation of incertohypothalamic DA neurons is mediated by 5HT neurons; but 5,7-dihydroxytryptamine-induced lesions of 5HT neurons did not alter the ability of morphine to increase DOPAC concentrations in MZI and DMN. These results indicate that the stimulatory effects of mu opioid receptor activation on incertohypothalamic DA neurons is not dependent upon the presence of 5HT neurons.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1984

The mechanism of cell-mediated cytotoxicity. IV. K-76 COONa, which inhibits the activity of Factor I and of C5, inhibits early events in cytotoxic T-lymphocyte-mediated cytolysis and in T-lymphocyte activation.

K-76 COONa is a derivative of a fungal product which blocks complement (C)-mediated lysis by combining with C5 and preventing its activation to C5b. K-76 COONa can also combine with Factor I and inhibit its ability to hydrolyze C3b to iC3b. The inclusion of K-76 COONa at concentrations similar to those which inhibit C lysis blocked both murine cytotoxic-T-lymphocyte (CTL)-mediated lysis (CML) and the lectin-stimulated proliferative response of murine and human T lymphocytes. A modified cation pulse procedure has been used to determine which phases of CML were most sensitive to the drug. K-76 COONa was inhibitory when it was added to CML prior to the early Mg+2-dependent binding phase, but was much less effective when it was added at any time after the formation of CTL-target conjugates. The principal effect of the drug on the proliferative response was also exerted during an early phase of the response. K-76 COONa did not appreciably decrease the production of T-cell growth factor (TCGF), but it did inhibit the induction of TCGF receptor expression by both functional criteria, i.e., induction of responsiveness to TCGF, and by morphological criteria, i.e., the expression of the Tac antigen. Later events, such as the TCGF-dependent proliferation of cycling T cells, were less sensitive to the drug. Evidence is discussed suggesting that molecules similar to Factor I and to C3 may be involved both in the early events of CML and of T-lymphocyte activation.

Cells, Cultured↗
PubMed1980

The effects of Haemophilus influenzae vaccination on anaphylactic mediator release and isoprenaline-induced inhibition of mediator release.

The influence of Haemophilus influenzae on anaphylactic mediator release from ovalbumin-sensitized isolated guinea pig lungs was investigated. Lungs from H. influenzae-vaccinated animals released prostaglandins and thromboxanes following a smaller dose of ovalbumin than was effective in non-vaccinated animals. Histamine release was significantly increased in 4 day-vaccinated animals but not 1 or 10 days after vaccination, while broncho-constriction was potentiated in 1 and in 4 day-vaccinated animals. This increased histamine release was achieved following 2 micrograms ovalbumin. In contrast, doses of 10 micrograms and 1 mg ovalbumin respectively did not affect and decreased histamine release in the vaccinated group. The inhibition of anaphylactic mediator release by an infusion of 6 x 10(-9) M isoprenaline was significantly attenuated by H. influenzae vaccination. These results indicate an increased sensitivity to antigenic challenge and suggest that the functioning of beta-adrenoceptors was decreased as a result of H. influenzae vaccination.

Anaphylaxis↗
PubMed1988

Action of loperamide on neuronally mediated and Ca2+- or cAMP-mediated secretion in rat colon.

The action of loperamide on the ion secretion evoked in rat colon descendens by electric field stimulation of enteric neurons, on the Ca2+-dependent secretion due to carbachol, and on the cAMP-mediated secretion elicited by forskolin was studied. Loperamide blocked all three types of secretion, but about 10 times higher concentrations of the drug were necessary to block the secretion caused by forskolin than to block the secretion mediated neuronally or by Ca2+. All the effects of loperamide were mimicked by trifluoperazine, a calmodulin antagonist. Neither morphine nor the Ca2+ channel blocker, verapamil, mimicked the effects of loperamide on ion transport. Therefore it seems reasonable to conclude that the antisecretory action of loperamide in the rat colon is caused by a block of the calmodulin system.

Animals↗
PubMed1990

Beta-glucuronidase mediated pathway essential for retinal pigment epithelial degradation of glycosaminoglycans. Disease expression and in vitro disease correction using retroviral mediated cDNA transfer.

