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)

In two patients, a man aged 54 years and a woman aged 49 years, stiff-person syndrome was diagnosed. This is a rare disorder of the central nervous system, with signs of an autoimmune pathogenesis. Patients present with pain and stiffness of the lower back, a complaint that is regularly seen in general practice. Moreover, the disease causes hypertonia and very painful cramps of the lower back and legs. Electromyographic examination in the resting condition reveals continuous muscle activity in the long back muscles, which decreases following the administration of diazepam. In 60% of patients, antibodies to glutamic acid decarboxylase may be found in the serum or cerebrospinal fluid; this enzyme is involved in the production of the inhibiting neurotransmitter gamma-aminobutyric acid. Both patients were treated with diazepam, baclofen and corticosteroids. Stiff-person syndrome is a rare but treatable disorder that should be considered when patients present with stiffness and pain in the lower back and upper legs.
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PMID:['Stiff-person'-syndrome]. 1284 59

Previous studies have shown that neurons in the ventral tegmental area (VTA) and substantia nigra (SN) project to the ventrolateral periaqueductal gray (PAGvl) and dorsal raphe nucleus (DR). Research has also shown that stimulation of neurons in the VTA/SN elicits cardiovascular depressor responses that are mediated by a projection to the PAGvl/DR. Anatomic and physiological experiments were done in the present study to determine the neurochemical identity of the VTA/SN projection to the PAGvl/DR. Experiments were done to characterize the origin and chemical nature of this projection by combining cholera toxin B tracing with immunofluorescence for the 67K isoform of glutamic acid decarboxylase (GAD) and tyrosine hydroxylase. The PAGvl/DR region was found to receive a substantial input from neurons in the VTA, SN, and deep mesencephalic nucleus. The DR was preferentially innervated by neurons in the VTA, whereas the PAGvl was preferentially innervated by neurons in the SN. A proportion of neurons in the VTA and the reticular portion of the SN found to project to the PAGvl/DR were GAD positive. In addition, experiments were done in urethane-anesthetized rats to determine whether injections of a gamma-aminobutyric acid (GABA) antagonist in the region of the PAGvl/DR attenuated the cardiovascular depressor responses produced by glutamate stimulation of the VTA/SN. Injections of the GABA-blocking agent picrotoxin (2.5 nmol, 500 nl) into the PAGvl/DR eliminated the cardiovascular responses from stimulation of the VTA/SN (0.01 M, 50 nl). The results of the present investigation provide evidence for a GABAergic projection from the VTA/SN to the PAGvl/DR. This projection may be an important regulator of the PAGvl/DR, an area of the midbrain involved in the production of behavioral and physiological responses to pain and stress.
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PMID:GABAergic projection from the ventral tegmental area and substantia nigra to the periaqueductal gray region and the dorsal raphe nucleus. 1469 32

Neuropathic pain after spinal cord injury (SCI) represents a difficult problem that is commonly refractory to conventional medical management. To determine if spinal release of gamma-amino butyric acid (GABA) could reduce below-level central neuropathic pain after SCI, we constructed a replication-incompetent herpes simplex virus (HSV)-based vector encoding one isoform of human glutamic acid decarboxylase (GAD67). Dorsal root ganglion (DRG) neurons transduced in vitro or in vivo by subcutaneous inoculation produced GAD and released GABA constitutively. T13 spinal cord hemisection resulted in central neuropathic pain manifested by mechanical allodynia and thermal hyperalgesia. Subcutaneous inoculation of the vector into both feet reduced both manifestations of below-level SCI pain; the vector-mediated effect was partially reversed by intrathecal bicuculline or phaclofen at doses that did not affect thresholds in normal or injured uninoculated animals. Vector-mediated GABA release attenuated the increase in spinal calcitonin gene-related peptide immunoreactivity caused by cord hemisection. These results suggest that HSV-mediated gene transfer to DRG could be used to treat below-level central neuropathic pain after incomplete SCI.
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PMID:Peripherally delivered glutamic acid decarboxylase gene therapy for spinal cord injury pain. 1523 42

