Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of acute and chronic treatment with three antidepressant drugs on the cortical L-type calcium channel (measured as [3H]nitrendipine binding sites) and on the responsiveness to pain (assessed in the hot-plate test) was tested on the Wistar rat. Acute administration of antidepressants did not affect the characteristics of calcium channels and did not significantly prolong the hot-plate latency. However, a combination of antidepressants with nifedipine brought about analgesia. Chronic administration of imipramine did not significantly affect the characteristics of calcium channels but produced a moderate analgesic effect. In contrast, chronic administration of citalopram and chlorprothixene increased the density of [3H]nitrendipine binding sites and induced hyperalgesia, which was nullified by acute administration of nifedipine. The results confirm that calcium channels may be involved in analgesia and hyperalgesia and indicate that chronic treatment with some antidepressant may induce an increase in the density of cortical calcium channels.
 ...
PMID:Role of calcium channels in effects of antidepressant drugs on responsiveness to pain. 166 65

During the inflammatory response, tissues release histamine (H), substance P, serotonin (5-HT), prostaglandins and kinins, agents that mediate manifestations of inflammation such as pain, vasodilation, increased capillary permeability and smooth muscle contraction. In this study we investigated whether racemic (R[+]) ketamine (K) and its isomers are spasmolytic on intestinal smooth muscle contracted by inflammatory mediators, and whether the spasmolytic effect of K is related to changes in calcium influx through the L-type calcium channel or to an interaction of K with opioid receptors. We measured the contractions of guinea-pig ileum mounted in an organ bath containing Tyrode's solution gassed with 95% O2/5% CO2 at 37 degrees C. In the first protocol we determined the effect of K and its isomers on contractions induced by five mediators: 10(-7) M H, 10(-8) M substance P, 10(-8) M neurokinin A, 5 x 10(-9) M bradykinin and 5 x 10(-7) M 5-HT. For each of these mediators, we plotted concentration-response curves for the inhibitory effect of K, and from regression fitting of these curves, we calculated the IC50 concentration of K that inhibited the contraction by 50%). In the second protocol we measured the contraction induced by the calcium ionophore A23187 (5.0 x 10(-6) M), both alone and after 1.8-7.2 x 10(-4) M R(+/-)K. Then we examined how the inhibition caused by R(+/-)K was affected by increases in the concentration of extracellular calcium by adding calcium (1.8-7.2 x 10(-3) M).(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Ketamine inhibits contractile responses of intestinal smooth muscle by decreasing the influx of calcium through the L-type calcium channel. 748 30

1. The present study addresses the involvement of voltage-dependent calcium channels of the N and L type in the spinal processing of innocuous and noxious input from the knee joint, both under normal conditions and under inflammatory conditions in which spinal cord neurons become hyperexcitable. In 30 anesthetized rats, extracellular recordings were performed from single dorsal horn neurons in segments 1-4 of the lumbar spinal cord. All neurons had receptive fields in the ipsilateral knee joint. In 22 rats, an inflammation was induced in the ipsilateral knee joint by kaolin and carrageenan 4-16 h before the recordings. The antagonist at N-type calcium channels, omega-conotoxin GVIA (omega-CTx GVIA), was administered topically in solution to the dorsal surface of the spinal cord at the appropriate spinal segments in 6 rats with normal joints and in 12 rats with inflamed knee joints. The antagonist at L-type channels, nimodipine, was administered topically in 5 rats with normal joints and in 11 rats with inflamed knee joints. In another five rats with inflamed joints, antagonists at L-type calcium channels (diltiazem and nimodipine) and omega-CTx GVIA were administered ionophoretically with multibarrel electrodes close to the neurons recorded. 2. The topical administration of omega-CTx GVIA to the spinal cord reduced the responses to both innocuous and noxious pressure applied to the knee joint in a sample of 11 neurons with input from the normal joint and in a sample of 16 neurons with input from the inflamed joint (hyperexcitable neurons). The responses were decreased to approximately 65% of the predrug values within administration times of 30 min. A similar reduction of the responses to innocuous and noxious pressure was observed when omega-CTx GVIA was administered ionophoretically to nine hyperexcitable neurons. In neurons with input from the normal or the inflamed knee joint, the administration of omega-CTx GVIA led also to a reduction of the responses to innocuous and noxious pressure applied to the noninflamed ankle joint. 3. The topical administration of nimodipine decreased the responses to innocuous and noxious pressure applied to the knee in a sample of 9 neurons with input from the normal joint and in a sample of 16 neurons with input from the inflamed knee joint (hyperexcitable neurons). Within administration times of 30 min, the responses were reduced to approximately 70% of the predrug values. In hyperexcitable neurons, the responses to innocuous and noxious pressure applied to the knee were also decreased during ionophoretic administration of nimodipine (6 neurons) and diltiazem (9 neurons). When the noninflamed ankle was stimulated, the responses to innocuous pressure were reduced neither in neurons with input from the normal knee nor in neurons with input from the inflamed knee, but the responses of hyperexcitable neurons to noxious pressure onto the ankle were reduced. The ionophoretic administration of the agonist at the L-type calcium channel, S(-)-Bay K 8644, enhanced the responses to mechanical stimulation of the knee joint in all 14 hyperexcitable neurons tested. The effect of S(-)-Bay K 8644 was counteracted by both diltiazem (in 6 of 6 neurons) and nimodipine (in 5 of 5 neurons). 4. These data show that antagonists at both the N- and the L-type voltage-dependent calcium channels influence the spinal processing of input from the knee joint. The data suggest, therefore, that voltage-dependent calcium calcium channels of both the N and the L type are important for the sensory functions of the spinal cord. They are involved in the spinal processing of nonnociceptive as well as nociceptive mechanosensory input from the joint, both under normal and inflammatory conditions. The present results show in particular that N- and L-type channels are likely to be involved in the generation of pain evoked by noxious mechanical stimulation in normal tissue as well as in the mechanical hyperalgesia that is usually pres
 ...
PMID:Effects of N- and L-type calcium channel antagonists on the responses of nociceptive spinal cord neurons to mechanical stimulation of the normal and the inflamed knee joint. 898 72

