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: EC:2.3.1.21 (CPT)
4,580 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study examined the spinal antinociceptive effects of adenosine analogs and inhibitors of adenosine kinase and adenosine deaminase in the carrageenan-induced thermal hyperalgesia model in the rat. The possible enhancement of the antinociceptive effects of adenosine kinase inhibitors by an adenosine deaminase inhibitor also was investigated. Unilateral hindpaw inflammation was induced by an intraplantar injection of lambda carrageenan (2 mg/100 microl), which consistently produced significant paw swelling and thermal hyperalgesia. Drugs were administered intrathecally, either by acute percutaneous lumbar puncture (individual agents and combinations) or via an intrathecal catheter surgically implanted 7-10 days prior to drug testing (antagonist experiments). N6-cyclohexyladenosine (CHA; adenosine A1 receptor agonist; 0.01-1 nmol), 2-[p-(2-carboxyethyl)phenylethylamino]-5'-N-ethylcarboxamidoadenos ine (CGS21680; adenosine A2A receptor agonist; 0.1-10 nmol), 5'-amino-5'-deoxyadenosine (NH2dAdo; adenosine kinase inhibitor: 10-300 nmol), and 5-iodotubercidin (ITU; adenosine kinase inhibitor; 0.1-100 nmol) produced, to varying extents, dose-dependent antinociception. No analgesia was seen following injection of 2'-deoxycoformycin (dCF; an adenosine deaminase inhibitor; 100-300 nmol). Reversal of drug effects by caffeine (non-selective adenosine A1/A2 receptor antagonist; 515 nmol) confirmed the involvement of the adenosine receptor, while antagonism by 8-cyclopentyl-1,3-dimethylxanthine (CPT; adenosine A1 receptor antagonist; 242 nmol), but not 3,7-dimethyl-1-propargylxanthine (DMPX; adenosine A2A receptor antagonist; 242 nmol), evidenced an adenosine A1 receptor mediated spinal antinociception by NH2dAdo. dCF (100 nmol), which was inactive by itself, enhanced the effects of 10 nmol and 30 nmol NH2dAdo. Enhancement of the antinociceptive effect of ITU by dCF was less pronounced. None of the antinociceptive drug regimens had any effect on paw swelling. These results demonstrate that both directly and indirectly acting adenosine agents, when administered spinally, produce antinociception through activation of spinal adenosine A1 receptors in an inflammatory model of thermal hyperalgesia. The spinal antinociceptive effects of selected adenosine kinase inhibitors can be significantly augmented when administered simultaneously with an adenosine deaminase inhibitor.
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PMID:Antinociception by adenosine analogs and inhibitors of adenosine metabolism in an inflammatory thermal hyperalgesia model in the rat. 952 Feb 38

The effect of the selective adenosine A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA) was investigated in CD1 mice by the elevated plus-maze and the light/dark test, two models for measuring anxiety in rodents. CCPA, administered i.p., had an anxiolytic effect at 0.3 nmol/kg in the elevated plus-maze and at 1 nmol/kg in the light/dark test. Brain levels of 22 nM were found after administration of 100 nmol/kg CCPA, as measured by ex vivo binding experiments. These values are consistent with the occupancy of adenosine A1 but not A2 receptors by CCPA, and suggest that the anxiolytic-like action of CCPA may be mediated by centrally located adenosine A1 receptors. Both CPT, a selective adenosine A1 receptor antagonist, and IBMX, a non-selective adenosine antagonist, had an anxiogenic effect in the two tests. It is thus possible that purinergic neurons may be involved in the tonic modulation of affective state in mice.
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PMID:Adenosine A1 receptors modulate anxiety in CD1 mice. 960 May 75