Substance P (SP) has been characterized as an excitatory neurotransmitter and/or neuromodulator in the peripheral and central nervous systems. It is involved in mediating various biological functions such as smooth muscle contraction, neuronal excitation, and pain transmission. Although Lieb et al. reported that intravenous infusion of SP into healthy men led to an increase of paradoxical sleep latency and time awake, little is known about the function and target of SP on sleep-wakefulness cycle in the central nervous system. The ventrolateral preoptic area (vLPO) plays an important role in modulation of sleep-wakefulness cycle. The present study investigated the effect of SP on sleep-wakefulness cycle in the vLPO of rats. Slow wave sleep (SWS) was enhanced after SP was microinjected into bilateral vLPO, while SP receptor antagonist, N-acetyl-l-tryptophan 3,5-bis(trifluoromethyl)-benzyl ester, led to the opposite effect. The effect induced by SP was blocked by U73122, a phospholipase C inhibitor. In addition, 3-mercaptopropionic acid, a glutamic acid decarboxylase inhibitor that inhibits gamma-aminobutyric acid (GABA) synthesis and release, blocked the SP-induced sleep-promoting effect in the vLPO. These results indicate that SP has sleep-promoting effect in the vLPO possibly by GABAergic neurons.
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PMID:Substance P promotes sleep in the ventrolateral preoptic area of rats. 1552 48

Opioid analgesics remain the choice for the treatment of moderate to severe pain. Recent research has established that the mu-opioid receptor is predominantly responsible for mediating many opioid actions, including analgesia and opioid tolerance. However, the function of delta-opioid receptors is rather puzzling at present, with inconsistent reports of system effects by agonists of delta-opioid receptors. The functional interaction between mu-opioid receptors and delta-opioid receptors is also poorly understood. In this study, we demonstrated that in a brainstem site critically involved in opioid analgesia, agonists of delta-opioid receptors, ineffective in opioid naive rats, significantly inhibit presynaptic GABA release in the brainstem neurons from morphine-tolerant rats. In membrane preparation from control brainstem tissues, Western blot detected no proteins of delta-opioid receptors, but consistent delta-opioid receptor proteins were expressed in membrane preparation from morphine-tolerant rats. Immunohistochemical studies revealed that long-term morphine treatment significantly increases the number of delta-opioid receptor-immunoreactive varicosities that appose the postsynaptic membrane of these neurons. The colocalization of delta-opioid receptor-immunoreactive varicosities with the labeling of the GABA-synthesizing enzyme glutamic acid decarboxylase is also significantly increased. From a behavioral perspective, activation of delta-opioid receptors in the brainstem nucleus, lacking an effect in opioid naive rats, became analgesic in morphine-tolerant rats and significantly reduced morphine tolerance. These findings indicate that long-term morphine treatment induces the emergence of functional delta-opioid receptors and delta-opioid receptor-mediated analgesia, probably through receptor translocation to surface membrane in GABAergic terminals. They also suggest that opioid drugs with preference for delta-opioid receptors may have better therapeutic effect in a mu-opioid-tolerant state.
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PMID:Emergence of functional delta-opioid receptors induced by long-term treatment with morphine. 1639 48

