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)

Complex and contradictory data have been reported regarding the changes in spinal opioidergic systems associated with chronic inflammatory pain in the rat. In an attempt to solve these discrepancies, the in vivo release of met-enkephalin and dynorphin and the expression of the corresponding propeptide genes were investigated at the spinal level in arthritic rats and paired controls. A dramatic increase in the concentration of prodynorphin mRNA (+300-550%) and a less pronounced elevation of that of dynorphin-like material (+40-50%) were found in the dorsal part of cervical and lumbar segments of the spinal cord in rats rendered arthritic by an intradermal injection of Freund's adjuvant four weeks prior to these measurements. In addition, the spinal release of dynorphin-like material (assessed through an intrathecal perfusion procedure in halothane-anaesthetized animals) was approximately twice as high in arthritic rats as in controls. In spite of significant elevations in the levels of both met-enkephalin (+30-70%) and proenkephalin A mRNA (+40-50%) in the dorsal part of cervical and lumbar segments, the spinal release of met-enkephalin-like material was decreased (-50%) in arthritic rats as compared to paired controls. Proenkephalin A mRNA (but not prodynorphin mRNA) could be measured in dorsal root ganglia, and its levels were dramatically reduced in ganglia at the lumbar segments in arthritic rats. Such parallel reductions in the spinal release of met-enkephalin-like material and the levels of proenkephalin A mRNA in dorsal root ganglia of arthritic rats support the idea that the activity of primary afferent enkephalinergic fibres decreases markedly during chronic inflammatory pain.
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PMID:Enkephalinergic and dynorphinergic neurons in the spinal cord and dorsal root ganglia of the polyarthritic rat - in vivo release and cDNA hybridization studies. 907 Jun 23

The opiate system is involved in a wide variety of neural functions including pain perception, neuroendocrine regulation, memory, drug reward, and tolerance. Such functions imply that endogenous opioid peptides should have anatomical interactions with limbic brain structures believed to be involved in the experience and expression of emotion. Using in situ hybridization histochemistry, the messenger RNA expression of the opioid precursors, prodynorphin and proenkephalin, was studied in whole hemisphere human brain tissue. Different components of the limbic system were found to be characterized by a high gene expression of either prodynorphin or proenkephalin messenger RNA. Brain regions traditionally included within the limbic system (e.g. amygdala, hippocampus, entorhinal cortex and cingulate cortex) as well as limbic-associated regions including the ventromedial prefrontal cortex and patch compartment of the neostriatum showed high prodynorphin messenger RNA expression. In contrast, high levels of proenkephalin messenger RNA were more widely expressed in the hypothalamus, periaqueductal gray, various mesencephalic nuclei, bed nucleus of the stria terminalis, and ventral pallidum; brain regions associated with endocrine-reticular-motor continuum of the limbic system. The marked anatomical dissociation between the expression of these two opioid peptide genes, seen clearly in whole hemisphere sections, indicates that distinct functions must be subserved by the prodynorphin and proenkephalin systems in the human brain.
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PMID:Differential messenger RNA expression of prodynorphin and proenkephalin in the human brain. 915 22

The endogenous opioid system has been implicated in the regulation of hormonal secretion, pain perception, and uterine contractility during pregnancy, but there is only limited information about the cellular location of opioid receptor and opioid peptide gene expression in the pregnant rodent uterus and placenta. In this study, we have used in situ hybridization to identify expression sites of mRNAs encoding the delta (delta), kappa (kappa), and mu ( micro) opioid receptors as well as the endogenous opioid peptide precursors proenkephalin (PENK), prodynorphin (PDYN), and proopiomelanocortin (POMC) in pregnant mouse uterus and placenta. Soon after implantation, all three opioid receptor genes as well as POMC and PENK, but not PDYN, were detected in the uterine environment. Each expressed gene exhibited a distinct expression pattern that was generally retained until late gestation. The delta receptor and POMC were coexpressed in the trophoblast giant cells, which remained the only cells of the placenta/uterus to express these two genes throughout gestation. Cells expressing kappa receptors were absent from the placenta but instead were found in the basal part of the decidualized uterine endometrium. While kappa and micro receptors were transiently expressed in the uterine myometrium (until embryonic day 8.5), substantial levels of PENK were continuously detected in this region until at least embryonic day 18. In addition, complementary expression of the micro receptor and PENK genes in the uterus was detected. Taken together, these results suggest multiple roles for the opioid receptors and opioid peptides in maternal adaptation to pregnancy and in supporting embryo growth.
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PMID:Expression of opioid receptors and ligands in pregnant mouse uterus and placenta. 974 45

