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)

RFamide related peptides (RFRP)-1 and RFRP-3 are neuropeptides derived from the same preproprotein. We have examined the distribution of RFRP-1 and RFRP-3 immunoreactivities (irs) in the rat central nervous system using specific antibodies. Neuronal cell bodies containing both RFRP-1 and RFRP-3 were detected within the caudal portion of the hypothalamus, the periventricular nucleus (PerVN), and the portion around or above the ventromedial nucleus of the hypothalamus. Both immunohistochemical and in situ hybridization analyses showed that neurons containing RFRP immunoreactivity and mRNA were distinct from those of neuropeptide FF, which contains the same structure at the C-terminus, Pro-Glu-Arg-Phe-NH2, as RFRP-3. Fibers containing both RFRP-1 and RFRP-3 were widely distributed in the brain: the lateral septal nucleus in the telencephalon, the paraventricular thalamic nucleus, various hypothalamic nuclei, the periaqueductal gray in the midbrain, the parabrachial nucleus in the pons, and the nucleus tractus solitarius (NTS) in the medulla oblongata. Only RFRP-1-ir was detected within the posterior gray horn in the spinal cord. Only RFRP-3-ir was detected in several thalamic nuclei and the spinal cord, especially at the posterior intermediate sulcus and within the anterior gray horn. Intracerebroventricular administration of RFRPs induced c-Fos expression in the anterior portion of the NTS, locus coeruleus, the nucleus of incertus, supraoptic nucleus, PerVN and the arcuate nucleus of the hypothalamus. These results show that RFRP-1 and RFRP-3 are widely distributed in the rat central nervous system and might be involved in various functions such as the neuroendocrine system or pain modulation.
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PMID:Localization and neuronal response of RFamide related peptides in the rat central nervous system. 1291 51

Experimental nerve injury results in exaggerated responses to tactile and thermal stimuli that resemble some aspects of human neuropathic pain. Neuronal hyperexcitability and neurotransmitter release have been suggested to promote such increased responses to sensory stimuli. Enhanced activity of Ca(2+) current is associated with increased neuronal activity and blockade of N- and P-types, but not L-type, calcium channels have been found to block experimental neuropathic pain. While T-type currents are believed to promote neuronal excitability and transmitter release, it is unclear whether these channels may also contribute to the neuropathic state. Rats were prepared with L(5)/L(6) spinal nerve ligation, and tactile and thermal hypersensitivities were established. Mibefradil or ethosuximide was administered either intraperitoneally, intrathecally (i.th.), or locally into the plantar aspect of the injured hindpaw. Systemic mibefradil or ethosuximide produced a dose-dependent blockade of both tactile and thermal hypersensitivities in nerve-injured rats; responses of sham-operated rats were unchanged. Local injection of mibefradil also blocked both end points. Ethosuximide, however, was inactive after local administration, perhaps reflecting its low potency when compared with mibefradil. Neither mibefradil nor ethosuximide given i.th. produced any blockade of neuropathic behaviors. The results presented here suggest that T-type calcium channels may play a role in the expression of the neuropathic state. The data support the view that selective T-type calcium channel blockers may have significant potential in the treatment of neuropathic pain states.
Pain 2003 Sep
PMID:Reversal of experimental neuropathic pain by T-type calcium channel blockers. 1449 32

Neuronal ubiquitin C-terminal hydrolase (UCH-L1) has been linked to Parkinson's disease (PD), the progression of certain nonneuronal tumors, and neuropathic pain. Certain lung tumor-derived cell lines express UCH-L1 but it is not expressed in normal lung tissue, suggesting that this enzyme plays a role in tumor progression, either as a trigger or as a response. Small-molecule inhibitors of UCH-L1 would be helpful in distinguishing between these scenarios. By utilizing high-throughput screening (HTS) to find inhibitors and traditional medicinal chemistry to optimize their affinity and specificity, we have identified a class of isatin O-acyl oximes that selectively inhibit UCH-L1 as compared to its systemic isoform, UCH-L3. Three representatives of this class (30, 50, 51) have IC(50) values of 0.80-0.94 micro M for UCH-L1 and 17-25 micro M for UCH-L3. The K(i) of 30 toward UCH-L1 is 0.40 micro M and inhibition is reversible, competitive, and active site directed. Two isatin oxime inhibitors increased proliferation of the H1299 lung tumor cell line but had no effect on a lung tumor line that does not express UCH-L1. Inhibition of UCH-L1 expression in the H1299 cell line using RNAi had a similar proproliferative effect, suggesting that the UCH-L1 enzymatic activity is antiproliferative and that UCH-L1 expression may be a response to tumor growth. The molecular mechanism of this response remains to be determined.
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PMID:Discovery of inhibitors that elucidate the role of UCH-L1 activity in the H1299 lung cancer cell line. 1452 54

