Complex formation between the vasopressin 1b receptor, β-arrestin-2, and the μ-opioid receptor underlies morphine tolerance.

Chronic morphine exposure upregulates adenylate cyclase signaling and reduces analgesic efficacy, a condition known as opioid tolerance. Nonopioid neurotransmitters can enhance morphine tolerance, but the mechanism for this is poorly understood. We show that morphine tolerance was delayed in mice lacking vasopressin 1b receptors (V1bRs) or after administration of V1bR antagonist into the rostral ventromedial medulla, where transcripts for V1bRs and μ-opioid receptors are co-localized.

[Easing human pain: challenges to a novel therapeutic drug in neuropathic pain].

Pain control is very important since, even today, 20 million people suffer from neuropathic pain. Although many basic science and clinical researchers have made efforts to control pain, the mechanism of neuropathic pain is unfortunately still not fully understood. Morphine, a prototypical opioid, is a useful medicine to relieve severe pain.

The kick-in system: a novel rapid knock-in strategy.

Knock-in mouse models have contributed tremendously to our understanding of human disorders. However, generation of knock-in animals requires a significant investment of time and effort. We addressed this problem by developing a novel knock-in system that circumvents several traditional challenges by establishing stem cells with acceptor elements enveloping a particular genomic target.

The statins fluvastatin and pravastatin exert anti-flushing effects by improving vasomotor dysfunction through nitric oxide-mediated mechanisms in ovariectomized animals.

Statins have pleiotropic vascular protective effects that are independent of their cholesterol-lowering effects. The aim of the present study was to determine if statins have anti-flushing actions in an animal model of forced exercise-induced temperature dysregulation in menopausal hot flushes, and to clarify the critical role of statins in regulating vascular reactivity in the tail arteries of ovariectomized rats. Administration of fluvastatin or pravastatin (3mg/kg/day for 7days, p.

Aldosterone-sensitive nucleus tractus solitarius neurons regulate sensitivity of the baroreceptor reflex in high sodium-loaded rats.

We examined the role of aldosterone-sensitive neurons in the nucleus tractus solitarius (NTS) in the arterial baroreceptor reflex (baroreflex) function. Baroreflex sensitivity was induced by phenylephrine in high sodium-loaded rats and was significantly reduced. This baroreflex sensitivity was reversed by microinjection of the mineralocorticoid receptor (MR) antagonist eplerenone into the NTS.

Involvement of Na+/Ca2+ exchanger in pentylenetetrazol-induced convulsion by use of Na+/Ca2+ exchanger knockout mice.

Involvement of Na+/Ca2+ exchanger (NCX) in pentylenetetrazol (PTZ)-induced convulsion by use of NCX knockout mice and the selective ligand SEA0400 to NCX was examined. In the SEA0400-administered group, the latency to clonic convulsion was extended into 210 s, although the latency to clonic convulsion was observed until 100 s in control group. SEA0400 had little effect on bicuculline-induced clonic seizure nicotine-induced wild running and 4-aminopyridine-induced tonic flexion, respectively.

Modulation of P2X receptors in dorsal root ganglion neurons of streptozotocin-induced diabetic neuropathy.

Painful diabetic neuropathy causes hyperalgesia and does not respond to commonly used analgesics such as non-steroidal anti-inflammatory drugs or opioids at doses below those producing disruptive side effects. In the present study, we examined the effect of P2X receptor antagonists, which are known to modulate the pain pathway, on mechanical hyperalgesia in streptozotocin (STZ)-induced diabetic mice. The paw withdrawal frequency measured by von Frey filaments, began to significantly increase 5 days after STZ injection and was maintained for more than 14 days.

New topics in vasopressin receptors and approach to novel drugs: involvement of vasopressin V1a and V1b receptors in nociceptive responses and morphine-induced effects.

Arginine vasopressin (AVP) receptors have been classified into V1a, V1b, and V2 subtypes. Recent studies have demonstrated the involvement of AVP in anti-nociception and in morphine-induced anti-nociception. However, the roles of individual AVP-receptor subtypes have not been fully elucidated.

The spinal muscarinic M(1) receptors and GABA(A) receptors contribute to the McN-A-343-induced antinociceptive effects during thermal stimulation of mice.

The present study was undertaken to clarify how spinal muscarinic receptors are involved in the antinociceptive effects in thermal stimulation. Intrathecal (i.t.

Rats harboring S284L Chrna4 mutation show attenuation of synaptic and extrasynaptic GABAergic transmission and exhibit the nocturnal frontal lobe epilepsy phenotype.

Mutations of genes encoding alpha4, beta2, or alpha2 subunits (CHRNA4, CHRNB2, or CHRNA2, respectively) of nAChR [neuronal nicotinic ACh (acetylcholine) receptor] cause nocturnal frontal lobe epilepsy (NFLE) in human. NFLE-related seizures are seen exclusively during sleep and are characterized by three distinct seizure phenotypes: "paroxysmal arousals," "paroxysmal dystonia," and "episodic wandering." We generated transgenic rat strains that harbor a missense mutation S284L, which had been identified in CHRNA4 in NFLE.