A beta-glucuronidase mediated pathway for the degradation of glycosaminoglycans is present in the retinal pigment epithelium. The pathway has been defined using ocular tissues and cultured cells from mutant animals having a recessively inherited deficiency of the lysosomal enzyme. In situ, storage products accumulate in secondary lysosomes of the retinal pigment epithelium, the cytoplasm fills with inclusions and the cells hypertrophy; severity of the disease increases with aging. Deficient activity of beta-glucuronidase is present in primary and second passage cultures. Radiolabel studies with 35SO4 show a significant retention of cell layer label by mutant retinal pigment epithelial cells during a 72-hr pulse or 24-hr chase period. The labels is in newly synthesized chondroitin sulfate and heparan sulfate, which are natural substrates for the deficient enzyme. There is no difference from normal in the total radioactivity and electrophoretic profile of the glycosaminoglycans that are synthesized and released into the media. A retroviral vector was used to transfer normal rat beta-glucuronidase cDNA into the mutant cells. The vector treatment results in restoration of enzyme activity and correction of the degradative defect; 35SO4 labeling shows that chondroitin sulfate and heparan sulfate levels return to normal. The vector treatment studies indicate that a single gene defect determines the abnormal beta-glucuronidase mediated pathway in the mutant retinal pigment epithelium.

Animals↗
PubMed1991

The use of a hapten-Fab conjugate to sensitize target cells for antibody-dependent complement-mediated lysis and antibody-dependent cell-mediated cytotoxicity.

NIP-conjugated Fab' fragments from a rabbit hyperimmunized with sheep red blood cells (SRBC) were used to link the hapten NIP to target cells for antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent complement-mediated lysis (ADCML). Target cells (SRBC) labelled with this NIP-Fab' complex were compared with SRBC directly haptenized with NIP in ADCC and ADCML assays using a NIP specific IgG1 chimeric antibody. Both methods yielded almost identical results. Using the NIP-FAb' conjugate identical target cell haptenization was readily achieved from experiment to experiment. Using conjugates of different NIP/Fab' ratios it should be possible to study how such changes influence antibody effector functions.

Animals↗
PubMed1993

Possible involvement of mu 2-mediated mechanisms in mu-mediated antitussive activity in the mouse.

The effect of pretreatment with naloxonazine on mu-opioid agonist-mediated antitussive effects was studied in mice. The antitussive effects of [D-Ala2, MePhe4, Gly-ol5]enkephalin (DAMGO) and morphine were significantly antagonized by naloxone pretreatment, 1 mg/kg given i.p. 5 min earlier, but not by naloxonazine pretreatment, 35 mg/kg given s.c. 24 h earlier. In contrast, the antinociceptive effects of these mu agonists, as determined by the tail-flick method, were significantly reduced by pretreatment with both naloxone and naloxonazine. These results suggest that mu 2 rather than mu 1 mechanisms are involved in mu-mediated antitussive effects.

Analgesics↗
PubMed1987

Extracellular hydrogen ions influence channel-mediated and carrier-mediated K+ fluxes in cultured mouse astrocytes.

Physiological (pH 7.2 and 7.0) and pathological (pH 6.8 and 6.6) changes of external pH, as they are measured in vivo, were imposed on mouse astrocytes in primary cultures and the effect on components of K+ transport pathways across the cell membrane was measured. Physiological pH changes had no effect at all. Pathological pH changes in inhibited K+ fluxes through channels by 40%. This effect occurred 3-6 min after a pH change and was not additive to a similar change induced by amiloride. This could be seen as an indication that the observed effects are mediated by subsequent changes in intracellular pH; however, direct intracellular pH measurements were not undertaken. A low pH of 6.6 inhibited the activity of the Na+, K+-ATPase by 65% and reduced the carrier-mediated K+ net accumulation into the cells by 60%. This suggests that measured extracellular pH changes in the brain may be functionally important, as they interfere with the K+ homeostasis of the nervous tissue.

Amiloride↗
PubMed1987

Role of the substantia nigra in the expression of dopamine D1 receptor-mediated and D2 receptor-mediated behaviours.

