Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The motor symptoms of Parkinson's disease (PD) are thought to result from increased inhibitory outflow from the basal ganglia to the pallidal receiving areas of thalamus (ventral oral anterior and posterior-Voa,Vop). To test this hypothesis, we examined the firing rates of neurons in pallidal and cerebellar receiving areas of thalamus in five PD patients and compared them to those of neurons in comparable regions of motor thalamus in two other patient groups where hyperactivity of GPi is not believed to occur [essential tremor (ET), pain]. Neuronal recordings were made during microelectrode-guided functional stereotactic neurosurgery. The mean spontaneous firing rate (MSFR) of neurons classified as voluntary neurons and presumed to be in pallidal receiving areas of thalamus in PD patients [7.4 +/- 1.0 (SE) Hz] was significantly lower (P < 0.01) than in the ET (18.1 +/- 3.0 Hz) and pain (19.0 +/- 1.9Hz) groups. In contrast, the MSFR of neurons classified as kinesthetic and presumed to be primarily in the cerebellar receiving area of thalamus (ventral intermediate-Vim), although some are probably in the deep shell region of the ventrocaudal nucleus (VPLa), was significantly greater in ET patients (25.8 +/- 3.5 Hz) than in the PD (14.3 +/- 1.6 Hz; P < 0.01) and pain (16.1 +/- 1.5 Hz; P < 0.05) groups. Similar findings were obtained when the neurons were grouped according to their estimated locations in Voa/Vop and Vim of motor thalamus. These data provide support for the prediction of the classical pathophysiological model of PD and moreover suggest that pathophysiology in the cerebello-thalamo-cortical pathway may be a possible cause of tremor in ET patients.
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PMID:Differences in neuronal firing rates in pallidal and cerebellar receiving areas of thalamus in patients with Parkinson's disease, essential tremor, and pain. 1570 31

This manuscript reviews the theories behind the propensity of prostate cancer to cause bone metastases and skeletal implications of the prostate cancer biology and treatment modalities. The escape of tumor cells from the primary tumor in the prostate to secondary tumor sites in the axial skeleton probably occurs before the primary tumor is detected. Several theories offer explanations for the observed proclivity of prostate tumors to selectively colonize the axial skeleton. The interaction between the tumor cells and cells that populate bone marrow, in particular osteoblasts and osteoclasts, is important for creating a 'fertile' environment where tumor cells can establish and grow. Prostate cancer cells are capable of producing growth factors that can affect both osteoblasts, resulting in osteoblastic bone formation, and osteoclasts, resulting in excessive bone resorption. In addition to the capability to progress from testosterone-dependent to testosterone-independent phenotype, the hallmark of metastatic prostate cancer is osteosclerosis similar to one induced experimentally in nude rats using CWR22 human prostate cancer cell line. Metastatic bone disease caused by excessive bone formation and bone resorption is the major cause of morbidity in patients with prostate cancer. The most common symptoms include pain, pathological fractures, spinal cord compression, cranial nerve palsies, bone marrow suppression and hypercalcemia. The introduction of prostate-specific antigen in clinical practice created a shift to where more prostate cancer patients with early disease receive androgen ablation treatment, which in return causes more bone loss and cancer-associated osteoporosis. Introduction of third generation bisphosphonates to treat skeletal consequences of malignancy further stressed the important interaction between the bone marrow stroma and cancer cells. Nevertheless, animal models and human prostate tumor cell lines that mimic all aspects of skeletal conditions in prostate cancer patients including osteoblastic bone response are needed to develop and screen for novel therapeutic and diagnostic modalities.
J Musculoskelet Neuronal Interact 2003 Jun
PMID:Skeletal implications of prostate cancer. 1575 51