In rats with abnormally low withdrawal thresholds ('allodynia') in one hindpaw induced by a photochemical sciatic lesion, an intrathecal catheter was inserted to the lumber enlargement and an epidural electrode was implanted at T11. I.t. administration of GABA(B) or adenosine A1 receptor agonists (baclofen, R(-)-N6-(2-phenylisopropyl)adenosine (R-PIA)) suppressed allodynia in a dose-dependent fashion. When the two agonists were given together, each in an ineffective dose, there was a normalization of the thresholds. Rats, in which spinal cord stimulation (SCS) could not suppress the allodynia (non-responders), were transformed into SCS-responders by injection of baclofen and R-PIA in low, ineffective doses, combined with SCS. In SCS responding rats, combination of a selective GABA(B) and an adenosine A1 receptor antagonist (CGP 55845, CPT) in low, ineffective doses abolished the SCS-induced threshold normalization. These results indicate that GABAergic and adenosine-dependent mechanisms are involved in the SCS effect and further suggest a strategy for enhancing the therapeutic efficacy of SCS.
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PMID:Effect of spinal cord stimulation on tactile hypersensitivity in mononeuropathic rats is potentiated by simultaneous GABA(B) and adenosine receptor activation. 965 23

Intracellular free Ca2+ concentration ([Ca2+]i) was measured by laser scanning confocal microscope, using Ca2+ indicator Fluo-3 in cultured hippocampal CA1 neurons isolated from newborn rat. The results showed that acute anoxia induced a rapid increase of [Ca2+]i in hippocampal CA1 neurons, and this increase could be attenuated by 100 mumol/L adenosine significantly. This effect of adenosine could be suppressed by adenosine A1 receptor antagonist CPT or potassium channel blockers, 4-AP and glipizide. These results suggest that adenosine activates 4-AP- or ATP-sensitive potassium channels through A1 receptors, and consequently inhibits the [Ca2+]i elevation in hippocampal neurons during anoxia.
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PMID:[Effect of adenosine on intracellular free calcium in cultured rat hippocampal CA1 neurons during anoxia]. 981 94

1. The actions of selective adenosine A1 and A2 receptor agonists were examined on synaptic currents in periaqueductal grey (PAG) neurons using patch-clamp recordings in brain slices. 2. The A1 receptor agonist 2-chloro-N-cyclopentyladenosine (CCPA), but not the A2 agonist, 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS21680), inhibited both electrically evoked inhibitory (eIPSCs) and excitatory (eEPSCs) postsynaptic currents. The actions of CCPA were reversed by the A1 receptor antagonist 8-cyclopentyl-1, 3-dipropylxanthine (DPCPX). 3. In the absence or presence of forskolin, DPCPX had no effect on eIPSCs, suggesting that concentrations of tonically released adenosine are not sufficient to inhibit synaptic transmission in the PAG. 4. CCPA decreased the frequency of spontaneous miniature action potential-independent IPSCs (mIPSCs) but had no effect on their amplitude distributions. Inhibition persisted in nominally Ca2+-free, high Mg2+ solutions and in 4-aminopyridine. 5. The CCPA-induced decrease in mIPSC frequency was partially blocked by the non-selective protein kinase inhibitor staurosporine, the specific protein kinase A inhibitor 8-para-chlorophenylthioadenosine-3',5'-cyclic monophosphorothioate (Rp-8-CPT-cAMPS), and by 8-bromoadenosine cyclic 3',5' monophosphate (8-Br-cAMP). 6. These results suggest that A1 adenosine receptor agonists inhibit both GABAergic and glutamatergic synaptic transmission in the PAG. Inhibition of GABAergic transmission is mediated by presynaptic mechanisms that partly involve protein kinase A.
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PMID:Inhibition by adenosine receptor agonists of synaptic transmission in rat periaqueductal grey neurons. 1006 36