A high-sodium diet in streptozotocin-induced diabetic rats impairs endothelium-derived hyperpolarizing factor-mediated vasodilation.

We examined endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxation of mesenteric arteries in high-sodium loaded streptozotocin (STZ)-induced diabetic rats. The study shows that acetylcholine (ACh)-induced, EDHF-mediated relaxation is relatively maintained in STZ-induced diabetic rats, but after a high-sodium diet was given, the function was significantly impaired in STZ-induced diabetic rats.

Contribution of Ca(2+) -dependent protein kinase C in the spinal cord to the development of mechanical allodynia in diabetic mice.

In this paper, we directly demonstrate, for the first time, the activation of Ca(2+)-dependent protein kinase C (PKC) in the spinal cord of diabetic mice. In streptozotocin (STZ)-treated (200 mg/kg, i.v.

The role of Na+/Ca2+ exchanger in endothelin-1-aggravated hypoxia/reoxygenation-induced injury in renal epithelial cells.

We analyzed the role of the Na+/Ca2+ exchanger (NCX) in endothelin-1-aggravated hypoxia/reoxygenation-induced injury in renal epithelial LLC-PK1 cells. KB-R7943, a selective NCX inhibitor, suppressed hypoxia/reoxygenation-induced cell damage, whereas overexpression of NCX1 into cells enhanced it. Endothelin-1 significantly aggravated hypoxia/reoxygenation-induced injury in parental and NCX1-overexpressing LLC-PK1 cells.

Impaired social interaction and reduced anxiety-related behavior in vasopressin V1a receptor knockout mice.

The arginine vasopressin (AVP) system plays an important role in social behavior. Autism, with its hallmark disturbances in social behavior, has been associated with the V1a receptor (V1aR) gene. Furthermore, impairments of social function are often observed in symptoms of schizophrenia.

The tumor metastasis suppressor gene Drg-1 down-regulates the expression of activating transcription factor 3 in prostate cancer.

The tumor metastasis suppressor gene Drg-1 has been shown to suppress metastasis without affecting tumorigenicity in immunodeficient mouse models of prostate and colon cancer. Expression of Drg-1 has also been found to have a significant inverse correlation with metastasis or invasiveness in various types of human cancer. However, how Drg-1 exerts its metastasis suppressor function remains unknown.

Interaction of KAI1 on tumor cells with DARC on vascular endothelium leads to metastasis suppression.

CD82, also known as KAI1, was recently identified as a prostate cancer metastasis suppressor gene on human chromosome 11p1.2 (ref. 1).

Mechanism of apoptosis induced by the inhibition of fatty acid synthase in breast cancer cells.

Fatty acid synthase (FAS) has been found to be overexpressed in a wide range of epithelial tumors, including breast cancer. Pharmacologic inhibitors of FAS cause apoptosis of breast cancer cells and result in decreased tumor size in vivo. However, how the inhibition of FAS induces apoptosis in tumor cells remains largely unknown.

[Vasopressin receptor knockout mice as an animal model of psychiatric disorders].

Arginine vasopressin (AVP) is a neurohypophyseal peptide best known as an antidiuretic hormone. AVP receptors have been classified into three subtypes: V1a, V1b, and V2 receptors. The V1a receptor (V1aR) and V1b receptor (V1bR) are widely distributed in the central nervous system, including the cortex and hippocampus.

Disruption of the prepulse inhibition of the startle reflex in vasopressin V1b receptor knockout mice: reversal by antipsychotic drugs.

In the present study, we investigated whether mice lacking the arginine vasopressin (AVP) V1b receptor (V1bR) exhibit deficits of prepulse inhibition (PPI) of the startle reflex, reminiscent of the sensorimotor gating deficits observed in a large majority of schizophrenic patients. V1bR knockout (KO) mice displayed significantly reduced levels of PPI of the startle reflex. In addition to PPI deficits, V1bR KO mice showed increased acoustic startle response.

Intrathecal clonidine inhibits mechanical allodynia via activation of the spinal muscarinic M1 receptor in streptozotocin-induced diabetic mice.

We examined the involvement of the spinal muscarinic receptors in the clonidine-induced antiallodynic effects. Mechanical sensitivity was assessed by stimulating the hind paw with von Frey filaments. In streptozotocin-treated (200 mg/kg, i.

PTEN up-regulates the tumor metastasis suppressor gene Drg-1 in prostate and breast cancer.

PTEN (phosphatase and tensin homologue deleted on chromosome 10) has been shown to be inactivated in a wide variety of cancers, and the role of this gene as a tumor suppressor has been well established. On the other hand, results of recent animal studies as well as clinical evidence indicate that PTEN is also involved in tumor metastasis suppression. Although PTEN is known to play a key role in controlling cell growth and apoptosis, how PTEN exerts the metastasis suppressor function remains largely unknown.

The spinal muscarinic receptor subtypes contribute to the morphine-induced antinociceptive effects in thermal stimulation in mice.

The present study was undertaken to clarify how spinal muscarinic receptors can be involved in the antinociceptive effects induced by morphine in thermal stimulation. The morphine-induced antinociceptive effects (26.6 micromol/kg, s.