Administration of antibiotics is considered to be an important factor, during or after operational procedures in the maxillofacial area, in order to avoid post-surgical complications. Furthermore, administration of anti-inflammatory drugs is often prescribed for control of the post-operative pain. The aim of this study was to determine the levels of quinolones in serum and tissues (parotid gland, tongue, mandible), during traumatic injury in the oral cavity, with or without co-administration of ibuprofen, a non-steroidal anti-inflammatory drug. Four groups of Wistar rats, (A, B control), (C, D experimental) were used. In the experimental group, traumatic injury was performed through the whole length of the cheek. Groups B and D received ibuprofen. The quinolone levels in serum and tissues were estimated by the inhibition zone of B. subtilis. Free fatty acid (FFA) levels and the adrenal weight, considered as a stress index, were increased in trauma groups. Quinolone concentrations in serum and in most of the tissues were significantly higher in the experimental groups compared to the controls. However, the co-administration of ibuprofen caused a higher increase of the quinolone levels in the control animals than in the experimental groups.
J Musculoskelet Neuronal Interact 2003 Jun
PMID:Quinolone levels in serum and maxillofacial tissues under ibuprofen co-administration following surgical trauma. 1575 58

Neuronal Kv7 channels are recognized as potential drug targets for treating hyperexcitability disorders such as pain, epilepsy, and mania. Hyperactivity of the amygdala has been described in clinical and preclinical studies of anxiety, and therefore, neuronal Kv7 channels may be a relevant target for this indication. In patch-clamp electrophysiology on cell lines expressing Kv7 channel subtypes, Maxipost (BMS-204352) exerted positive modulation of all neuronal Kv7 channels, whereas its R-enantiomer was a negative modulator. By contrast, at the Kv7.1 and the large conductance Ca2+-activated potassium channels, the two enantiomers showed the same effect, namely, negative and positive modulation at the two channels, respectively. At GABA(A) receptors (alpha1beta2gamma2s and alpha2beta2gamma2s) expressed in Xenopus oocytes, BMS-204352 was a negative modulator, and the R-enantiomer was a positive modulator. The observation that the S- and R-forms exhibited opposing effects on neuronal Kv7 channel subtypes allowed us to assess the potential role of Kv7 channels in anxiety. In vivo, BMS-204352 (3-30 mg/kg) was anxiolytic in the mouse zero maze and marble burying models of anxiety, with the effect in the burying model antagonized by the R-enantiomer (3 mg/kg). Likewise, the positive Kv7 channel modulator retigabine was anxiolytic in both models, and its effect in the burying model was blocked by the Kv7 channel inhibitor 10,10-bis-pyridin-4-ylmethyl-10H-anthracen-9-one (XE-991) (1 mg/kg). Doses at which BMS-204352 and retigabine induce anxiolysis could be dissociated from effects on sedation or memory impairment. In conclusion, these in vitro and in vivo studies provide compelling evidence that neuronal Kv7 channels are a target for developing novel anxiolytics.
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PMID:Anxiolytic effects of Maxipost (BMS-204352) and retigabine via activation of neuronal Kv7 channels. 1581 69

Neurons and synapses in the central nervous system are plastic, undergoing long-term changes throughout life. Studies of molecular and cellular mechanisms of such changes not only provide important insight into how we learn and store new knowledge in our brains, but they also reveal the mechanisms of pathological changes that occur following injury. The author proposes that during induction, neuronal mechanisms underlying physiological functions, such as learning and memory, may share some common signaling molecules with abnormal or injury-related changes in the brain. Distinct synaptic and neuronal network mechanisms are involved in pathological pain as compared to cognitive learning and memory. Nociceptive information is transmitted and regulated at different levels of the brain, from the spinal cord to the forebrain. Furthermore, N-methyl-D-aspartate receptor-dependent and calcium-calmodulin activated adenylyl cyclases (AC1 and AC8) in the anterior cingulate cortex play important roles in the induction and expression of persistent inflammatory and neuropathic pain. Neuronal activity in the anterior cingulate cortex can also influence nociceptive transmission in the dorsal horn of the spinal cord by activating the endogenous facilitatory system. Our results provide important synaptic and molecular insights into physiological responses to injury.
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PMID:Canadian Association of Neuroscience review: Cellular and synaptic insights into physiological and pathological pain. EJLB-CIHR Michael Smith Chair in Neurosciences and Mental Health lecture. 1582 43