Induction of the prodynorphin gene has been implicated in medium and long-term adaptation during memory acquisition and pain. By 5' deletion mapping and site-directed mutagenesis of the human prodynorphin promoter, we demonstrate that both basal transcription and protein kinase A (PKA)-induced transcription in NB69 and SK-N-MC human neuroblastoma cells are regulated by the GAGTCAAGG sequence centered at position +40 in the 5' untranslated region of the gene (named the DRE, for downstream regulatory element). The DRE repressed basal transcription in an orientation-independent and cell-specific manner when placed downstream from the heterologous thymidine kinase promoter. Southwestern blotting and UV cross-linking experiments with nuclear extracts from human neuroblastoma cells or human brain revealed a protein complex of approximately 110 kDa that specifically bound to the DRE. Forskolin treatment reduced binding to the DRE, and the time course paralleled that for an increase in prodynorphin gene expression. Our results suggest that under basal conditions, expression of the prodynorphin gene is repressed by occupancy of the DRE site. Upon PKA stimulation, binding to the DRE is reduced and transcription increases. We propose a model for human prodynorphin activation through PKA-dependent derepression at the DRE site.
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PMID:Protein kinase A-dependent derepression of the human prodynorphin gene via differential binding to an intragenic silencer element. 981 80

Fluxes in amounts of intracellular calcium ions are important determinants of gene expression. So far, Ca2+-regulated kinases and phosphatases have been implicated in changing the phosphorylation status of key transcription factors and thereby modulating their function. In addition, direct effectors of Ca2+-induced gene expression have been suggested to exist in the nucleus, although no such effectors have been identified yet. Expression of the human prodynorphin gene, which is involved in memory acquisition and pain, is regulated through its downstream regulatory element (DRE) sequence, which acts as a location-dependent gene silencer. Here we isolate a new transcriptional repressor, DRE-antagonist modulator (DREAM), which specifically binds to the DRE. DREAM contains four Ca2+-binding domains of the EF-hand type. Upon stimulation by Ca2+, DREAM's ability to bind to the DRE and its repressor function are prevented. Mutation of the EF-hands abolishes the response of DREAM to Ca2+. In addition to the prodynorphin promoter, DREAM represses transcription from the early response gene c-fos. Thus, DREAM represents the first known Ca2+-binding protein to function as a DNA-binding transcriptional regulator.
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PMID:DREAM is a Ca2+-regulated transcriptional repressor. 1007 26

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.
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PMID:Generation of dynorphin knockout mice. 1116 73

Whereas tissue injury increases spinal dynorphin expression, the functional relevance of this upregulation to persistent pain is unknown. Here, mice lacking the prodynorphin gene were studied for sensitivity to non-noxious and noxious stimuli, before and after induction of experimental neuropathic pain. Prodynorphin knock-out (KO) mice had normal responses to acute non-noxious stimuli and a mild increased sensitivity to some noxious stimuli. After spinal nerve ligation (SNL), both wild-type (WT) and KO mice demonstrated decreased thresholds to innocuous mechanical and to noxious thermal stimuli, indicating that dynorphin is not required for initiation of neuropathic pain. However, whereas neuropathic pain was sustained in WT mice, KO mice showed a return to baselines by post-SNL day 10. In WT mice, SNL upregulated lumbar dynorphin content on day 10, but not day 2, after injury. Intrathecal dynorphin antiserum reversed neuropathic pain in WT mice at post-SNL day 10 (when dynorphin was upregulated) but not on post-SNL day 2; intrathecal MK-801 reversed SNL-pain at both times. Opioid (mu, delta, and kappa) receptor density and G-protein activation were not different between WT and KO mice and were unchanged by SNL injury. The observations suggest (1) an early, dynorphin-independent phase of neuropathic pain and a later dynorphin-dependent stage, (2) that upregulated spinal dynorphin is pronociceptive and required for the maintenance of persistent neuropathic pain, and (3) that processes required for the initiation and the maintenance of the neuropathic pain state are distinct. Identification of mechanisms that maintain neuropathic pain appears important for strategies to treat neuropathic pain.
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PMID:Pronociceptive actions of dynorphin maintain chronic neuropathic pain. 1122 67

Physiological gestation, as well as the simulation of the associated changes in estrogen and progesterone, is associated with significant elevations in nociceptive response thresholds. This is mediated by spinal cord kappa- and delta-opIoid systems. The predominant spinal mu-opioid system does not appear to participate. One hallmark of pregnancy- and hormonally-induced antinociception is the multiplicative interaction among its components. Approximately 40% results from spinal kappa/delta analgesic synergy on which is superimposed an additional increment (approximately 60%) of synergy that results from the interaction between descending spinal alpha 2-noradrenergic and spinal kappa/delta activities. An intact hypogastric nerve is required for the spinal alpha 2-noradrenergic component. This would explain the requirement for an intact hypogastric nerve in order for the antinociception of pregnancy and its hormonal simulation to be fully manifest. The predominant means by which spinal dynorphin-containing neurons adjust to increased demand is increased post-translational processing of dynorphin precursor intermediates which are present at approximately 10x the concentration of mature dynorphin peptides (1-17 and 1-8). This is indicated by the concomitant decline (approximately 50%) in the spinal cord content of dynorphin precursors and increase (approximately 87%) in the content of prohormone convertase 2, a processing enzyme sufficient to generate mature dynorphin peptides from prodynorphin. The presence of 'high gain' multiplicative spinal opioid antinociceptive pathways that can be activated by estrogen and progesterone has hyperalgesic implications as well, i.e. it could result in disproportionately increased pain responsiveness. This might explain, in part, findings that women are more prone to recurrent pain and pain of greater duration and intensity than men. The underlying mechanisms of gestational antinociception could point the way to pain pharmacotherapies that are gender-based.
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PMID:The maternal spinal cord: biochemical and physiological correlates of steroid-activated antinociceptive processes. 1158 47