Neuronal KCNQ (Kv7) channels (KCNQ2-5 or Kv7.2-7.5, disclosed to date) were discovered by virtue of their homology with a known cardiac channel involved in long QT syndrome (KvLQT or KCNQ1, Kv7.1) and first disclosed in 1998. The involvement of KCNQ2 (Kv7.2) and KCNQ3 (Kv7.3) in a benign idiopathic neonatal epilepsy, KCNQ4 (Kv7.4) in a form of congenital deafness, and the discovery that neuronal KCNQ heteromultimers were among the molecular substrates of M-channels, resulted in a high level of interest for potential drug development strategies. A number of small-molecule modulators were quickly identified, including openers or activators such as the antiepileptic drug candidate retigabine and the structurally-related analgesic drug flupirtine (Katadolon trade mark Asta Medica), and a group of KCNQ channel inhibitors/blockers originally developed for cognition enhancement. All of these data have suggested a rich target profile for modulators of neuronal KCNQ channels, including a variety of neuronal hyperexcitability disorders and conditions for openers, such as the epilepsies, acute pain, neuropathic pain, migraine pain and some neurodegenerative and psychiatric disorders. KCNQ blockers could likewise have utility in disorders characterised by neuronal hypoactivity, including cognition enhancement and perhaps disorders of mood. Emerging patent literature suggests significant interest in neuronal KCNQ modulation in the pharmaceutical industry and significant chemical diversity concerning KCNQ modulation.
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PMID:The therapeutic potential of neuronal KCNQ channel modulators. 1464 Sep 9

The chronic administration of morphine and related opioid drugs results in tolerance and dependence which limits the clinical utility of these agents. Neuronal plasticity is probably responsible in large part for tolerance and dependence. Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) plays a crucial role in the neuroplastic events underlying memory formation and other phenomena. However, the role of this kinase in morphine tolerance remains unclear. To clarify this issue we explored mRNA and protein expression of CaMKIIalpha in spinal cord tissue from control and morphine treated mice using real-time polymerase chain reaction, Western blot analysis and confocal microscopy. Our chronic exposure paradigm involved the subcutaneous implantation of morphine pellets for 6 days prior to tissue analysis. The results indicate that the levels of CaMKIIalpha mRNA and protein were robustly increased in spinal cord tissue from morphine-treated mice. Confocal microscopy demonstrated that the increase in CaMKIIalpha expression was primarily localized to superficial laminae of the dorsal horn. In addition, the abundance of phosphorylated CaMKIIalpha was increased in spinal cord tissue from morphine-treated mice. We conclude that enhanced CaMKIIalpha expression and activity in spinal cord tissue may contribute to the development of morphine tolerance in mice. The involvement of this enzyme in opioid tolerance suggests other parallels may exist between the neuroplastic events related to memory formation and those related to opioid tolerance or pain.
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PMID:Increased expression of Ca2+/calmodulin-dependent protein kinase II alpha during chronic morphine exposure. 1470 89

Neuronal nicotinic acetylcholine receptors (nAChRs) are an important class of ion channels that have been associated with a number of neurological conditions. A great deal of research has been focused on attempting to understand the exact physiological role of these receptors. As drug targets, the nAChRs are quite complex, both in their structure (multiple receptor subtypes) and their physiological function. Initially, the difficulty encountered in identifying small-molecule modulators led to doubts about the validity of this class of receptors as drug targets. More recently, in vitro and in vivo data, homology modelling, and the identification of small-molecule agonists, have confirmed nAChRs as valid drug discovery targets. In fact, several compounds are now in clinical development for the treatment of pain, smoking cessation and cognitive disorders.
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PMID:Neuronal nicotinic acetylcholine receptors as drug targets. 1510 49

Recent experimental results have demonstrated a glial activation during long-term pain that produces and releases cytokines, free oxygen radicals, nitric oxide, and other neuroactive substances in the spinal cord dorsal horns. Such activation might generate a vicious circle by increasing the neuronal excitability level due to a decreased astroglial glutamate uptake and thereby reinforce pain signals that travel up to the thalamus and further up into the parietal cortex for identification and interpretation. In this paper, we adapt new knowledge on neuronal-glial signaling in the CNS to develop tentative explanations at the cellular level for the maintenance of pain signals in the brain, for formation of "pain memory," and even for the increased pain sensitivity that persons with chronic pain often experience in body regions other than those originally affected. We also suggest a hypothetical mechanism at the cellular level underlying the mental fatigue from which persons with chronic pain may suffer. This hypothesis relies on the impaired astroglial glutamate uptake capacity due to the production of neuroactive substances, altered conditions in the chronic pain state, and the anxiety and stress reactions that may occur secondary to the pain. Neuronal activity over time in the dysfunctional state of the astroglial network leads to an increase in extracellular glutamate levels in the vicinity of glutamate synapses. In turn, this increase leads over time to less precision in glutamate transmission. The increased extracellular glutamate levels lead to increased excitability and increased energy requirements. When cellular energy decreases the glutamate transmission decreases, and according to our hypothesis, this is one cause of mental fatigue. New strategies for treatment of chronic pain and the associated mental fatigue are formulated and should be explored.
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PMID:Altered neuronal-glial signaling in glutamatergic transmission as a unifying mechanism in chronic pain and mental fatigue. 1513 97