Retigabine [D23129; N-(2-amino-4-(4-fluorobenzylamino)-phenyl)carbamic acid ethyl ester] is an antiepileptic drug with a recently described novel mechanism of action that involves opening of neuronal K(V)7.2-7.5 (formerly KCNQ2-5) voltage-activated K(+) channels. These channels (primarily K(V)7.2/7.3) enable generation of the M-current, a subthreshold K(+) current that serves to stabilize the membrane potential and control neuronal excitability. In this regard, retigabine has been shown to have a broad-spectrum of activity in animal models of electrically-induced (amygdala-kindling, maximal electroshock) and chemically-induced (pentylenetetrazole, picrotoxin, NMDA) epileptic seizures. These encouraging results suggest that retigabine may also prove useful in the treatment of other diseases associated with neuronal hyperexcitability. Neuropathic pain conditions are characterized by pathological changes in sensory pathways, which favor action potential generation and enhanced pain transmission. Although sometimes difficult to treat with conventional analgesics, antiepileptics can relieve some symptoms of neuropathic pain. A number of recent studies have reported that retigabine can relieve pain-like behaviors (hyperalgesia and allodynia) in animal models of neuropathic pain. Neuronal activation within several key structures within the CNS can also be observed in various animal models of anxiety. Moreover, amygdala-kindled rats, which have a lowered threshold for neuronal activation, also display enhanced anxiety-like responses. Retigabine dose-dependently reduces unconditioned anxiety-like behaviors when assessed in the mouse marble burying test and zero maze. Early clinical studies have indicated that retigabine is rapidly absorbed and distributed, and is resistant to first pass metabolism. Tolerability is good in humans when titrated up to its therapeutic dose range (600-1200 mg/day). No tolerance, dependence or withdrawal potential has been reported, although adverse effects can include mild dizziness, headache, nausea and somnolence. Thus, retigabine may prove to be useful in the treatment of a diverse range of disease states in which neuronal hyperexcitability is a common underlying factor.
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PMID:Retigabine: chemical synthesis to clinical application. 1586 50

In halothane-anesthetized rats, neurons stereotaxically located in the region of the medullary lateral reticular nucleus (LRN) and responsive to urinary bladder distension (UBD) were characterized using extracellular electrodes. Most neurons excited by UBD were also excited by noxious stimuli applied to bilateral receptive fields comprising at least half of the body surface. These bilateral nociceptive specific (bNS) neurons exhibited graded responses to graded intensities of UBD. Neuronal responses to noxious UBD were highly positively correlated with responses to noxious colorectal distension, suggesting a convergence of visceral sensory information in the area of LRN. Bilateral lateral mid-cervical spinal cord lesions virtually abolished activity of bNS neurons evoked by noxious UBD, while dorsal midline lesions had no significant effect. These data support a role for neurons in the region of the LRN in visceral nociception and implicate traditional lateral spinal cord pain pathways in the transmission of visceral information to caudal ventrolateral medullary structures.
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PMID:Visceral nociceptive input to the area of the medullary lateral reticular nucleus ascends in the lateral spinal cord. 1589 94

Nitric oxide (NO) is a ubiquitous gaseous neurotransmitter that has been ascribed to a large number of physiological roles in sensory neurons. It is produced by the enzyme nitric oxide synthase (NOS). To identify the NOS-containing structures of rat trigeminal primary afferent neurons, located in the trigeminal ganglion (TrG) and mesencephalic trigeminal nucleus (MTN), histochemistry to its selective marker nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) was applied in this study. In the TrG approximately half of the neuronal population was NADPH-d reactive. Strongly positive were neurons mainly of small-to-medium size. Neuronal profiles of large diameter were less intensely stained. In addition, NADPH-d-positive nerve fibers were dispersed throughout the ganglion. Nitrergic neurons were located in the caudal part and mesencephalic-pontine junction of the MTN. Most of them were large-sized pseudounipolar cells. In a more rostral aspect, the reactive psedounipolar MTN profiles gradually decreased in number and intensity of staining. There, only a fine meshwork of stained thin fibers and perisomatic terminal arborizations, and also some isolated perikarya of NADPH-d stained multipolar MTN neurons, were observed. The predominant NADPH-d localization in smaller in size TrG neurons, which are considered nociceptive, suggests that NO may play a role in the pain transmission in the rat trigeminal afferent pathways. In addition, the wide distribution of NADPH-d activity in large pseudounipolar and certain multipolar MTN neurons provides substantial evidence that NO may also participate in mediating proprioceptive information from the orofacial region. The differential expression patterns of nitrergic fibers in the TrG and MTN suggest that trigeminal sensory information processing is controlled by nitrergic input through different mechanisms.
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PMID:Localization of nitric oxide synthase in rat trigeminal primary afferent neurons using NADPH-diaphorase histochemistry. 1590 Apr 9