The effects of the intrathecal (i.t.) administration of different voltage-sensitive calcium channel (VSCC) blockers were studied in the formalin model of inflammation. The responses of convergent dorsal horn neurones after the subcutaneous injection of formalin (5% formaldehyde, 50 microliters volume) were recorded extracellularly in rats under halothane anaesthesia. Administration of the L-type calcium channel blocker verapamil, 5 and 50 micrograms, before formalin injection had no effect on either the first or second phase of the formalin response. Pre-treatment with the N-type calcium channel blocker omega-Conotoxin-GVIA, 0.1 and 0.4 microgram, reduced both phases of the formalin response. The low dose of omega-Conotoxin-GVIA significantly inhibited the first phase response whereas the high dose significantly reduced the second phase. Pre-treatment with the P-type calcium channel blocker omega-Agatoxin-IVA, 0.125 and 0.5 microgram, did not cause a significant inhibition of the first phase whereas a marked dose-related reduction in the second phase of formalin response was found with the high dose producing 95% inhibition. These results demonstrate that spinal N- and P-type, but not L-type, VSCCs are involved in the inflammation-evoked hyperexcitability of dorsal horn neurones after peripheral formalin injection. Since selective antagonists for each type of VSCC had differential effects on the formalin response, it is suggested that each type of VSCC could be preferentially regulating or coupled to the release of certain neurotransmitters in the enhanced nociceptive transmission at the spinal level following formalin inflammation.
Pain 1997 Jan
PMID:Blockade of spinal N- and P-type, but not L-type, calcium channels inhibits the excitability of rat dorsal horn neurones produced by subcutaneous formalin inflammation. 906 18