The role of adenosine in reversible inhibition of synaptic function during the early stage of anoxia and its mechanisms were investigated with extracellular recording technique in rat hippocampal slices. The results showed that acute anoxia led to the reversible inhibition of synaptic function, which is similar to the response to addition of high concentration of exogenous adenosine. The reversible inhibition could be suppressed by adenosine A1 receptor antagonist CPT and potassium channel blocker 4-AP, whereas TEA and ATP-sensitive potassium channel blocker glipzide had no effect. These results suggest that during the early stage of anoxia, the enhanced release of endogenous adenosine can inhibit the synaptic transmission by activating 4-AP-sensitive potassium channels via A1 receptors and thus play a role in protenction against anoxic injury. ATP-sensitive potassium channels may not be involved in the mechanisms of adenosine action.
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PMID:[The role of adenosine in the early stage of anoxia of hippocampal slices and its mechanisms]. 1007 22

The effects of purinoceptor subtypes on hippocampal extracellular serotonin levels were determined by using in vivo microdialysis. Perfusion with adenosine-5'-triphosphate (ATP) for 20 min produced concentration-dependent changes in hippocampal extracellular serotonin levels, which consisted of an initial rise phase, with levels increasing to 309% of control with 100 microM ATP, followed by a later rebound reduction phase, with levels decreasing to 6% of control. The P2X1-7 active P2 purinoceptor agonist, 2-methylthioATP (2-MeSATP: 100 microM) increased the extracellular serotonin level drastically (638%), while the P2X1,3 active P2 purinoceptor agonist, alpha, beta-methylene-L-ATP (alpha, beta-meATP: 100 microM) produced a small increase (132%) in the serotonin level. The P2X1,2,3,5,7 active P2 purinoceptor antagonist, suramin (100 microM), reduced the basal serotonin level (86%) and the ATP-evoked initial rise phase (from 309 to 254%) without affecting the late reduction phase. The adenosine A1 receptor antagonist, 8-cyclopentyl-1,3-dimethylxanthine (CPT: 50 microM) potentiated the rising phase (167%) and abolished the subsequent ATP-evoked reduction phase. Perfusion with CPT and an adenosine A2 receptor antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX: 10 microM), reduced the ATP-evoked initial rise (to 181%) and abolished the late reduction phases of serotonin release. These results indicate that ATP-evoked hippocampal serotonin release is composed of an initial rise phase and a later reduction phase. The ATP-evoked initial rise phase might be produced by an activation of P2X purinoceptor function, whereas the late reduction phase was modulated by the activation of adenosine A1 receptor function by adenosine, metabolized from ATP in the synaptic cleft.
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PMID:Interaction between purinoceptor subtypes on hippocampal serotonergic transmission using in vivo microdialysis. 1034 Mar 8

1. The effects of adenosine on synaptic transmission in magnocellular neurosecretory cells were investigated using whole-cell patch-clamp recordings in acute rat hypothalamic slices that included the supraoptic nucleus. 2. Adenosine reversibly reduced the amplitude of evoked inhibitory (IPSCs) and excitatory (EPSCs) postsynaptic currents in a dose-dependent manner (IC50 approximately 10 microM for both types of current). 3. Depression of IPSCs and EPSCs by adenosine was reversed by the application of the A1 adenosine receptor antagonist 8-cyclopentyl-1, 3-dimethylxanthine (CPT; 10 microM). 4. When pairs of stimuli were given at short intervals, adenosine inhibitory action was always less effective on the second of the two responses than on the first, resulting in an increased paired-pulse facilitation and suggesting a presynaptic site of action. This observation was confirmed by analysis of spontaneous miniature synaptic currents whose frequency, but not amplitude or kinetics, was reversibly reduced by 100 microM adenosine. 5. CPT had no effect on synaptic responses evoked at a low frequency of stimulation (0.05-0.5 Hz), indicating the absence of tonic activation of A1 receptors under these recording conditions. However, CPT inhibited a time-dependent depression of both IPSCs and EPSCs induced during a 1 Hz train of stimuli. 6. Taken together, these results suggest that adenosine can be released within the supraoptic nucleus at a concentration sufficient to inhibit the release of GABA and glutamate via the activation of presynaptic A1 receptors. By its inhibitory feedback action on the major afferent inputs to oxytocin and vasopressin neurones, adenosine could optimally adjust electrical and secretory activities of hypothalamic magnocellular neurones.
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PMID:Adenosine-induced presynaptic inhibition of IPSCs and EPSCs in rat hypothalamic supraoptic nucleus neurones. 1054 29