Schizophrenia is considered to be a neurodevelopmental disorder with origins in the prenatal or neonatal period. Brains from subjects with schizophrenia have enlarged ventricles, reduced cortical thickness (CT) and increased neuronal density in the prefrontal cortex compared with those from normal subjects. Subjects with schizophrenia have reduced pain sensitivity and niacin skin flare responses, suggesting that capsaicin-sensitive primary afferent neurons might be abnormal in schizophrenia. This study tested the hypothesis that intrinsic somatosensory deprivation, induced by neonatal capsaicin treatment, causes changes in the brains of rats similar to those found in schizophrenia. Wistar rats were treated with capsaicin, 50 mg kg(-1) subcutaneously, or vehicle (control) at 24-36 h of life. At 5-7 weeks behavioural observations were made, and brains removed, fixed and sectioned. The mean body weight of capsaicin-treated rats was not significantly different from control, but the mean brain weight of male, but not female, rats, was significantly lower than control. Capsaicin-treated rats were hyperactive compared with controls. The hyperactivity was abolished by haloperidol. Coronal brain sections of capsaicin-treated rats had smaller cross-sectional areas, reduced CT, larger ventricles and aqueduct, smaller hippocampal area and reduced corpus callosum thickness, than brain sections from control rats. Neuronal density was increased in several cortical areas and the caudate putamen, but not in the visual cortex. It is concluded that neonatal capsaicin treatment of rats produces brain changes that are similar to those found in brains of subjects with schizophrenia.
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PMID:Intrinsic sensory deprivation induced by neonatal capsaicin treatment induces changes in rat brain and behaviour of possible relevance to schizophrenia. 1604 96

Neuronal hyperexcitability in both injured and adjacent uninjured neurons is associated with states of chronic injury and pain and is likely subject to neuroinflammatory processes. Chronic inflammatory responses are largely orchestrated by chemokines. One chemokine, monocyte chemoattractant protein-1 (MCP-1), in the presence of its cognate receptor, the beta chemokine receptor 2 (CCR2), produces neural activity in dissociated neuronal cultures of neonatal dorsal root ganglion (DRG) neurons. Using a neuropathic pain model, chronic compression of the DRG (CCD), we compared anatomically separate populations of noncompressed lumbar DRG (L3/L6) with compressed lumbar DRG (L4/L5) for changes in the gene expression of CCR2. In situ hybridization revealed that CCR2 mRNA was up-regulated in neurons and nonneuronal cells present in both compressed L4/L5 and ipsilateral noncompressed L3/L6 DRGs at postoperative day 5 (POD5). The total percentages of compressed and noncompressed neurons exhibiting CCR2 mRNA transcripts in L3, L5, and L6 DRG were 33 +/- 3.5%, 49 +/- 6.2%, and 41 +/- 5.6%, respectively, and included cell bodies of small, medium, and large size. In addition, the preferred CCR2 ligand, MCP-1, was up-regulated by POD5 in both compressed L4/L5 and noncompressed L3/L6 DRG neurons. Application of MCP-1 to the cell bodies of the intact formerly compressed DRG in vitro produced potent excitatory effects not observed in control ganglia. MCP-1/CCR2 signaling is directly involved with a chronic compression injury and may contribute to associated neuronal hyperexcitability and neuropathic pain.
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PMID:Excitatory monocyte chemoattractant protein-1 signaling is up-regulated in sensory neurons after chronic compression of the dorsal root ganglion. 1617 30


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