We have demonstrated that dorsal root ganglion neurons transduced with a recombinant replication-defective herpes simplex virus vector coding for glutamic acid decarboxylase (QHGAD67) release GABA to produce an analgesic effect in rodent models of pain. In this study, we examined the mechanism of transgene-mediated GABA release from dorsal root ganglion neurons in vitro and in vivo. Release of GABA from dorsal root ganglion neurons transduced with QHGAD67 was not increased by membrane depolarization induced by 60 mM extracellular K+ nor reduced by the removal of Ca2+ from the medium. Release of GABA from transduced dorsal root ganglion neurons was, however, blocked in a dose-dependent manner by NO-711, a selective inhibitor of the GABA transporter-1. The amount of GABA released from a spinal cord slice preparation, prepared from animals transduced by subcutaneous inoculation of QHGAD67 in the hind paws, was substantially increased compared to animals transduced with control vector Q0ZHG or normal animals, but the amount of GABA released was not changed by stimulation of the dorsal roots at either low (0.1 mA, 0.5-ms duration) or high (10 mA, 0.5-ms duration) intensity. We conclude that QHGAD67-mediated GABA release from dorsal root ganglion neurons is non-vesicular, independent of electrical depolarization, and that this efflux is mediated through reversal of the GABA transporter.
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PMID:Release of GABA from sensory neurons transduced with a GAD67-expressing vector occurs by non-vesicular mechanisms. 1646 Jul 7

We have previously demonstrated that hyperpolarization-activated and cyclic nucleotide-gated cation channel subunit 2 (HCN2) is expressed by terminals of peptidergic nociceptive primary afferents in laminae I-IIo of the rat spinal dorsal horn. In this study, we investigated the possible neurotransmitters and postsynaptic targets of these HCN2-expressing primary afferent terminals in the superficial spinal dorsal horn by using immunocytochemical methods. We demonstrated that HCN2 widely colocalizes with substance P (SP), and that HCN2-positive terminals that are also immunoreactive for SP form serial close appositions with dendrites and perikarya of neurokinin 1 receptor-immunoreactive neurons. It was also found that HCN2-immunoreactive terminals are frequently apposed to neurons that are immunoreactive for calbindin, micro-opioid receptor and the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor subunit GluR2, markers for excitatory interneurons. Investigating HCN2 immunoreactivity in glutamic acid decarboxylase 65-green fluorescent protein transgenic mice, we found that HCN2-positive terminals occasionally also contact cells that contain an isoform of glutamic acid decarboxylase (glutamic acid decarboxylase 65), a marker for GABAergic inhibitory neurons. Application of ZD7288, an antagonist of HCN channels, onto neurons that were recorded in spinal cord slices with whole-cell patch-clamp electrodes reduced the number of monosynaptic excitatory postsynaptic potentials evoked by electrical stimulation of primary afferents at nociceptive intensities. The results suggest that HCN2 may contribute to the modulation of membrane excitability of SP-containing nociceptive primary afferent terminals, may increase the reliability of synaptic transmission from primary afferents to secondary sensory neurons and thus may play a role in the fine-tuning of pain transmission from nociceptive primary afferents to neurons in the spinal dorsal horn.
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PMID:Hyperpolarization-activated and cyclic nucleotide-gated cation channel subunit 2 ion channels modulate synaptic transmission from nociceptive primary afferents containing substance P to secondary sensory neurons in laminae I-IIo of the rodent spinal dorsal horn. 1698 20

Injury to the spinal cord or peripheral nerves can lead to the development of allodynia due to the loss of inhibitory tone involved in spinal sensory function. The potential of intraspinal transplants of GABAergic cells to restore inhibitory tone and thus decrease pain behaviors in a rat model of neuropathic pain was investigated. Allodynia of the left hind paw was induced in rats by unilateral L5- 6 spinal nerve root ligation. Mechanical sensitivity was assessed using von Frey filaments. Postinjury, transgenic fetal green fluorescent protein mouse GABAergic cells or human neural precursor cells (HNPCs) expanded in suspension bioreactors and differentiated into a GABAergic phenotype were transplanted into the spinal cord. Control rats received undifferentiated HNPCs or cell suspension medium only. Animals that received either fetal mouse GABAergic cell or differentiated GABAergic HNPC intraspinal transplants demonstrated a significant increase in paw withdrawal thresholds at 1 week post-transplantation that was sustained for 6 weeks. Transplanted fetal mouse GABAergic cells demonstrated immunoreactivity for glutamic acid decarboxylase and GABA that colocalized with green fluorescent protein. Intraspinally transplanted differentiated GABAergic HNPCs demonstrated immunoreactivity for GABA and beta-III tubulin. In contrast, intraspinal transplantation of undifferentiated HNPCs, which predominantly differentiated into astrocytes, or cell suspension medium did not affect any behavioral recovery. Intraspinally transplanted GABAergic cells can reduce allodynia in a rat model of neuropathic pain. In addition, HNPCs expanded in a standardized fashion in suspension bioreactors and differentiated into a GABAergic phenotype may be an alternative to fetal cells for cell-based therapies to treat chronic pain syndromes.
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PMID:Spinal GABAergic transplants attenuate mechanical allodynia in a rat model of neuropathic pain. 1770 82