This study examines the proposal that striatonigral pathways support circling mediated by dopamine D1 receptors, but not D2 receptors, in unilaterally 6-hydroxydopamine-treated rats. In this model the D1/D2 agonist apomorphine, the D1 agonist 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine hydrochloride and the D2 agonists N-n-propyl-N-phenylethyl-P-(3-hydroxyphenyl) ethylamine hydrochloride, trans-(-)-4aR,4,4a,5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo-(3, 4-g) quinolino monohydrochloride and lisuride evoked a characteristic spectrum of motor responses when administered systemically. In addition apomorphine, 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine hydrochloride and lisuride replicated their systemic effects following stereotaxic injection into the supersensitive caudate nucleus. Three months after injecting the pars reticulata of the dopamine-denervated nigra with kainic acid (1 microgram in 1 microliter), all motor responses to intracaudate dopamine agonists were reduced or abolished. Systemic responses were modified differentially, often as early as one day post-kainate. Contraversive circling and posturing were reduced, or even reversed (apomorphine only), grooming was attenuated (all drugs) and 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine hydrochloride-induced forepaw nibbling and dyskinesia were abolished. By contrast, sniffing, movements of the head and locomotion were either unaffected, or significantly potentiated, suggesting these components of behaviour arose from dopamine receptors outside the denervated striatum. These behavioural changes showed no signs of recovery three months after kainate, and were not produced by partial lesions of the reticulata (1 microgram kainate in 0.2 microliter). Contrary to earlier opinion our results indicate that the structural integrity of the substantia nigra pars reticulata is essential for the development of all forms of dopamine behaviour mediated by striatal D1 and D2 receptors, though not necessarily by dopamine receptors present at other locations.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1992

Evolution of regulation of steroid-mediated intercellular communication in vertebrates: insights from flavonoids, signals that mediate plant-rhizobia symbiosis.

Various flavonoids, such as genistein, luteolin, and coumestrol, have actions in mammals that are mediated by binding either to classical estrogen receptors or to type II receptors, which also bind estrogen. These actions are of intense interest because they may be the basis for the protective actions of plants against certain cancers, such as breast cancer. The biological activity of flavonoids in mammals raises some questions. Is the hormonal action of flavonoids "an accident" derived from their phenolic groups and general hydrophobicity, which gives them some properties in common with estrogens? Or do flavonoids regulate gene transcription in other organisms? And, if so, is there a connection between their actions in these organisms and in mammals? Some answers to these questions are provided by the actions of plant-derived flavonoids in regulating gene transcription in rhizobia, bacteria that form nitrogen-fixing nodules in the roots of legumes, which has several interesting similarities with steroid-mediated actions in vertebrates. First, there is specificity in the actions of flavonoids in rhizobia; oxidation or reduction of the flavonoid or removal of a hydroxyl group can alter its biological activity. Moreover, some flavonoids are anti-inducers functioning like steroid antagonists to negate the actions of inducers. Also there are sequence similarities between various steroid metabolizing enzymes and proteins found in rhizobia, which indicates that these proteins are derived from a common ancestor. For example, 17 beta-hydroxysteroid dehydrogenase, which catalyzes the interconversion of the alcohol and ketone a C17 on estrogens and androgens, 11 beta-hydroxysteroid dehydrogenase, which catalyzes the interconversion of the alcohol and ketone at C11 of glucocorticoids, and 3 alpha,20 beta-hydroxysteroid dehydrogenase, which catalyzes the interconversion of the alcohol and ketone at C20 of corticosteroids, are homologs of proteins found in rhizobia. Thus, the binding of flavonoids to vertebrate proteins may represent an evolutionary linkage between the actions of steroids in mammals and communication between plants and rhizobia.

Animals↗
PubMed2005

Intestinal SGLT1-mediated absorption and metabolism of benzyl beta-glucoside contained in Prunus mume: carrier-mediated transport increases intestinal availability.

