Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The opioid system has important roles in controlling pain, reward and addiction, and is implicated in numerous other processes within and outside the nervous system, such as mood states, immune responses, and prenatal developmental processes. The effects of the opioid system are mediated by at least three ligands, enkephalin, endorphin, and dynorphin, which act through the opioid receptors mu, delta, and kappa. In order to dissect the roles of individual components of the opioid system, mutant mice lacking single ligands or receptors are instrumental. We report here on the generation and initial characterization of a mutant mouse strain lacking pre-prodynorphin. Dynorphin 'knockout' mice are viable, healthy, and fertile and show no overt behavioral differences to wildtype littermates. Dynorphin knockout mice constitute a valuable tool for many research areas, among them research into pain, substance abuse, and epilepsy.
Brain Res Mol Brain Res 2001 Jan 31
PMID:Generation of dynorphin knockout mice. 1116 73

Stress-induced analgesia is a well-documented phenomenon that occurs in all mammalian species. Forced cold water swim produces a type of stress-induced analgesia that is independent of mu opioid receptors. The neuropeptide neurotensin (NT) has been implicated in mu opioid-independent analgesia (MOIA), but the circuitry of this system is largely unknown. The medial preoptic area (MPO) and lateral hypothalamus (LH) are two regions that are known to modulate pain processing. These two regions also contain neurotensinergic projections to the periaqueductal gray, a region that has been shown to produce MOIA upon injection of NT. The goal of this study was to determine if cold water swim (CWS) stress, which produces MOIA, activates the NT-ergic systems in these two regions. In situ hybridization results indicate that CWS increases the level of NT mRNA within neurons in the MPO and LH, suggesting that these two regions are activated during this process.
Brain Res Mol Brain Res 2001 Jan 31
PMID:Cold water swim stress increases the expression of neurotensin mRNA in the lateral hypothalamus and medial preoptic regions of the rat brain. 1116 81

It is widely assumed that all exercise, regardless of the degree of difficulty or strenuousness, is good (no pain-no gain). In this speculative review of the literature and our research findings we highlight the fact that strenuous exercise taken to the extreme initiates an immune and vascular proinflammatory situation. However, mild cyclic exercise appears to produce health benefits for an individual. In part, this is due to vascular cyclic pulsations, occurring in mild exercise, stimulating constitutive nitric oxide synthase derived nitric oxide release. This in turn down-regulates vascular endothelial cells and immunocytes, as well as their interaction and inhibits the disassociation of NF-kappaB, preventing the production of proinflammatory cytokines. The nitric oxide so generated may even scavenge excess free radicals, preventing tissue damage. Prolonged strenuous exercise appears to limit these positive phenomena because of the maintained and prolonged high blood pressure that reduces the cyclic pulsations, limiting nitric oxide production. We further note that pathological conditions, i.e., Parkinson's disorder, may benefit from mild exercise, i.e., cyclic nitric oxide production, since the inactivity associated with this disease may lead to compromised nitric oxide production, initiating a progressive deterioration of tissues, including peripheral adrenergic neurons, due to a lack of adequate basal nitric oxide levels required to maintain the vascular microenvironment in a mild state of inhibition. We conclude that mild exercise represents an alternate and economical therapy to preserve health and/or diminish the rate of decline of the normal physiological processes that may even be associated with aging.
Int J Mol Med 2001 Feb
PMID:Vascular pulsations stimulating nitric oxide release during cyclic exercise may benefit health: a molecular approach (review). 1117 14