We previously reported that beta-endorphin and morphine administered supraspinally produce antinociception by activating different descending pain-inhibitory systems. To determine the role of spinal calcium channels, calmodulin and calcium/calmodulin-dependent protein kinase II in the production of antinociception induced by morphine, [D-Ala2,N-MePhe4,Gly-ol5]-enkephalin (DAMGO) or beta-endorphin administered supraspinally, the effects of nimodipine (an L-type calcium channel blocker), omega-conotoxin GVIA (an N-type voltage-dependent calcium channel blocker), calmidazolium (a calmodulin antagonist) or KN-62 (a calcium/calmodulin-dependent protein kinase II inhibitor) injected intrathecally (i.t.) on the antinociception induced by morphine, DAMGO or beta-endorphin administered intracerebroventricularly (i.c.v.) were examined in the present study. Antinociception was assessed by the mouse tail-flick test. The i.t. injection of nimodipine (from 0.024 to 2.4 pmol), omega-conotoxin GVIA (from 0.0033 to 0.33 pmol), calmidazolium (from 0.0015 to 0.15 pmol) or KN-62 (from 0.0014 to 0.14 pmol) alone did not affect the basal tail-flick latencies. The i.t. pretreatment of mice with nimodipine, omega-conotoxin GVIA, calmidazolium or KN-62 dose dependently attenuated the inhibition of the tail-flick response induced by beta-endorphin administered i.c.v. However, the inhibition of the tail-flick response induced by morphine or DAMGO administered i.c.v. was not changed by i.t. pretreatment with nimodipine, omega-conotoxin GVIA, calmidazolium or KN-62. The results suggest that spinally located L- and N-type calcium channels, calmodulin and calcium/calmodulin-dependent protein kinase II may be involved in the modulation of antinociception induced by beta-endorphin, but not morphine and DAMGO, administered supraspinally.
 ...
PMID:Differential effects of omega-conotoxin GVIA, nimodipine, calmidazolium and KN-62 injected intrathecally on the antinociception induced by beta-endorphin, morphine and [D-Ala2,N-MePhe4,Gly-ol5]-enkephalin administered intracerebroventricularly in the mouse. 926 64

High voltage calcium channels are implicated in nociceptive transmission after nerve injury, capsaicin or formalin injection. The purpose of this study was to investigate the role of calcium channels in secondary heat hyperalgesia associated with acute joint inflammation. After induction of acute inflammation (knee joint injection of kaolin and carrageenan), decreased paw withdrawal latency (PWL) to radiant heat (i.e., secondary heat hyperalgesia), increased guarding of the limb and increased joint circumference occurs. Spinal administration (through a microdialysis fiber placed in dorsal horn) of an N-type calcium channel blocker (MVIIA, SNX 111, ziconotide, 0.001-0.1 mM), before induction of inflammation, prevents the decrease in PWL. Treatment with SNX 111 4 hr after inflammation reverses heat hyperalgesia. A small reduction in spontaneous pain-related behaviors (guarding of the limb) occurs after pre- or post-treatment with SNX 111. Spinal blockade of P/Q-type calcium channels (with omega-agatoxin IVA) had no effect on the decrease in PWL to radiant heat when administered after induction of inflammation. However, pre-treatment with omega-agatoxin IVA prevents secondary heat hyperalgesia. omega-Agatoxin IVA has no effect on spontaneous pain-related behaviors whether administered before or after induction of inflammation. In contrast, pre or post-treatment with nifedipine (L-type calcium channel blocker, 0.01-1.0 mM), had no effect on heat hyperalgesia or spontaneous pain-related behaviors induced by acute inflammation. There were no differences in joint circumference between groups with any treatment. Thus, N-type calcium channels contribute to both the development and maintenance of secondary heat hyperalgesia while P-type calcium channels are only involved during development of hyperalgesia.
 ...
PMID:Blockade of N- and P/Q-type calcium channels reduces the secondary heat hyperalgesia induced by acute inflammation. 976 42

The neuropeptide calcitonin gene-related peptide (CGRP) is expressed by one-third of adult rat lumbar dorsal root ganglion (DRG) neurons, many of which mediate pain sensation or cause vasodilation. The factors that regulate the developmental expression of CGRP are poorly understood. Embryonic DRG neurons initially lack CGRP. When these neurons were stimulated in culture by serum or persistent 50 mM KCl application, the same percentage of CGRP-immunoreactive (CGRP-IR) neurons developed in vitro as was seen in the adult DRG in vivo. The addition of the L-type calcium channel blockers, 5 microM nifedipine or 10 microM verapamil, dramatically decreased the proportion of CGRP-IR neurons that developed, although the N-type calcium channel blocker, 2.5 microM omega-conotoxin, was less effective. By contrast, the sodium channel blocker 1 microM tetrodotoxin had no effect on CGRP expression after depolarization. Fura-2 ratiometric imaging demonstrated that mean intracellular free calcium levels increased from 70 to 135 nM with chronic depolarization, and the addition of nifedipine inhibited that increase. Only a subpopulation of neurons had elevated calcium concentrations during chronic depolarization, and they were correlated with CGRP expression. Key signal transduction pathways were tested pharmacologically for their role in CGRP expression after depolarization; the addition of the CaM kinase inhibitor KN-62 reduced the proportion of CGRP-IR neurons to basal levels. By contrast, protein kinase A and protein kinase C were not implicated in the depolarization-induced CGRP increases. These data suggest that depolarization and the subsequent Ca2+-based signal transduction mechanisms play important roles in the de novo expression of CGRP by specific embryonic DRG neurons.
 ...
PMID:Depolarization stimulates initial calcitonin gene-related peptide expression by embryonic sensory neurons in vitro. 980 68

