Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Some chronic pain syndromes are characterized by episodes of intense burning and hyperalgesia in localized areas of skin. These sensations are thought to be mediated, at least in part, by the activity of damaged, unmyelinated C nociceptors. These phenomena were modeled by assaying responses of macaques to thermal and chemical stimuli that produced periodic activation and sensitization of C nociceptors. Upon validation of this method, a recombinant herpes simplex vector encoding human preproenkephalin was topically applied to the dorsal surface of the feet of the monkeys. Immunohistochemistry and radioimmunoassay revealed that enkephalin peptides were being produced in releasable pools in sensory neurons innervating the treated skin area. Behavioral responses evoked by periodic sensitization and activation of C nociceptors innervating the vector-treated skin area revealed a substantial and long-lasting (at least 20 weeks) antihyperalgesic and analgesic effect limited to the areas to which the virus was applied. This approach may be a viable means of treating localized cutaneous burning pain and hyperalgesia.
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PMID:Recombinant herpes vector-mediated analgesia in a primate model of hyperalgesia. 1628 1

Hetero-oligomerization among G protein-coupled receptors has been proposed to contribute to signal integration. Because sensory neuron-specific receptors (SNSRs) and the opioid receptors (OR) share a common ligand, the bovine adrenal medulla peptide (BAM) 22, and have opposite effects on pain modulation, we investigated the possible consequences of deltaOR/SNSR-4 hetero-oligomerization on the signaling properties of both receptor subtypes. Bioluminescence resonance energy transfer revealed that the human deltaOR has similar propensity to homo-oligomerize and to form hetero-oligomers with human SNSR-4 when coexpressed in human embryonic kidney 293 cells. The hetero-oligomerization leads to a receptor form displaying unique functional properties. Individual activation of either deltaOR or SNSR-4 in cells coexpressing the two receptors led to the modulation of their respective signaling pathways; inhibition of adenylyl cyclase and activation of phospholipase C, respectively. In contrast, the deltaOR/SNSR-4 bivalent agonist BAM22, which could activate each receptor expressed individually, fully activated the SNSR-4-dependent phospholipase C but did not promote deltaOR-mediated inhibition of adenylyl cyclase in deltaOR/SNSR-4-coexpressing cells. Likewise, concomitant activation of the deltaOR/SNSR-4 hetero-oligomer by selective deltaOR and SNSR-4 agonists promoted SNSR-4 but not deltaOR signaling, revealing an agonist-dependent dominant-negative effect of SNSR-4 on deltaOR signaling. Furthermore, the deltaOR selective antagonist naltrexone trans-inhibited the SNSR-4-promoted phospholipase C activation mediated by BAM22 but not by the SNSR-4-selective agonists, suggesting a bivalent binding mode of BAM22 to the deltaOR/SNSR-4 hetero-oligomer. The observation that BAM22 inhibited the Leu-enkephalin-promoted cAMP inhibition in rat dorsal root ganglia neurons supports the potential physiological implication of such regulatory mechanism.
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PMID:Simultaneous activation of the delta opioid receptor (deltaOR)/sensory neuron-specific receptor-4 (SNSR-4) hetero-oligomer by the mixed bivalent agonist bovine adrenal medulla peptide 22 activates SNSR-4 but inhibits deltaOR signaling. 1668 4

