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)

The effects of capsaicin injections into neonatal rats on the ultrastructure of the neonatal dorsal horn and on some biochemical and behavioral parameters in the adult were examined. Electron microscopic observations revealed degeneration and glial engulfment of boutons and umyelinated axons in the dorsal horn 2 and 6 h after neonatal subcutaneous capsaicin injections. Capsaicin treatment had no effect on the activities of glutamic acid decarboxylase and choline acetyltransferase in the dorsal horn. Results of substance P measurements in the CNS showed no effect of capsaicin administration on striatal, hypothalamic or nigral substance P content, whereas substance P levels in the dorsal horn of the spinal cord were reduced by half. The density of [3H]naloxone binding sites in the dorsal horn was significantly reduced, while the affinity was not affected. Capsaicin-treated animals showed significantly increased latencies to respond to a noxious thermal stimulus in both tail-flick and hot-plate tests. The results are discussed in relation to the current concepts of the involvement of substance P and opiate systems in nociception and the potential use of neonatal capsaicin as a selective neurotoxin for the elucidation of the spinal mechanisms of pain.
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PMID:Neurotoxic action of capsaicin on spinal substance P neurons. 615 57

THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) is a potent and specific GABA receptor agonist which does not influence the GABA uptake system or GABA metabolizing enzymes. The specificity for the GABA receptor is also demonstrated by lack of action on monoaminergic, cholinergic, histaminergic or opiate receptors. Since in recent years GABA receptor stimulants-among others THIP--have become available many have speculated as to what clinical indication GABA-ergic stimulation might be an important element. The first suggestion was that GABA-ergic drugs by an inhibitory effect on the dopamine neurons would improve the antischizophrenic effect of neuroleptics and improve tardive dyskinesia. Furthermore, studies on brains of deceased Parkinson and Huntington's chorea patients have demonstrated a low level of GABA and its synthesizing enzyme glutamic acid decarboxylase (GAD) in the basal ganglia. Also in epilepsy and diseases with dementia a deficit in the GABA system has been proposed. Therefore a therapeutic strategy for these diseases may be supplementary treatment with drugs which increase GABA receptor activity. Furthermore, recent results in humans have shown that GABA agonists perhaps also could be of benefit in mania and depressions. When considering the neurophysiological elements of nociception and muscle tone it is also reasonable to suggest that GABA-ergic stimulation may reduce pain perception and muscle tone.
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PMID:Pharmacodynamic effects and possible therapeutic uses of THIP, a specific GABA-agonist. 629 18

Following several months of low back pain, a 36-year-old man developed progressive stiffness of the abdominal, low back, and thigh muscles. On examination, these muscles demonstrated marked hypertonia consistent with the clinical diagnosis of stiff-person syndrome. The patient demonstrated increased lumbar lordosis and had focal hyperhidrosis at different sites. Electromyography showed continuous activity of the paraspinal and thigh muscles, and serum and cerebrospinal fluid antibodies to glutamic acid decarboxylase (GAD) were markedly elevated. Diazepam and Lioresal offered partial pain relief. Paraspinal muscle administration of botulinum toxin A reduced the tone of paraspinal and thigh muscles significantly and resulted in marked improvement of ambulation and cessation of pain.
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PMID:Significant improvement of stiff-person syndrome after paraspinal injection of botulinum toxin A. 834 5

The chemical structure of gabapentin (Neurontin) is derived by addition of a cyclohexyl group to the backbone of gamma-aminobutyric acid (GABA). Gabapentin prevents seizures in a wide variety of models in animals, including generalized tonic-clonic and partial seizures. Gabapentin has no activity at GABAA or GABAB receptors of GABA uptake carriers of brain. Gabapentin interacts with a high-affinity binding site in brain membranes, which has recently been identified as an auxiliary subunit of voltage-sensitive Ca2+ channels. However, the functional correlate of gabapentin binding is unclear and remains under study. Gabapentin crosses several lipid membrane barriers via system L amino acid transporters. In vitro, gabapentin modulates the action of the GABA synthetic enzyme, glutamic acid decarboxylase (GAD) and the glutamate synthesizing enzyme, branched-chain amino acid transaminase. Results with human and rat brain NMR spectroscopy indicate that gabapentin increases GABA synthesis. Gabapentin increases non-synaptic GABA responses from neuronal tissues in vitro. In vitro, gabapentin reduces the release of several mono-amine neurotransmitters. Gabapentin prevents pain responses in several animal models of hyperalgesia and prevents neuronal death in vitro and in vivo with models of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Gabapentin is also active in models that detect anxiolytic activity. Although gabapentin may have several different pharmacological actions, it appears that modulation of GABA synthesis and glutamate synthesis may be important.
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PMID:Mechanisms of action of gabapentin. 968 47