The intestinal absorption of benzyl beta-glucoside (BNZ beta glc) contained in the fruit of Prunus mume SIEB. et ZUCC. (Rosaceae), which is traditionally used as a medicinal food in Japan, was studied in rat intestines. BNZ beta glc was absorbed from the mucosal to serosal sides. Its metabolite, benzyl alcohol (BAL), was also detected on both the mucosal and serosal sides. In the presence of phloridzin (Na(+)/glucose cotransporter (SGLT1) inhibitor) or in the absence of Na+ (driving force), BNZ beta glc absorption was significantly decreased. Transport clearance of BNZ beta glc across the brush border membrane decreased as its concentration increased. These results indicate that BNZ beta glc is transported by SGLT1. Metabolic clearance of BNZ beta glc also decreased as its concentration increased. The amount ratio of BNZ beta glc to BAL on the serosal side increased with the increase of BNZ beta glc concentration. The intestinal availability of BNZ beta glc was lower in the absence of Na+ than in the presence of Na+, indicating that the SGLT1-mediated transport of BNZ beta glc increases intestinal availability by decreasing the intestinal extraction ratio. This neutraceutical study concluded that intestinal carrier-mediated transport across the brush border membrane improves the intestinal availability of nutritionally, pharmacologically or physiologically active compounds that undergo intestinal metabolism (first-pass effect).

Animals↗
PubMed2007

Reduced imipenem susceptibility in Klebsiella pneumoniae clinical isolates with plasmid-mediated CMY-2 and DHA-1 beta-lactamases co-mediated by porin loss.

We investigated the resistance mechanisms and clonality among 42 imipenem-non-susceptible Klebsiella pneumoniae isolated at a tertiary care hospital in Korea. Two isolates had bla(VIM-2) alleles, whereas bla(CMY-2)- and bla(DHA-1)-like alleles were detected in 24 and 16 isolates, respectively, with these enzymes confirmed by sequencing for representative isolates. Transfer of bla(CMY-2) and bla(DHA-1) was achieved by conjugation. Addition of 300 mg/L 3-aminophenylboronic acid (APB) reduced the minimum inhibitory concentration for 90% of the organisms (MIC(90)) of imipenem and meropenem eight- and four-fold, respectively, for the bla(CMY-2)- and bla(DHA-1)-positive isolates, confirming the role of these enzymes in resistance. SDS-PAGE of outer membrane proteins for representative isolates showed lack or greatly diminished expression of OmpK35 and OmpK36 porins. Pulsed-field gel electrophoresis of XbaI-restricted genomic DNA revealed two closely related clusters among 23 bla(CMY-2)-positive isolates, whereas those with bla(DHA-1) were more heterogeneous. In conclusion, reduced imipenem susceptibility among K. pneumoniae at this Korean hospital was largely co-mediated by production of plasmid-mediated AmpC beta-lactamases along with lack or greatly diminished expression of OmpK35 and OmpK36 porins.

Anti-Bacterial Agents↗
PubMed2005

Endogenous opioid-mediated antinociception in cholestatic mice is peripherally, not centrally, mediated.

BACKGROUND/AIMS: Cholestasis is associated with naloxone reversible antinociception and opiate receptor antagonists are used clinically to treat pruritus. Pain and pruritus are closely interrelated and opioids modulate both sensations. Therefore, we undertook a series of experiments to characterize opioid-mediated antinociception in cholestasis and determine if it occurs inside or outside the CNS. METHODS: Antinociception scores to both thermal and mechanical stimuli were determined in mice with cholestasis due to bile duct resection vs sham controls. RESULTS: Cholestatic mice demonstrated significant antinociception to both stimuli compared to controls, which was reversible by the opiate receptor antagonist naloxone. The experiments were repeated with a naloxone derivative, which does not cross the blood-brain-barrier (i.e. naloxone methiodide) with similar results, indicating an opioid antinociceptive effect mediated outside of the CNS. Experiments with intraplantar injections of low dose naloxone methiodide confirmed that cholestasis-associated antinociception occurs at the level of cutaneous nerve endings. These findings were supported by findings of increased dermal met-enkephalin expression in cholestatic mice. CONCLUSIONS: Cholestasis in mice is associated with antinociception due to local effects of endogenous opioids (i.e. met-enkephalin) at the level of sensory nerve endings. These findings may have direct implications in the management of cholestasis associated pruritus.

Animals↗
PubMed2004

c-FLIP-L recombinant adeno-associated virus vector infection prevents Fas-mediated but not nerve growth factor withdrawal-mediated cell death in PC12 cells.

