Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0344307 (analgesia)
 28,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent reports demonstrated that K+ channels could contribute to signal transmission in the brain and spinal cord, and opioids' action may be related to K+ channels' functions. We investigated the antinociceptive effect of epidurally injected ATP-sensitive K+ channel opener, nicorandil, using tail flick test in rats. Epidural nicorandil (100 micrograms.rat-1) increased % maximum possible effect (%MPE) of epidural morphine (1, 10 micrograms.rat-1) from -3% to 40% (P < 0.05) and 46% to 65%, respectively. Epidural glibenclamide (10 micrograms.rat-1), ATP-sensitive K+ channel blocker, antagonized this effect. Epidural nicorandil alone (10 approximately 100 micrograms.rat-1) showed no antinociceptive effects. Systemic nicorandil (100 micrograms.rat-1, i.m.) did not increase the epidural morphine analgesia. These data suggest that the K+ channel opener could point the way to a new approach to pain treatment.
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PMID:[Nicorandil, as ATP-sensitive K+ channel opener, potentiated morphine analgesia]. 895 67

1. The effect of the administration of pertussis toxin (PTX) as well as modulators of different subtypes of K+ channels on the antinociception induced by clonidine and guanabenz was evaluated in the mouse hot plate test. 2. Pretreatment with pertussis toxin (0.25 microg per mouse i.c.v.) 7 days before the hot-plate test, prevented the antinociception induced by both clonidine (0.08-0.2 mg kg(-1), s.c.) and guanabenz (0.1-0.5 mg kg(-1), s.c.). 3. The administration of the K(ATP) channel openers minoxidil (10 microg per mouse, i.c.v.), pinacidil (25 microg per mouse, i.c.v.) and diazoxide (100 mg kg(-1), p.o.) potentiated the antinociception produced by clonidine and guanabenz whereas the K(ATP) channel blocker gliquidone (6 microg per mouse, i.c.v.) prevented the alpha2 adrenoceptor agonist-induced analgesia. 4. Pretreatment with an antisense oligonucleotide (aODN) to mKv1.1, a voltage-gated K+ channel, at the dose of 2.0 nmol per single i.c.v. injection, prevented the antinociception induced by both clonidine and guanabenz in comparison with degenerate oligonucleotide (dODN)-treated mice. 5. The administration of the Ca2+-gated K+ channel blocker apamin (0.5-2.0 ng per mouse, i.c.v.) never modified clonidine and guanabenz analgesia. 6. At the highest effective doses, none of the drugs used modified animals' gross behaviour nor impaired motor coordination, as revealed by the rota-rod test. 7. The present data demonstrate that both K(ATP) and mKv1.1 K+ channels represent an important step in the transduction mechanism underlying central antinociception induced by activation of alpha2 adrenoceptors.
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PMID:Role of potassium channels in the antinociception induced by agonists of alpha2-adrenoceptors. 1020 11

Potassium (K(+)) channels may play some role in the analgesic actions of mu-opioid agonists and alpha(2)-adrenergic agonists (alpha(2) agonists). We examined whether the adenosine triphosphate-sensitive K(+)(K(+)(ATP)) channel openers, levcromakalim and nicorandil, (given epidurally), might have antinociceptive effects in a tail flick test in adult male Sprague-Dawley rats implanted with a lumbar epidural catheter. The interactions with morphine and an alpha(2) agonist were also examined. The epidural administration of levcromakalim (10 microg, 100 microg) or nicorandil (10 microg, 100 microg) alone did not produce antinociception, but 100 microg levcromakalim or nicorandil did potentiate the antinociceptive effect induced by epidural morphine. Epidural glibenclamide (10 microg), a K(+)(ATP) channel blocker, or naloxone (10 microg) antagonized this potentiation. Systemic administration of levcromakalim or nicorandil (at the same dose as that given into the epidural space) did not potentiate the epidural morphine-induced analgesia. A combination of epidural dexmedetomidine (1 microg) and morphine (1 microg) (each at a subantinociceptive dose) had a significant antinociceptive effect, and epidural glibenclamide (10 microg) partly antagonized this antinociception. These data suggest that levcromakalim and nicorandil potentiate the analgesic action of both morphine and dexmedetomidine, probably via an activation of K(+)(ATP) channels at the spinal cord level.
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PMID:Antinociceptive action of epidural K+(ATP) channel openers via interaction with morphine and an alpha(2)- adrenergic agonist in rats. 1078 69

We found that spinorphin, a novel neuropeptide showed analgesia in a different manner compared with morphine. By measuring flexor responses induced by the intraplanter injection of substances, the presence of three different types of sensory neurons were demonstrated. Although spinorphin completely blocked 2-metylthioadenosine (2-MeS ATP, a P2X(3) agonist)-induced responses, morphine did not. On the other hand, morphine-induced blockade of bradykinin (BK, a B(2)-receptor agonist)-responses was attenuated by pertussis toxin (PTX) treatment, whereas that of spinorphin was not. Thus it is suggested that spinorphin has a spectrum of analgesia which covers the blockade of nociception insensitive to morphine.
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PMID:Complete inhibition of purinoceptor agonist-induced nociception by spinorphin, but not by morphine. 1103 8

