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)

Perinatal Delta(9)-tetrahydrocannabinol (Delta(9)-THC) exposure in rats resulted in enhanced morphine self-administration behavior, naloxone-precipitated withdrawal signs or changes in pain sensitivity, which have been related to changes in micro-opioid receptor binding and/or proenkephalin mRNA levels in several brain regions. However, despite exposure of these animals to Delta(9)-THC from fetal ages, the effects were studied only when animals matured, whereas there is no study on possible changes caused by this cannabinoid during the prenatal ontogeny of opioidergic neurons. The purpose of the present study was to examine the changes in proenkephalin mRNA levels, measured by using in situ hybridization, in several brain nuclei of rat fetuses that had been daily exposed to Delta(9)-THC from the 5th day of gestation. Results were as follows. Prenatal Delta(9)-THC exposure altered proenkephalin mRNA levels in most of the brain areas studied at different fetal ages, but the effects were different between sexes. Thus, proenkephalin mRNA levels increased in females, but decreased in males that had been prenatally exposed to Delta(9)-THC. This was observed in the caudate-putamen, hypothalamic paraventricular and ventromedial nuclei and cerebral cortex. No changes were observed, however, in the subventricular zones of the caudate-putamen, neocortex and nucleus accumbens. In summary, prenatal Delta(9)-THC exposure produced a sex-dependent effect in proenkephalin mRNA levels in several brain structures of rat fetuses.
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PMID:Prenatal Delta(9)-tetrahydrocannabinol exposure modifies proenkephalin gene expression in the fetal rat brain: sex-dependent differences. 1072 32

The phenomenon of acupuncture is both complex and dynamic. Recent information demonstrates that acupuncture may exert its actions on pain and immune processes. The coupling of these two systems occurs via common signaling molecules, i.e., opioid peptides. In this regard, we surmise that opioid activation leads to the processing of opioid peptides from their precursor, proenkephalin, and the simultaneous release of antibacterial peptides contained within the precursor as well. Thus, central nervous system pain circuits may be coupled to immune enhancement. Furthermore, acupuncture needle manipulation elicited signal increases bilaterally in the region of the primary and secondary somatosensory corticies in human brain as determined by magnetic resonance imaging. The maps reveal marked signal decreases bilaterally in multiple limbic and deep gray structures including the nucleus accumbens, amygdala, hypothalamus, hippocampus, and ventral tegmental area. Taken together, we surmise a major central nervous system pathway as well as local pain and immune modulation during acupuncture.
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PMID:Acupuncture: pain management coupled to immune stimulation. 1124 83

Endogenous opiate peptides acting pre- and post-synaptically in the dorsal horn of spinal cord inhibit transmission of nociceptive stimuli. We transfected neurons of the dorsal root ganglion in vivo by footpad inoculation with 30 microl (3 x 10(7) p.f.u.) of a replication-incompetent (ICP4-deleted) herpes simplex virus (HSV) vector with a cassette containing a portion of the human proenkephalin gene coding for 5 met- and 1 leu-enkephalin molecules under the control of the human cytomegalovirus immediate-early promoter (HCMV IEp) inserted in the HSV thymidine kinase (tk) locus. Vector-directed expression of enkephalin produced a significant antinociceptive effect measured by the formalin footpad test, that was most prominent in the delayed ("tonic") phase 20-70 min after the administration of formalin. The magnitude of the antinociceptive effect diminished over 4 weeks after transduction, but reinoculation of the vector reestablished the analgesic effect, without evidence for the development of tolerance. The antinociceptive effect was blocked completely by intrathecal naltrexone. These results suggest that gene therapy with an enkephalin-producing herpes-based vector may prove useful in the treatment of pain.
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PMID:Antinociceptive effect of a genomic herpes simplex virus-based vector expressing human proenkephalin in rat dorsal root ganglion. 1131 22

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

Inflammatory bladder disorders such as interstitial cystitis (IC) deserve attention since a major problem of the disease is diagnosis. IC affects millions of women and is characterized by severe pain, increased frequency of micturition, and chronic inflammation. Characterizing the molecular fingerprint (gene profile) of IC will help elucidate the mechanisms involved and suggest further approaches for therapeutic intervention. Therefore, in the present study we used established animal models of cystitis to determine the time course of bladder inflammatory responses to antigen, Escherichia coli lipopolysaccharide (LPS), and substance P (SP) by morphological analysis and cDNA microarrays. The specific aim of the present study was to compare bladder inflammatory responses to antigen, LPS, and SP by morphological analysis and cDNA microarray profiling to determine whether bladder responses to inflammation elicit a specific universal gene expression response regardless of the stimulating agent. During acute bladder inflammation, there was a predominant infiltrate of polymorphonuclear neutrophils into the bladder. Time-course studies identified early, intermediate, and late genes that were commonly up-regulated by all three stimuli. These genes included: phosphodiesterase 1C, cAMP-dependent protein kinase, iNOS, beta-NGF, proenkephalin B and orphanin, corticotrophin-releasing factor (CRF) R, estrogen R, PAI2, and protease inhibitor 17, NFkB p105, c-fos, fos-B, basic transcription factors, and cytoskeleton and motility proteins. Another cluster indicated genes that were commonly down-regulated by all three stimuli and included HSF2, NF-kappa B p65, ICE, IGF-II and FGF-7, MMP2, MMP14, and presenilin 2. Furthermore, we determined gene profiles that identify the transition between acute and chronic inflammation. During chronic inflammation, the urinary bladder presented a predominance of monocyte/macrophage infiltrate and a concomitant increase in the expression of the following genes: 5-HT 1c, 5-HTR7, beta 2 adrenergic receptor, c-Fgr, collagen 10 alpha 1, mast cell factor, melanocyte-specific gene 2, neural cell adhesion molecule 2, potassium inwardly-rectifying channel, prostaglandin F receptor, and RXR-beta cis-11-retinoic acid receptor. We conclude that microarray analysis of genes expressed in the bladder during experimental inflammation may be predictive of outcome. Further characterization of the inflammation-induced gene expression profiles obtained here may identify novel biomarkers and shed light into the etiology of cystitis.
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PMID:Gene expression profiling of mouse bladder inflammatory responses to LPS, substance P, and antigen-stimulation. 1205 14