Fas is a cell surface death receptor that may play an important role in regulating cell death in neuronal cell types by activation of caspase 8. Cellular FLICE inhibitory protein-long (c-FLIP-L) is an endogenous inhibitor of the activation of caspase 8 by Fas. The current study addresses the role of c-FLIP-L in regulation of cell death in PC12 cells induced by nerve growth factor (NGF) withdrawal and Fas antibody, which acts as a Fas ligand and activates the Fas receptor. A recombinant adeno-associated virus (rAAV) vector that expresses c-FLIP-L was constructed. PC12 cells infected with the c-FLIP-L rAAV were resistant to apoptosis induced by treatment with Fas antibody compared to cells infected with enhanced green fluorescent protein (EGFP) expressing rAAV. Overexpression of c-FLIP-L rAAV inhibited cleavage of caspase 8 induced by Fas antibody treatment. In contrast, treatment with the c-FLIP-L rAAV did not protect PC12 cells from cell death induced by NGF withdrawal. In conclusion, overexpression of c-FLIP-L rAAV inhibits Fas antibody-mediated cell death, but not NGF withdrawal-mediated cell death in PC12 cells.

Adenoviridae Infections↗
PubMed2004

Gaba(A) receptors in the pedunculopontine tegmental nucleus play a crucial role in rat shell-specific dopamine-mediated, but not shell-specific acetylcholine-mediated, turning behaviour.

The role of GABA(A) receptors in the pedunculopontine tegmental nucleus in turning behaviour of rats was studied. Unilateral injection of the GABA(A) receptor agonist, muscimol (25-100 ng), into the pedunculopontine tegmental nucleus dose-dependently produced contraversive pivoting, namely tight head-to-tail turning marked by abnormal hindlimb backward stepping. This effect was GABA(A) receptor specific, since it was prevented by the GABA(A) receptor antagonist, bicuculline (50 ng), which alone did not elicit turning behaviour. Unilateral injection of a mixture of dopamine D(1) ((+/-)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol [SKF 38393], 5 microg) and D(2) (quinpirole, 10 microg) receptor agonists into the nucleus accumbens shell has been found to elicit contraversive pivoting, whilst unilateral injection of the acetylcholine receptor agonist (carbachol, 5 microg) into the same site is known to elicit contraversive circling, namely turning marked by normal stepping. The pivoting induced by a mixture of SKF 38393 (5 microg) and quinpirole (10 microg) injected into the nucleus accumbens shell was significantly inhibited by bicuculline (50 ng) injected into the pedunculopontine tegmental nucleus, whereas muscimol (25 ng) had no effect. Neither muscimol (25 ng) nor bicuculline (50 ng) modulated the contraversive circling induced by carbachol (5 microg) injected into the nucleus accumbens shell. It is therefore concluded that unilateral stimulation of GABA(A) receptors in the pedunculopontine tegmental nucleus can elicit contraversive pivoting and that the pedunculopontine tegmental nucleus is one of the output stations of the accumbens region that mediates shell-specific, dopaminergic pivoting, but not of the accumbens region that mediates shell-specific, cholinergic circling.

Acetylcholine↗
PubMed2005

TRPV4 mediates pain-related behavior induced by mild hypertonic stimuli in the presence of inflammatory mediator.

The ligand-gated ion channel, TRPV4, functions as a transducer of hypotonic stimuli in primary afferent nociceptive neurons and contributes to inflammatory and neuropathic pain. Hypertonic saline also stimulates primary afferent nociceptors and the injection of mild hypertonic saline (2-5%) is widely used as an experimental model of pain in humans. Therefore, we tested whether TRPV4 participates in the transduction of hypertonic stimuli. Intradermal injection of 2% (607 mOsm) or 10% (3,250 mOsm) saline solution in the hind paw of rats induced a concentration-dependent pain-related behavior, flinching. Sensitization with prostaglandin E(2) (PGE(2)) caused a 7-fold increase in the number of flinches induced by 2% saline but failed to increase those caused by 10% saline. Spinal administration of antisense oligodeoxynucleotides to TRPV4 caused a 46% decrease in the number of flinches induced by 2% saline, but there was no change in flinching induced by 10% saline. Similarly, only the nociceptive behavior caused by 2% saline was reduced in TRPV4(-/-) knockout mice. The TRPV4-mediated nociceptive behaviors induced by hyper- and hypotonic stimuli were dependent on Src tyrosine kinase. We suggest TRPV4 is a transducer in primary afferents that mediates nociceptive behavior induced by small increases or decreases in osmolarity. Such changes in osmolarity might contribute to pain in inflammatory and neuropathic states.

Animals↗