We have previously observed that, while acute stress induces analgesia, chronic stress causes a hyperalgesic response in male rats. No effect was observed in females. There is increasing evidence that both ATP and adenosine can modulate pain. Extracellular ATP and ADP are hydrolyzed by an apyrase in synaptosomes from the peripheral and central nervous systems. In the present study, we investigated the effect of chronic and acute stress on ATPase-ADPase and 5'-nucleotidase activities in spinal cord of male and female rats. Adult male and female Wistar rats were submitted to 1 h restraint stress/day for 1 day (acute) or 40 days (chronic) and were sacrificed 24 h later. ATPase-ADPase activities were assayed in the synaptosomal fraction obtained from the spinal cord of control and stressed animals. ADP hydrolysis was decreased 25% in chronically stressed males, while no change was observed on ATPase activity. There was an increase in the 5'-nucleotidase activity in the same group. No effect on ADPase, ATPase or on 5'-nucleotidase activity was observed in females with chronic stress, or after acute stress neither in males or females. Chronic stress reduced ADP hydrolysis and increased 5'-nucleotidase activity in the spinal cord in male rats.
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PMID:Effect of chronic and acute stress on ectonucleotidase activities in spinal cord. 1189 Sep 46

Central and regional block procedures have a well-defined role as safe and effective methods in modern anesthesia and analgesia with long-acting local anesthetics. Recent studies have shown that the incidence of intoxication by these drugs is a rare but catastrophic event. As classic neuronal sodium channel inhibitors, local anesthetics block peripheral fast voltage-gated sodium channels on neuronal axons, and these drugs have a particularly high level of activity in the CNS and the cardiovascular system. CNS-toxicity follows a two-stage process, whereby at lower concentrations inhibitory neurons are blocked first resulting in generalized convulsions, and at higher concentrations a global CNS depression can be seen. Although seizures are an impressive clinical syndrome, they can often be treated safely without permanent damage. More important is the cardiotoxicity of these drugs, which can be divided into indirect cerebrally mediated and a direct myocardial component. Like CNS-toxicity in general, indirect cardiotoxicity demonstrates an initial stimulating effect, followed by a depressive component at higher concentrations. Direct myocardial actions are comprised of negative chronotropic, dromotropic and inotropic effects. For dromotropy, stereoselectivity was found. The S-(-)-isomers of the longacting local anesthetics were less delayed compared to racemic mixtures and the R-(+)-enantiomers. For inotropy, no stereospecific depression of this parameter was noted between isomers of ropivacaine or bupivacaine, but bupivacaine produced a significantly greater depression of LV pressure than ropivacaine, mepivacaine, or lidocaine. Pharmacokinetic differences in lipophilicity of local anesthetics correlate well with the depression mitochondrial ATP-synthesis in fast metabolizing cells. Intracellular ATP-level may be involved in contractility and resuscitation of cardiomyocytes, as be proven by in-vitro and in-vivo data. Therefore the use of pure optical S-(-)-isomers of local anesthetics may help to reduce these rare but catastrophic events. Presently, ropivacaine appears to be the safest long-acting local anesthetic.
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PMID:The cardiotoxicity of local anesthetics: the place of ropivacaine. 1189 38

The inhibitory effect of repetitiously administered loperamide, a peripheral mu-opioid receptor agonist and well-recognized antidiarrheal agent, on mouse gastrointestinal transit was compared with that of morphine in order to examine the development of tolerance to mu-opioid receptor agonist-induced constipation (antitransit effect). When administered subcutaneously 15 min before the oral injection of charcoal meal, loperamide (0.1-30 mg/kg) and morphine (1-8 mg/kg) dose-dependently and significantly inhibited gastrointestinal transit of charcoal with the ID(50) values of 1.6 (0.3-7.1) mg/kg and 3.6 (1.5-8.5) mg/kg, respectively. When loperamide (30 mg/kg) was administered twice daily for 2 days, the antitransit effect was significantly reduced. On the other hand, morphine did not develop tolerance in even more severe conditions than those of loperamide. It is known that P-glycoprotein, an ATP-dependent drug efflux pump, is involved in the development of tolerance to morphine analgesia. The tolerance observed with loperamide was significantly prevented by cyclosporin (30 mg/kg, i.p.), a P-glycoprotein inhibitor, thus the ID(50) value in loperamide-tolerant mice was markedly reduced from >1000 mg/kg to 40 (2.7-603.0) mg/kg by cyclosporin. These results indicate that loperamide, different from morphine, readily develops tolerance to the inhibitory effect on mouse gastrointestinal transit, and the P-glycoprotein may be involved in the development of tolerance to the antitransit effect of loperamide.
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PMID:Development of tolerance to the inhibitory effect of loperamide on gastrointestinal transit in mice. 1459 2