Central nociceptive processing includes spinal and supraspinal neurons, but the supraspinal mechanisms mediating changes in pain threshold remain unclear. We investigated the role of forebrain neurons in capsaicin-induced hyperalgesia. Long-Evans rat pups at 21 days were randomized to undisturbed control group, or to receive tactile stimulation, saline injection (0.9% w/v) or capsaicin injection (0.01% w/v) applied to each paw at hourly intervals. Thermal paw withdrawal latency was measured 1 h later, forebrains were removed and purified forebrain neuronal membranes were assayed for adenylyl cyclase activity and opioid receptor function. Capsaicin-injected rats had decreased thermal latency (P < 0.0001) compared to the other groups. Neuronal membranes showed increased basal (P = 0.0003) and forskolin-stimulated (P=0.0002) adenylyl cyclase activity in the capsaicin group compared to other groups. The selective mu-opioid receptor agonist, [D-Ala2, N-Me-Phe4, Gly5-ol]enkephalin (DAMGO) was less effective in inhibiting adenylyl cyclase activity in the capsaicin group (P < 0.001) compared to other groups. These effects were naloxone-reversible and pertussis toxin-sensitive (P < 0.01) in the control, tactile stimulation and saline injection groups but not in the capsaicin group. Binding capacity and affinity for micro-opioid receptors were similar in all four groups, suggesting that receptor downregulation was not involved. Exposure to DAMGO increased [35S]GTPgammaS binding to neuronal membranes from the control, tactile and saline groups (P<0.001) in a naloxone-reversible and pertussis toxin-sensitive manner (P < 0.01) but not in the capsaicin group, suggesting mu-opioid receptor desensitization. Dose responses to systemic morphine were also reduced in the capsaicin group compared to the tactile group (P < 0.05). Capsaicin-induced hyperalgesia in 21-day-old rats was associated with an uncoupling of micro-opioid receptors in the forebrain. Opioid receptor desensitization in the forebrain may reduce opioidergic inputs to the descending inhibitory controls, associated with behavioral hyperalgesia and reduced responsiveness to morphine analgesia in capsaicin-injected young rats.
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PMID:Opioid receptor desensitization contributes to thermal hyperalgesia in infant rats. 1514 Jun 29

The relationship between neuronal activity in the rat cervical and lumbar spinal cord was examined using functional magnetic resonance imaging (fMRI) and immunohistochemistry. Neuronal activity determined by c-fos staining was greatest between L4 and L6, and C5 to C7 spinal cord segments during noxious electrical stimulation of the rat hindpaw and forepaw, respectively. Areas of activity determined by fMRI are consistent with spinal cord physiology, and are predominantly found in regions of the spinal cord associated with pain, namely the dorsal horn. Activity in the ventral region of the cord was also observed, as expected. Combined results from repeated experiments demonstrated consistent areas of activity in response to stimulation, and show a high degree of reproducibility. Good correspondence was observed between functional MRI and sites of neuronal activity determined by c-fos labeling.
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PMID:Correlation of functional activation in the rat spinal cord with neuronal activation detected by immunohistochemistry. 1527 36

Cancer-induced bone diseases are common and can have a devastating impact at the end of life. One of the most difficult sequelae of cancer is metastases to the skeleton, an event that results in bone destruction and bone cancer pain. Bone cancer pain is usually progressive as the disease advances, and is particularly difficult to treat. Recently, experimental models of bone cancer pain have been developed and have provided seminal insight in understanding the pathophysiology of bone cancer pain. Animal models of bone cancer provided the finding that bone destruction (osteolysis) is associated with pain, and it has been determined that cancer-induced osteolysis is mediated by osteoclasts. Having established that RANK ligand contributed to cancer-induced osteoclastogenesis, it was determined that disruption of the RANKL-RANK axis with OPG inhibited tumor-induced osteoclastogenesis and decreased bone cancer pain.
J Musculoskelet Neuronal Interact 2004 Sep
PMID:Bone cancer pain and the role of RANKL/OPG. 1561 97


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