Neuropathic pain is a long-lasting clinical problem that is often refractory to medical management. Gene transfer of specific genes for therapeutic benefit offers a novel approach to the treatment of neuropathic pain. In this study, we tested whether the transfer of the glutamic acid decarboxylase (GAD) gene to dorsal root ganglion (DRG) cells would attenuate below-injury level central neuropathic pain after spinal cord injury (SCI) by using a novel human foamy virus (HFV) vector to achieve release of gamma-aminobutyric acid (GABA). Subcutaneous inoculation of a replication-defective HFV vector, which expresses GAD (vector rdvGAD67) for 7days after T13 spinal cord hemisection, reversed mechanical allodynia and thermal hyperalgesia evoked by SCI. The antiallodynic effect lasted 6 weeks and was reestablished by reinoculation. We also found that subcutaneous inoculation of rdvGAD67 resulted in enhanced production of GAD and tonical GABA release from transduced DRG neurons. These results suggest that HFV-mediated gene transfer to DRG could be employed to treat below-injury level central neuropathic pain after incomplete SCI.
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PMID:A novel human foamy virus mediated gene transfer of GAD67 reduces neuropathic pain following spinal cord injury. 1818 Jan 6

In this study, we evaluated whether propentofylline, a methylxanthine derivative, modulates spinal glial activation and GABAergic inhibitory tone by modulation of glutamic acid decarboxylase (GAD)(65), the GABA synthase enzyme, in the spinal dorsal horn following spinal cord injury (SCI). Sprague-Dawley rats (225-250 g) were given a unilateral spinal transverse injury, from dorsal to ventral, at the T13 spinal segment. Unilateral spinal injured rats developed robust bilateral hindlimb mechanical allodynia and hyperexcitability of spinal wide dynamic range (WDR) neurons in the lumbar enlargement (L4-L5) compared to sham controls, which was attenuated by intrathecal (i.t.) administration of GABA, dose-dependently (0.01, 0.1, 0.5 microg). Western blotting and immunohistochemical data demonstrated that the expression level of GAD(65) protein significantly decreased on both sides of the lumbar dorsal horn (L4/5) after SCI (p<0.05). In addition, astrocytes and microglia showed soma hypertrophy as determined by increased soma area and increased GFAP and CD11b on both sides of the lumbar dorsal horn compared to sham controls, respectively (p<0.05). Intrathecal treatment with propentofylline (PPF 10 mM) significantly attenuated the astrocytic and microglial soma hypertrophy and mechanical allodynia (p<0.05). Additionally, the Western blotting and immunohistochemistry data demonstrated that i.t. treatment of PPF significantly prevented the decrease of GAD(65) expression in both sides of the lumbar dorsal horn following SCI (p<0.05). In conclusion, our present data demonstrate that propentofylline modulates glia activation and GABAergic inhibitory tone by modulation of GAD(65) protein expression following spinal cord injury.
Pain 2008 Aug 31
PMID:Propentofylline attenuates allodynia, glial activation and modulates GABAergic tone after spinal cord injury in the rat. 1835 56


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