We describe a patient with type 1 diabetes with recurrent diabetic ketoacidosis and severe insulin resistance. Extensive evaluation of the etiology of the insulin resistance did not reveal an etiology, and well over 1000 U of daily insulin did not prevent the ketoacidosis. Her blood glucose and insulin requirements were improved with glucocorticoids and octreotide, but the effects of both of these agents were short-lived. She was given a trial of insulin lispro with immediate and dramatic effects, lowering her HbA1c from 14.6 to 5.1% in 7 months with a decrease in insulin requirements of 1600-100 U per day. Besides her diabetes, she had a history of pain and stiffness affecting numerous muscle groups, and hospitalization was required for pain control. The diagnosis of stiff-man syndrome (SMS) was confirmed with high titers of glutamic acid decarboxylase 65 antibodies in both serum and cerebral spinal fluid. In summary, we describe the first patient with type 1 diabetes, SMS, and severe insulin resistance. Although the etiology of the insulin resistance is unknown, due to the efficacious response to insulin lispro, hydrocortisone, and perhaps octreotide, we propose an immune-mediated etiology. Although rare, this syndrome needs to be considered as an etiology of insulin resistance.
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PMID:Severe insulin resistance in a patient with type 1 diabetes and stiff-man syndrome treated with insulin lispro. 982 49

Cannabinoids can modulate motor behaviour, learning and memory, cognition and pain perception. These effects correlate with the expression of the cannabinoid receptor 1 (CB1) and with the presence of endogenous cannabinoids in the brain. In trying to obtain further insights into the mechanisms underlying the modulatory effects of cannabinoids, CB1-positive neurons were determined in the murine forebrain at a single cell resolution. We performed a double in situ hybridization study to detect mRNA of CB1 in combination with mRNA of glutamic acid decarboxylase 65k, neuropeptide cholecystokinin (CCK), parvalbumin, calretinin and calbindin D28k, respectively. Our results revealed that CB1-expressing cells can be divided into distinct neuronal subpopulations. There is a clear distinction between neurons containing CB1 mRNA either at high levels or low levels. The majority of high CB1-expressing cells are GABAergic (gamma-aminobutyric acid) neurons belonging mainly to the cholecystokinin-positive and parvalbumin-negative type of interneurons (basket cells) and, to a lower extent, to the calbindin D28k-positive mid-proximal dendritic inhibitory interneurons. Only a fraction of low CB1-expressing cells is GABAergic. In the hippocampus, amygdala and entorhinal cortex area, CB1 mRNA is present at low but significant levels in many non-GABAergic cells that can be considered as projecting principal neurons. Thus, a complex mechanism appears to underlie the modulatory effects of cannabinoids. They might act on principal glutamatergic circuits as well as modulate local GABAergic inhibitory circuits. CB1 is very highly coexpressed with CCK. It is known that cannabinoids and CCK often have opposite effects on behaviour and physiology. Therefore, we suggest that a putative cross-talk between cannabinoids and CCK might exist and will be relevant to better understanding of physiology and pharmacology of the cannabinoid system.
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PMID:Expression of the cannabinoid receptor CB1 in distinct neuronal subpopulations in the adult mouse forebrain. 1059 47