Presynaptic inhibition is one of the major control mechanisms in the CNS. Previously we reported that A1 adenosine receptors are highly concentrated in the brain, including optic tectum, of trout and that they inhibited the release of glutamate. The optic tectum is heavily innervated by cholinergic nerve terminals. We have investigated whether A1 receptors inhibit the presynaptic release of acetylcholine and whether the inhibition is triggered by calcium. The release of [3H]ACh evoked by 30 mM KCl was Ca2+ dependent and it was dose-dependently inhibited by the A1 adenosine receptor agonist 2-chloro-N(6)-cyclopentyladenosine (CCPA) ranging between 10 nM to 100 microM. The maximum of inhibition was reached at 10 microM. The A1 receptor antagonist 8-cyclopentyltheopylline (CPT, 10 microM), reversed almost completely the inhibition induced by CCPA 10 microM. In Fura-2/AM loaded synaptosomes, K(+) depolarization raised [Ca2+](i) by about 64%. CCPA (10 microM) reduced the K(+)-evoked Ca2+ influx increase by about 48% and this effect was completely antagonised by CPT 10 microM. Synaptosome pretreatment with different Ca2+ channel blockers differently affected K(+)-evoked Ca2+ influx. This was not significantly modified by nifedipine (1 microM, L-type blocker) nor by omega-agatoxin IVA (0.3 microM, P/Q-type blocker), whereas about 50% reduction was shown by 0.5 microMomega-conotoxin GVIA (N-type blocker). Neurochemical parameters associated with cholinergic transmission and the density of A(1) adenosine receptors were measured in the trout optic tectum 12 days after unilateral eye ablation. A significant drop of both acetylcholinesterase (AChE) activity (24%) and choline acetyltransferase (CAT) activity (32%) was observed in deafferentated optic tectum, whereas the high affinity choline uptake did not parallel the decrease in enzyme activity. Eye ablation caused a marked decrease (43%) of A1 receptor density without changing the affinity. The K(+)-evoked release of [3H]ACh from synaptosomes of deafferentated was not modify as well as the efficacy of 10 microMCCPA in decreasing [3H]ACh release was not apparently modified.
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PMID:The calcium-dependent [3H]acetylcholine release from synaptosomes of brown trout (Salmo trutta) optic tectum is inhibited by adenosine A1 receptors: effects of enucleation on A1 receptor density and cholinergic markers. 1117 51

The influence of adenosine receptor agonists and antagonists on amphetamine-induced stereotypy was examined in male Wistar rats. Adenosine A2 receptor agonists CGS 21680 (0.5-2 mg/kg ip) and a non-specific A2/A1 receptor agonist NECA (0.05-0.1 mg/kg ip) attenuated in a dose dependent manner amphetamine-induced stereotypy (2 mg/kg sc). CPA as specific agonist of adenosine A1 receptors counteracted this stereotypy, but only in a narrow range of doses (0.1-0.2 mg/kg ip). Adenosine A2A receptor antagonist, DMPX (3 and 6 mg/kg ip) potentiated stereotypy induced by either subthreshold dose of amphetamine 0.5 mg/kg or a high one 2 mg/kg. A non-selective adenosine receptor antagonist, caffeine (10 mg/kg ip) potentiated effect of low dose of amphetamine, but only in a dose of 20 mg/kg ip increased stereotypy induced by 2 mg/kg ip of amphetamine. A selective adenosine A1 receptor antagonist CPT (1 and 3 mg/kg ip) was ineffective in reversing amphetamine-induced stereotypy. These results confirm the existence of adenosine-dopamine interactions in the brain, and the suggestions that A2 adenosine receptor agonists may have antipsychotic properties.
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PMID:Influence of adenosine receptor agonists and antagonists on amphetamine-induced stereotypy in rats. 1133 36


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