We have reported that transplantation of adrenal medullary chromaffin cells that release endogenous opioid peptides into pain modulatory regions in the CNS produce significant antinociceptive effects in patients with terminal cancer pain. However, the usefulness of this procedure is minimal because the availability of human adrenal tissue is very limited. Alternative xenogeneic materials, such as porcine and bovine adrenal chromaffin cells present problems of immune rejection and possible pathogenic contamination. In an attempt to develop opioid peptide-producing cells of autologous origin, we have transfected human mesenchymal stem cells (hMeSCs) with a mammalian expression vector containing a fusion gene of green fluorescent protein (GFP) and human preproenkephalin (hPPE), a precursor protein for enkephalin opioid peptides. Enkephalins are major neurotransmitters that play an important role in analgesia by activating peripheral opioid receptors. Following the establishment of stable transfection of hMeSCs, the expressions of hPPE and GFP were confirmed and the production of methionine enkephalin (Met-enkephalin) was significantly increased compared to control naive hMeSCs (p < 0.05). Our in vitro data demonstrated that genetically engineered hMeSCs with transfected hPPE gene can constitutively produce opioid peptide Met-enkephalin at an augmented high level. hMeSCs are relatively easy to isolate from a patient's bone marrow aspirates and expand in culture by repeated passages. Autologous hMeSCs would not require immunosuppression when transplanted back into the same patient. Through targeted gene manipulation such as hPPE gene transfection, this may offer a virtually unlimited safe cell supply for the treatment of opioid-sensitive pain in humans.
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PMID:Genetically engineered human mesenchymal stem cells produce met-enkephalin at augmented higher levels in vitro. 1671 57

Cyclophosphamide (CP)-induced cystitis is often used as an animal model of visceral pain. Various neuropeptides in the hypothalamic and amygdaloid nuclei are implicated in pain-induced responses. However, little information is available regarding the regulation of the neuropeptides in response to visceral pain. In the present study, we examined the effects of CP-induced cystitis on the levels of mRNAs encoding galanin, corticotropin-releasing hormone (CRH), substance P, and enkephalins in the hypothalamic and limbic nuclei using in situ hybridization histochemistry in mouse. Galanin mRNA levels in CP-treated group increased significantly in the arcuate nucleus and the paraventricular nucleus (PVN) but not in the medial preoptic area after the intraperitoneal administration of CP (200 mg/kg body weight) in comparison to those in saline-treated group. CRH mRNA levels in CP-treated group also increased significantly in the central amygdala as well as the PVN after the CP administration. In contrast, CP-induced cystitis failed to upregulate the preprotachykinin-A and preproenkephalin genes which encode substance P and enkephalins, respectively in the hypothalamic and limbic nuclei at any of the time points examined. These results suggest that visceral nociception may upregulate both galanin and CRH gene expression in the hypothalamic and limbic nuclei.
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PMID:Up-regulation of galanin and corticotropin-releasing hormone mRNAs in the key hypothalamic and amygdaloid nuclei in a mouse model of visceral pain. 1733 20

Chronic neuropathic pain is a common symptom in clinical practice and patients with chronic pain are subject to a greatly impaired quality of life. Grafted genetically-modified cells secreting enkephalin have been considered an encouraging treatment for chronic pain. Importantly, the transplanted cell as a therapeutic agent should be reproducible, safe, and controllable. In this study, by combining a tetracycline-controlled (Tet-on) gene expression system and immortalized astrocytes, we attempted to engineer an immortalized astrocyte line carrying the human preproenkephalin gene (IASL/hPPE) under the transcriptional control of doxycycline. These cells were then implanted into the subarachnoid space of chronic constrictive injury (CCI) rats and their analgesic potential was investigated by behavioral tests. The results showed that the secretion of enkephalin from IASL/hPPE cells could be switched on and off under the regulation of doxycycline in a dose-dependent manner. In addition, the mechanical and thermal hyperalgesia induced by CCI was significantly alleviated during the 2-7 week period after grafts of IASL/hPPE cells and the analgesic effect could be regulated by doxycycline. Moreover, spinal enkephalin level could be modulated by the presence or absence of doxycycline in drinking water. Taken together, these data suggest that regulatable release of enkephalin from transplanted cells near the spinal dorsal horn was able to reverse the development of chronic neuropathic pain. Although improvements in the Tet-on system are necessary, this may provide an alternative approach for ex vivo cell transplantation to treat chronic pain.
Eur J Pain 2008 May
PMID:Lumbar transplantation of immortalized enkephalin-expressing astrocytes attenuates chronic neuropathic pain. 1790 99