Ion channels can be divided in two main groups, receptor-operated channels (ROC) and voltage-operated channels (VOC). The function of ROC depends on the action of agonists and antagonists, the function of VOC is closely connected with the activity of enzymes and the processes of phosphorylation of membrane proteins. Electrophysiological studies indicate the existence of three types of VOC (K+, Na+, Ca2+ channels). In number of neurons various subtypes of Ca2+ channels (P, T, N and L-type) occur together. Among them, the L-type Ca2+ channel has been first described and most studied. The L-type calcium channel is localized on nerve terminals in the pre- and postsynaptic parts, as well as on cell bodies and may be involved in the mechanism of action of psychotropic drugs. Our own experiments have shown that chronic treatment with various psychotropic drugs changes the density of L-type Ca2+ channels in the central nervous system. We have found the involvement of L-type VOC in responsiveness to pain, morphine tolerance and dependence, and adaptation changes induced by several chronic administration of psychotropic drugs. Thus, according to pharmacological and also clinical data, L-type Ca2+ channels may be involved in etiology of variety of psychiatric disorders.
 ...
PMID:Voltage-operated calcium channels: characteristics and their role in the mechanism of action of psychotropic drugs. 1042 48

Although an increase in the excitability and ectopic spontaneous discharge (ESD) of primary sensory neurons can lead to abnormal burst activity, which is associated with neuropathic pain, the underlying molecular mechanisms are not fully understood. To investigate the relationship between these electrical abnormalities in injured neurons and voltage-gated calcium channel (VGCC) gene expression, reverse transcription-polymerase chain reaction (RT-PCR) was used to monitor the expression of the VGCC alpha(1) gene in the dorsal root ganglion (DRG) following chronic constriction injury (CCI) and axotomy of the rat sciatic nerve. Electrophoresis of the RT-PCR products showed the presence of multiple types of VGCC alpha(1) transcripts with various levels of basal expression in lumbar 4, 5, and 6 DRGs. CCI decreased alpha(1C), alpha(1D), alpha(1H), and alpha(1I) mRNA expression at 7 days in the ipsilateral DRG, to approximately 34-50% of the contralateral side. The same transcripts were repressed 7 days after sciatic axotomy and their reduction levels proved similar to those of CCI. Considering that changes of the intracellular calcium concentration modify the maintenance of ESD in injured DRG, these results suggest that the downregulation of alpha(1C), alpha(1D), alpha(1H) and alpha(1I) subunit gene expression in the rat DRG following peripheral nerve injury may contribute to the production of ESD associated with damaged nerves.
 ...
PMID:Changes in voltage-gated calcium channel alpha(1) gene expression in rat dorsal root ganglia following peripheral nerve injury. 1173 Oct 20

Cortical spreading depression (CSD) may be the underlying mechanism of migraine aura. The role of CSD in initiating a migraine headache remains to be determined, but it might involve specific changes in gene expression in the brain. To examine these changes, four episodes of CSD at 5-minute intervals were induced in the mouse brain by application of 300mM KCl, and gene expression was examined 2 hours later using cDNA array and reverse transcriptase-polymerase chain reaction. Controls consisted of groups that received anesthesia only, attachment of recording electrodes only, and application of 0.9% NaCl. Of the over 1,180 genes examined in our experiments, those consistently regulated by CSD included vasoactive peptides; the vasodilator atrial natriuretic peptide was induced by CSD, while the vasoconstrictor neuropeptide Y was downregulated. Other genes specifically regulated by CSD were involved in oxidative stress responses (major prion protein, glutathione-S-transferase-5, and apolipoprotein E). L-type calcium channel mRNA was upregulated. In summary, CSD regulates genes that are intrinsic to its propagation, that identify accompanying vascular responses as a potential source of pain, and that protect against its potential pathological consequences. We believe these observations have strong relevance to the mechanisms of migraine and its outcomes.
 ...
PMID:Cortical spreading depression and gene regulation: relevance to migraine. 1192 Oct 56


1 2 3 4 5 6 7 8 9 Next >>