The advance in our understanding of the biogenesis of various endogenous opioid peptides, their anatomical distribution, and the characteristics of the multiple receptors with which they interact open a new avenue for understanding the role of opioid peptide systems in chronic pain. The main groups of opioid peptides: enkephalins, dynorphins and beta-endorphin derive from proenkephalin, prodynorphin and proopiomelanocortin, respectively. Recently, a novel group of peptides has been discovered in the brain and named endomorphins, endomorphin-1 and -2. They are unique in comparison with other opioid peptides by atypical structure and high selectivity towards the mu-opioid receptor. Another group, which joined the endogenous opioid peptide family in the last few years is the pronociceptin system comprising the peptides derived from this prohormone, acting at ORL1 receptors. Three members of the opioid receptor family were cloned in the early 1990s, beginning with the mouse delta-opioid receptor (DOR1) and followed by cloning of mu-opioid receptor (MOR1) and kappa-opioid receptor (KOR1). These three receptors belong to the family of seven transmembrane G-protein coupled receptors, and share extensive structural homologies. These opioid receptor and peptide systems are significantly implicated in antinociceptive processes. They were found to be represented in the regions involved in nociception and pain. The effects of opioids in animal models of inflammatory pain have been studied in great detail. Inflammation in the periphery influences the central sites and changes the opioid action. Inflammation increased spinal potency of various opioid receptor agonists. In general, the antinociceptive potency of opioids is greater against various noxious stimuli in animals with peripheral inflammation than in control animals. Inflammation-induced enhancement of opioid antinociceptive potency is characteristic predominantly for mu opioid receptors, since morphine elicits a greater increase in spinal potency of mu- than of delta- and kappa-opioid receptor agonists. Enhancement of the potency of mu-opioid receptor agonists during inflammation could arise from the changes occurring in opioid receptors, predominantly in affinity or number of the mu-opioid receptors. Inflammation has been shown to alter the expression of several genes in the spinal cord dorsal horn. Several studies have demonstrated profound alterations in the spinal PDYN system when there is peripheral inflammation or chronic arthritis. Endogenous dynorphin biosynthesis also increases under various conditions associated with neuropathic pain following damage to the spinal cord and injury of peripheral nerves. Interestingly, morphine lacks potent analgesic efficacy in neuropathic pain. A vast body of clinical evidence suggests that neuropathic pain is not opioid-resistant but only that reduced sensitivity to systemic opioids is observed in this condition, and an increase in their dose is necessary in order to obtain adequate analgesia. Reduction of morphine antinociceptive potency was postulated to be due to the fact that nerve injury reduced the activity of spinal opioid receptors or opioid signal transduction. Our recent study with endogenous ligands of the mu-opioid receptor, endomorphins, further complicates the issue, since endomorphins appear to be effective in neuropathic pain. Identification of the involved differences may be of importance to the understanding of the molecular mechanism of opioid action in neuropathic pain, as well as to the development of better and more effective drugs for the treatment of neuropathic pain in humans.
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PMID:Opioids in chronic pain. 1169 29

Activation of ERK (extracellular signal-regulated kinase) MAP (mitogen-activated protein) kinase in dorsal horn neurons of the spinal cord by peripheral noxious stimulation contributes to short-term pain hypersensitivity. We investigated ERK activation by peripheral inflammation and its involvement in regulating gene expression in the spinal cord and in contributing to inflammatory pain hypersensitivity. Injection of complete Freund's adjuvant (CFA) into a hindpaw produced a persistent inflammation and a sustained ERK activation in neurons in the superficial layers (laminae I-IIo) of the dorsal horn. CFA also induced an upregulation of prodynorphin and neurokinin-1 (NK-1) in dorsal horn neurons, which was suppressed by intrathecal delivery of the MEK (MAP kinase kinase) inhibitor U0126. CFA-induced phospho-ERK primarily colocalized with prodynorphin and NK-1 in superficial dorsal horn neurons. Although intrathecal injection of U0126 did not affect basal pain sensitivity, it did attenuate both the establishment and maintenance of persistent inflammatory heat and mechanical hypersensitivity. Activation of the ERK pathway in a subset of nociceptive spinal neurons contributes, therefore, to persistent pain hypersensitivity, possibly via transcriptional regulation of genes, such as prodynorphin and NK-1.
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PMID:ERK MAP kinase activation in superficial spinal cord neurons induces prodynorphin and NK-1 upregulation and contributes to persistent inflammatory pain hypersensitivity. 1178 93


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