Enkephalins are opioid peptides that are found at high levels in the brain and endocrine tissues. Studies have shown that enkephalins play an important role in behavior, pain, cardiac function, cellular growth, immunity, and ischemic tolerance. Our global hypothesis is that enkephalins are released from non-neuronal tissues in response to brief ischemia or exercise, and that this release contributes to cardioprotection. To identify tissues that could serve as potential sources of enkephalins, we used real-time PCR, Western blot analysis, ELISA, immunofluorescence microscopy, and ex vivo models of enkephalin release. We found widespread expression of preproenkephalin (pPENK) mRNA and production of the enkephalin precursor protein proenkephalin (PENK) in rat and mouse tissues, as well as in tissues and cells from humans and pigs. Immunofluorescence microscopy with anti-enkephalin antisera demonstrated immunoreactivity in rat tissues, including heart and skeletal muscle myocytes, intestinal and kidney epithelium, and intestinal smooth muscle cells. Finally, isolated tissue studies showed that heart, skeletal muscle, and intestine released enkephalins ex vivo. Together our studies indicate that multiple non-neuronal tissues produce PENK and release enkephalins. These data support the hypothesis that non-neuronal tissues could play a role in both local and systemic enkephalin-mediated effects.
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PMID:Proenkephalin expression and enkephalin release are widely observed in non-neuronal tissues. 1808 11

5-Hydroxytryptamine (5-HT)(3) receptors have been proposed to modulate nociception and pain responses at the spinal level. To gain insight into the cellular mechanism of 5-HT(3) receptors, we examined their expression in GABAergic and enkephalinergic (ENKergic) neurons in the spinal dorsal horn (SDH) using single-cell reverse transcription-polymerase chain reaction (RT-PCR). The glutamic acid decarboxylase (GAD)(67)-green fluorescent protein (GFP) knock-in mouse was used in which all GABAergic neurons were fluorescent. The general tissue RT-PCR results showed that 5-HT(3A) receptor subunit mRNA was present in the mouse SDH, while 5-HT(3B) receptor subunit was absent. Single-cell RT-PCR results showed that 76.2% (16/21) and 33.3% (7/21) of the total 5-HT(3A)-expressing neurons were positive for GAD(67) and preproenkephalin (PPE, a precursor of ENK), respectively. 5-HT(3A) receptor subunit was detected in 28.1% (16/57) of GABAergic neurons and 22.6% (7/31) of ENKergic neurons. About 40.4% (23/57) of GABAergic neurons expressed PPE mRNA. Of the neurons that co-express GAD(67) mRNA and PPE mRNA, about 22% expressed 5-HT(3A) mRNA. These observations indicate that 5-HT(3A) receptor co-localizes with GABA and ENK in the SDH, suggesting that serotonin may activate GABAergic and ENKergic neurons via 5-HT(3A) receptor subunit and therefore affect the release of GABA and ENK. The different cellular localization of 5-HT(3A) receptor subunit suggest the complex participation of this receptor in the inhibitory neuronal circuits of the SDH neurons.
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PMID:5-HT(3A) receptor subunit is expressed in a subpopulation of GABAergic and enkephalinergic neurons in the mouse dorsal spinal cord. 1858 98