Nociceptin/orphanin FQ (N/OFQ) and nocistatin (NST) are two neuropeptides derived from the same precursor protein that exhibit opposing effects on spinal neurotransmission and nociception. Here, we have used whole-cell, patch-clamp recordings from visually identified neurons in spinal cord dorsal horn slices of genetically modified mice to investigate the role of the N/OFQ receptor (N/OFQ-R) in the modulatory action of both peptides on excitatory glutamatergic and inhibitory glycinergic and gamma-aminobutyric acid (GABA)-ergic synaptic transmission. In wild-type mice, N/OFQ selectively suppressed excitatory transmission in a concentration-dependent manner but left inhibitory synaptic transmission unaffected. In contrast, NST reduced only inhibitory but not alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor-mediated excitatory synaptic transmission. N/OFQ-mediated inhibition of excitatory transmission was completely absent in N/OFQ-R receptor-deficient (N/OFQ-R(-/-)) mice and significantly reduced in heterozygous (N/OFQ-R(+/-)) mice, whereas the action of NST on inhibitory neurotransmission was completely retained. To test for the relevance of these results for spinal nociception, we investigated the effects of intrathecally injected N/OFQ in the mouse formalin test, an animal model of tonic pain. N/OFQ (3 nmol/mouse) induced significant antinociception in wild-type mice, but had no antinociceptive effects in N/OFQ-R(-/-) mice. These results indicate that the inhibitory action of N/OFQ on excitatory glutamatergic synaptic transmission and its spinal antinociceptive action are mediated via the N/OFQ receptor, whereas the action of NST is independent of this receptor.
Mol Pharmacol 2001 Mar
PMID:Modulation of synaptic transmission by nociceptin/orphanin FQ and nocistatin in the spinal cord dorsal horn of mutant mice lacking the nociceptin/orphanin FQ receptor. 1117 57

Corticotropin releasing factor (CRF) is an important regulator of the endocrine, behavioral, autonomic and immune responses to stress. Two high affinity CRF receptors have been identified, which are distributed in distinct anatomical regions. CRF(1) receptors have been relatively well characterized and antagonists to this receptor effectively block stress-induced behaviors in rodents. The function of CRF(2) receptors, which are highly expressed in limbic brain regions, is less well understood. Therefore, an antisense oligonucleotide approach was used to study the role of CRF(2) receptors in the lateral septum in rats. An antisense oligonucleotide directed against the CRF(2) receptor mRNA reduced expression of CRF(2) receptors by 60--80%. In shock-induced freezing tests, animals administered the antisense oligonucleotide exhibited a significant reduction in freezing duration. However, pain sensitivity and locomotor activity were unaltered. A four-base mismatch of the antisense sequence had no significant effects on CRF(2) receptor density and on freezing behavior. These data support the involvement of CRF(2) receptors in fear conditioning. CRF(1) receptor antagonists also reduce freezing in this test. Additional studies to determine the effects of simultaneous inhibition of both receptor subtypes show that rats receiving both CRF(2) receptor antisense oligonucleotide and CRF(1) receptor antagonist froze significantly less than animals treated with either agent alone. These results provide additional evidence for the role of CRF(2) receptors in mediating the stress-induced actions of endogenous CRF.
Brain Res Mol Brain Res 2001 Apr 18
PMID:Attenuation of fear conditioning by antisense inhibition of brain corticotropin releasing factor-2 receptor. 1131 73

The recent cloning of two GABA(B) receptor subunits, GABA(B1) and GABA(B2), has raised the possibility that differences in GABA(B) receptor subunit composition may give rise to pharmacologically or functionally distinct receptors. If present, such molecular diversity could permit the selective targeting of GABA(B) receptor subtypes specifically involved in pathologies such as drug addiction, spasticity, pain, and epilepsy. To address these issues we have developed a GABA(B1) subunit knockout mouse using gene targeting techniques. In the brains of GABA(B1) null mice, all pre- and postsynaptic GABA(B) receptor function was absent demonstrating that the GABA(B1) subunit is essential for all GABA(B) receptor-mediated mechanisms. Despite this, GABA(B1) null mice appeared normal at birth, although by postnatal week four their growth was retarded and they developed a generalized epilepsy that resulted in premature death. In addition, GABA(B1) heterozygote animals showed enhanced prepulse inhibition responses compared to littermate controls, suggesting that GABA(B1) deficient mice exhibit increased sensorimotor gating mechanisms. These data suggest that GABA(B) receptor antagonists may be of benefit in the treatment of psychiatric and neurological disorders in which attentional processing is impaired.
Mol Cell Neurosci 2001 Jun
PMID:Epileptogenesis and enhanced prepulse inhibition in GABA(B1)-deficient mice. 1141 94