We report the effects of double filtration plasma exchange and immunoadsorption therapy which were performed for a case of stiff-man syndrome even though the patient was negative for anti-glutamic acid decarboxylase (GAD) antibody. The patient underwent a course of four double filtration plasma exchanges, which resulted in marked clinical improvement. Painful muscle cramps disappeared and muscle stiffness reduced within a day after the first plasma exchange. The patient's improvement continued, but his condition declined again about ten months after plasma exchange. Immunoadsorption therapy was then performed, and this treatment was also effective.
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PMID:Double filtration plasma exchange and immunoadsorption therapy in a case of stiff-man syndrome with negative anti-GAD antibody. 1085 65

There is growing evidence suggesting that neurotrophins have modulating effects on the pain signaling system at spinal levels. In order to determine whether neurotransmitter expression is modulated in response to the elevation of neurotrophins, the changes in c-fos, neuropeptide and glutamic acid decarboxylase (GAD) mRNAs expression was evaluated after BDNF or NT-3 was applied to cultured spinal neurons. Reverse transcription polymerase chain reaction analysis revealed that BDNF induced a significant increase in the expression of preprodynorphin (pDYN), preproenkephalin (pENK), neuropeptide Y (NPY) and GAD mRNAs. In contrast, the pENK, not the pDYN, NPY and GAD, mRNA levels increased after the treatment of NT-3. Both BDNF and NT-3 produced a rapid increase in c-fos mRNA. These results suggest that BDNF and NT-3 have differential neuronal effects on the synthesis of spinal cord neurotransmitters that are involved in the modulation of nociceptive information.
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PMID:Effects of brain-derived neurotrophic factor and neurotrophin-3 on expression of mRNAs encoding c-Fos, neuropeptides and glutamic acid decarboxylase in cultured spinal neurons. 1111 6

Stiff-person syndrome was diagnosed in a patient with chronic low back pain. The diagnosis of this rare neurological condition rests mainly on the clinical findings of axial and proximal limb rigidity, increased lumbar lordosis often accompanied with pain, and normal neurological findings apart from brisk deep tendon reflexes. Electromyography of the lumbar paraspinal muscles shows motor unit firing at rest with normal appearance of the motor unit potentials. Titers of antibody to glutamic acid decarboxylase are elevated. Diazepam is the treatment of reference. Physical therapy can substantially improve quality of life.
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PMID:Atypical low back pain: stiff-person syndrome. 1202 16

The inhibitory neurotransmitter GABA is synthesized by glutamic acid decarboxylase (GAD), and two isoforms of this enzyme exist: GAD65 and GAD67. Immunocytochemical studies of the spinal cord have shown that whilst both are present in the dorsal horn, GAD67 is the predominant form in the ventral horn. The present study was carried out to determine the pattern of coexistence of the two GAD isoforms in axonal boutons in different laminae of the cord, and also to examine the relation of the GADs to the glycine transporter GLYT2 (a marker for glycinergic axons), since many spinal neurons are thought to use GABA and glycine as co-transmitters. Virtually all GAD-immunoreactive boutons throughout the spinal grey matter were labelled by both GAD65 and GAD67 antibodies; however, the relative intensity of staining with the two antibodies varied considerably. In the ventral horn, most immunoreactive boutons showed much stronger labelling with the GAD67 antibody, and many of these were also GLYT2 immunoreactive. However, clusters of boutons with high levels of GAD65 immunoreactivity were observed in the motor nuclei, and these were not labelled with the GLYT2 antibody. In the dorsal horn, some GAD-immunoreactive boutons had relatively high levels of labelling with either GAD65 or GAD67 antibody, whilst others showed a similar degree of labelling with both antibodies. GLYT2 immunoreactivity was associated with many GAD-immunoreactive boutons; however, this did not appear to be related to the pattern of GAD expression. It has recently been reported that there is selective depletion of GAD65, accompanied by a loss of GABAergic inhibition, in the ipsilateral dorsal horn in rats that have undergone peripheral nerve injuries [J Neurosci 22 (2002) 6724]. Our finding that some boutons in the superficial laminae showed relatively high levels of GAD65 and low levels of GAD67 immunoreactivity is therefore significant, since a reduction in GABA synthesis in these axons may contribute to neuropathic pain.
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PMID:Distribution and colocalisation of glutamate decarboxylase isoforms in the rat spinal cord. 1277 May 60


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