During chronic pain, the supraspinal pain modulatory system undergoes plastic changes with enhancement of facilitation transmission at the spinal cord. The changes induced by chronic pain at descending modulation often affect opioidergic modulation, and were never described for a key facilitatory component of the system, the dorsal reticular nucleus (DRt). Neurochemical characterization of the DRt-spinal pathway showed that delta-opioid receptors are positioned as to indirectly modulate the activity of non-projecting DRt neurons, whereas neurons expressing mu-opioid receptors project to the spinal dorsal horn or act as interneurons, the latter of which co-expressing GABA(B) receptors. In monoarthritic rats, the expression of mu-opioid receptors decreased in the DRt whereas the levels of endogenous enkephalin remained unaltered. To increase the opioidergic inhibition of the DRt, we locally injected selective agonists of delta- and mu-opioid receptors or a viral vector containing the human preproenkephalin transgene. Injection of the Herpes Simplex viral vector encoding preproenkephalin induced thermal hypoalgesia in non-inflamed animals and hyperalgesia in monoarthritic rats. The opioid agonists [D-Ala(2), Glu(4)]-deltorphin (DELT) and [D-Ala(2), NMePhe(4)Gly-ol(5)]-enkephalin (DAMGO) induced thermal hyperalgesia in both non-inflamed and monoarthritic rats, but with lower doses in the latter group. The present study shows that opioidergic neurons at the DRt are modulated by GABAergic cells herein controlling the descending facilitation of pain transmission. The DRt exhibits plastic changes during chronic inflammatory pain, with decrease opioid receptor expression which may account for increased descending facilitation during chronic pain.
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PMID:Opioids modulate pain facilitation from the dorsal reticular nucleus. 1872

GABA (gamma-aminobutyric acid)ergic neurons in the spinal dorsal horn have been reported to be divided into distinctive populations, with different cotransmitters and neuropeptides. In this study, we examined the colocalization of enkephalin (ENK) mRNA with GABA in the spinal dorsal horn using the glutamic acid decarboxylase (GAD)(67)-green fluorescence protein (GFP) knock-in mouse. Our approach was to perform in situ hybridization histochemistry to detect mRNA for preproenkephalin (PPE, the precursor protein for ENK), combined with immunohistochemistry for GFP to reveal GABAergic neurons. Quantitative analysis indicated that more than 44.4% (2967/6681) of GFP-immunoreactive neurons showed signals for PPE mRNA in the spinal dorsal horn. While 53.9% (2967/5501) of PPE mRNA-expressing neurons were immunoreactive for GFP. The double-labeled neurons were observed throughout the spinal dorsal horn, although they had a preferential localization in superficial layers. The present results provide a detailed morphological evidence that ENK and GABA colocalized in a subpopulation of neurons in the spinal dorsal horn, which are likely to represent local inhibitory dorsal horn interneurons involved in the modulation of pain transmission.
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PMID:Preproenkephalin mRNA is expressed in a subpopulation of GABAergic neurons in the spinal dorsal horn of the GAD67-GFP knock-in mouse. 1878 Mar

Herpes Simplex Virus type 1 (HSV-1) vectors are known to inhibit nociceptive transmission at the spinal cord after peripheral applications. Similar approaches may also be useful when applied at the supraspinal pain control system as the system includes pronociceptive (facilitatory) components. We performed a study aimed to analyse the migration of HSV-1 along with the inhibition of pronociception from the medullary dorsal reticular nucleus (DRt), a major facilitatory component of the supraspinal pain control system. To study the migration, a HSV-1 vector expressing lacZ under control of the human cytomegalovirus (hCMV) promoter was injected in the DRt and the expression of beta-galactosidase (beta-gal) was detected at 2, 4, 7, 10 and 14 days. Numerous beta-gal-immunoreactive neurons were observed at the injection site until day 4, and at some of the brain areas projecting to the DRt until day 7. To block the pronociceptive effects of the DRt, a HSV-1 vector expressing the preproenkephalin transgene, under the control of hCMV promoter, was injected into the DRt. Behavioural evaluation was performed at the time-points referred above, using the paw withdrawal latency test to evaluate thermal nociceptive responses. Anti-hyperalgesic effects persisted during 4 days, decreasing after that time-point. The present study demonstrates that selective migration of HSV-1 should be considered in gene therapy strategies based on HSV-1 injections into the brain. The study also shows that it is possible to decrease pain facilitation from the brain using opioidergic inhibition of pronociceptive supraspinal areas.
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PMID:Dynamic of migration of HSV-1 from a medullary pronociceptive centre: antinociception by overexpression of the preproenkephalin transgene. 1904 88


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