Introduction of the herpes simplex type I thymidine kinase (HSV-TK) gene into tumor tissue, followed by ganciclovir, initiates a phosphorylation cascade that induces formation of a toxic ganciclovir triphosphate. Animal trials suggest that this ganciclovir triphosphate has antitumor activity. Here we report application of the HSV-TK transfection approach using a retroviral construct. Sixteen patients (median age 61.5 years) with refractory carcinoma (13 melanoma, 1 breast cancer, 1 nonsmall-cell lung cancer, and 1 osteogenic sarcoma) received intratumoral injection of HSV-TK retroviral vector at escalating doses (0.2x10(7) cfu per injection x 5 daily doses) and we evaluated them for toxicity and activity. We observed grade III pain associated with cellulitis in one patient following injection. Analysis of blood samples drawn between 3 and 28 weeks from 14 patients for replication-competent retrovirus by PCR analysis of the amphotrophic envelope revealed no replication-competent retrovirus. We injected 21 lesions. We identified no tumor responses of the injected lesions. Of 13 patients with advanced melanoma, 6 survived over one year. Thus, injection of retroviral delivered HSV-TK in patients with refractory cancer was well-tolerated.
Mol Ther 2001 Aug
PMID:Toxicity assessment of intratumoral injection of the herpes simplex type I thymidine kinase gene delivered by retrovirus in patients with refractory cancer. 1148 88

A 15-year-old black male presented with shortness of breath, leg weakness, and pain in his back and rib cage. Four years previously he had noticed a lump in his upper back and complained of pain when playing basketball, especially on contact to that area. Recently, the pain had become more constant and increased in intensity. This was associated with loss of control in his legs, weakness, and paraesthesia. General physical examination revealed a palpable mass in the right midline upper back. Laboratory results were within normal limits. Radiographic scans demonstrated a destructive soft tissue mass at T6 vertebral body with scattered stippled calcification (Figure 1). The patient underwent a biopsy followed by excision of the mass (Figure 2) and decompressive laminectomy with reconstruction.
Pediatr Pathol Mol Med
PMID:Pathology quiz: small cell osteosarcoma. 1148 38

Human placental leucine aminopeptidase (P-LAP) plays a major role in the clearance of oxytocin, which is a key hormone in regulating labour pain. To explore the transcriptional regulation of P-LAP gene expression in placenta, we performed systematic studies using human choriocarcinoma cells, BeWo and JEG-3, as a model of placental trophoblastic cells. Transient transfection and luciferase assays using various 5'-deleted P-LAP-luciferase constructs showed that the region from -297 to +49 of the transcription start site was responsible for promoter activity in these cells. Footprinting analysis with nuclear extracts from both cell lines demonstrated at least four sites for nucleoprotein interactions in this region (FP1 to FP4). Site-directed deletion of FP1-4 in luciferase assays indicated the significance of the FP3 region (-214 to -183) for high promoter activity in the cells. Electrophoretic mobility shift assays to identify the proteins interacting with DNA at FP3 revealed three retarded bands, one of which was generated by activator protein-2 (AP-2) binding. Our findings suggest that AP-2 may be one of the important factors regulating P-LAP gene expression in human placenta.
Mol Hum Reprod 2001 Sep
PMID:Transcriptional regulation of human placental leucine aminopeptidase/oxytocinase gene. 1151 97

Calcium influx through N-type calcium channels mediates synaptic transmission at numerous central synapses and transduces nociceptive information in the spinal dorsal horn. However, the precise role of N-type calcium channels in pain perception is not fully elucidated. To address this issue, we generated and analyzed knockout mice for alpha(1B,) the pore-forming subunit of the N-type calcium channel. Homozygous mutants are viable, fertile, and show normal motor coordination. In small-diameter dorsal root ganglion neurons from mutants the density of calcium channel currents is significantly reduced, which can be accounted for by the abolition of N-type currents. We performed several pain-related behavioral tests using the mutant mice. alpha(1B)-Deficient mice show reduced response to mechanical stimuli in the von Frey test and increased tail flick latency in response to radiant heat, indicating altered spinal reflexes. However, pain response in the hot plate test is normal. In the formalin paw test, the mutant mice exhibit significantly attenuated response in Phase 2, but normal pain behaviors in Phase 1. The response to visceral inflammatory pain caused by acetic acid is also reduced in alpha(1B) knockout mice. These results suggest that the alpha(1B) subunit of N-type calcium channel plays a major role in pain perception by acting at the spinal level, but not at the supraspinal level.
Mol Cell Neurosci 2001 Aug
PMID:Altered nociceptive response in mice deficient in the alpha(1B) subunit of the voltage-dependent calcium channel. 1152 Jan 83


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