We examined whether a herpes simplex virus vector that expresses human proenkephalin could be used to attenuate nociception in a model of bone cancer pain in mice. Osteolytic sarcoma cells were implanted into the medullary space of the right femur, followed by a subcutaneous inoculation of a replication-defective herpes simplex virus vector expressing human proenkephalin (vector SHPE) or a lacZ-expressing control vector (vector SHZ). SHPE-inoculated mice demonstrated a significant, naltrexone-reversible decrease in pain-related behavior assessed during open-field motor activity. These results suggest that gene transfer with an enkephalin-expressing vector may be used to treat pain resulting from cancer in bone.
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PMID:Herpes vector-mediated expression of proenkephalin reduces bone cancer pain. 1240 68

Neurotrophic factors are highly potent macromolecules with protean effects. Although they are highly effective in vitro and in animal models in vivo, they have not been successfully applied to the treatment of human disease. Our laboratories have developed recombinant herpes simplex virus (HSV)-based vectors, that we have demonstrated may be used to deliver and express neurotrophic factor genes in dorsal root ganglion neurons to protect against the development of neuropathy in animal models, without causing systemic side effects. In a similar fashion, we have demonstrated that a vector expressing proenkephalin to mediate the release of opioid peptides from afferent nerve terminals in the spinal cord can be used to produce a localized antinociceptive effect in animal models of pain. Targeted gene delivery using HSV-based vectors offers a means to utilize short-lived peptides to produce specific effects in the nervous system.
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PMID:Targeted gene delivery to the nervous system using herpes simplex virus vectors. 1252 87

We examined the pharmacologic characteristics of herpes simplex virus (HSV) vector-mediated expression of proenkephalin in the dorsal root ganglion in a rodent model of neuropathic pain. We found that: (i). vector-mediated enkephalin produced an antiallodynic effect that was reversed by naloxone; (ii). vector-mediated enkephalin production in animals with spinal nerve ligation prevented the induction of c-fos expression in second order sensory neurons in the dorsal horn of spinal cord; (iii). the effect of vector-mediated enkephalin enhanced the effect of morphine, reducing the ED(50) of morphine 10-fold; (iv). animals did not develop tolerance to the continued production of vector-mediated enkephalin over a period of several weeks; and, (v). vector transduction continued to provide an analgesic effect despite the induction of tolerance to morphine. This is the first demonstration of gene transfer to provide an analgesic effect in neuropathic pain. The pharmacologic analysis demonstrates that transgene-mediated expression and local release of opioid peptides produce some effects that are distinct from peptide analogues delivered pharmacologically.
Pain 2003 Mar
PMID:Transgene-mediated enkephalin release enhances the effect of morphine and evades tolerance to produce a sustained antiallodynic effect in neuropathic pain. 1262 Jun 4

Chronic pain is often difficult to treat effectively. We have exploited the high affinity of herpes simplex virus (HSV) for peripheral sensory neurons to create HSV-based vectors for the treatment of chronic pain. We have demonstrated that an HSV-based vector expressing proenkephalin reduces pain-related responses in rodent models of inflammatory pain, neuropathic pain, and pain resulting from cancer in bone. A human trial has been proposed.
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PMID:Development of HSV-mediated gene transfer for the treatment of chronic pain. 1459 22

The dorsal horn of the spinal cord represents an attractive site for interventions designed to treat chronic pain, but it has been difficult to identify small molecules that act selectively on pain transmission at the spinal level. One approach is the use of viral vector-mediated gene transfer to achieve focal production and release of short-lived analgesic peptides. Herpes simplex virusbased vectors, expressing proenkephalin delivered by subcutaneous inoculation, transduce neurons of the dorsal root ganglion, leading to release of enkephalin from nerve terminals in dorsal horn to produce an analgesic effect in several models of chronic pain. A clinical trial is set to commence.
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PMID:Gene therapy for chronic pain. 1460 16


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