Kyotorphin (Kyo) is synthesized in specific brain regions where it may modulate synaptic transmission. Kyo directly excites cortical neurons, and indirectly exerts opioid actions to produce analgesia via the release of [Met]-enkephalin. Kyo is formed by a specific enzyme from L-tyrosine, L-arginine (L-arg) and ATP in the presence of Mg2+. Kyo and its analogues Tyr-cav and Tyr(Cl2)-cav exert naloxone-reversible antinociception in the paw-pressure test. The aim of the present study was to investigate the effect of D-arginine (D-arg) on the analgesic effects of Kyo, Tyr-cav and Tyr(Cl2)-cav during acute pain. The changes in the nociceptive effects were examined in male Wistar rats using the tail flick (TF) and hot plate (HP) tests. Kyo, Tyr-cav, Tyr(Cl2)-cav, L-canavanine (L-cav) and D-arg were applied in rats intracerebroventricularly (i.c.v.) at a dose of 20 microg/20 microl. Kyo, Tyr-cav, Tyr(Cl2)-cav and L-cav exerted antinociceptive activity in both tests used. Applied alone, D-arg had no antinociceptive activity in TF and HP tests. D-arg decreased the TF and HP latency of the Kyo, Tyr-cav, Tyr(Cl2)-cav and L-cav. Taken together, these results reveal D-arg as a potential inhibitor of the investigated peptides during acute pain.
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PMID:Effect of D-arginine on antinociception induced by kyotorphin, Tyr-cav, L-cav and Tyr(Cl2)-cav in rats. 1531 11

Opioids are commonly used analgesics in clinical practice. Three opioid receptors (mu, delta and kappa) that mediate opioid effects have been identified by molecular cloning. Each type of opioid receptors consists of subtypes of receptors as suggested by pharmacological studies. Although mu opioid receptors are the major receptor to mediate the analgesic effects of opioids, delta and kappa receptors are also important in anti-nociception (for example, delta and kappa receptors can mediate spinal analgesia). Recently, the cytoprotective effects of opioids have been recognized. The presence of opioids during harmful events such as ischemia reduces cell injury in multiple organs including heart and brain. These effects appear to be mediated by delta receptors in most studies. A new form of cytoprotection in which a prior exposure to opioids renders protection against cell ischemia (opioid preconditioning) has been identified. In the heart, this opioid preconditioning-induced protection has been well documented by multiple studies and may be mediated by delta receptors, G(i/o) proteins, protein kinase C, ATP-sensitive potassium channels and free radicals. Our initial study suggests that opioid preconditioning also induces neuroprotection. This neuroprotection involves delta(1) receptors, mitochondrial ATP-sensitive potassium channels and free radical production. In this review, we will briefly describe the analgesic effects of opioids. We will focus our discussion on opioid preconditioning-induced protection and its mechanisms. Opioids and agents that specifically work on the signaling molecules for opioid preconditioning-induced protection may prove to be useful in inducing protection against ischemia in clinical practice.
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PMID:Opioids: old drugs for potential new applications. 1585 89

In our previous work, we demonstrated that Trigonella foenum (TFG) leaves extract can exert analgesic effects in both formalin (F.T.) and tail flick (T.F.) tests. Spinal serotonergic system, but not endogenous opioid system, was involved in TFG induced analgesia (in the second phase of formalin test). Some reports concern the similarity between NSAIDs and TFG extract in many pharmacological effects or the interaction between NSAIDs and purinergic system; so the present study was designed to investigate the relationship between TFG extract and purinergic system or the inhibition of cyclo-oxygenase (COX). We examined the effect of TFG extract on: (1) the response of rabbit platelets to ADP induced aggregation, (2) the contraction of mouse vas deferens induced by alpha,beta-Me-ATP (a P(2) receptor agonist; this receptor mediates the rapid phase of ADP- and ATP-evoked influx of Ca(2+) through a non-specific cation channel in platelets), (3) alpha,beta-Me-ATP induced hyperalgesia in tail flick test in male rats and (4) the specific inhibition of COX-1 and COX-2. Our results showed that TFG extract (0.5, 1, 1.5, 3 mg/ml) inhibited ADP (10(-5) mol) induced platelet aggregation (IC(50)=1.28 mg/ml). alpha,beta-Me-ATP (30 microM) induced isometric contraction in vas deferens while suramin (a P(2) receptor antagonist, 50, 150, 300 microM) or TFG extract (0.5, 1, 2, 3 mg/ml) inhibited this effect significantly (IC(50) were 91.07 microM and 1.57 mg/ml, respectively). Moreover, alpha,beta-Me-ATP (3 microg/rat, i.t.) induced hyperalgesia in tail flick test, but it was prevented by co-injection of alpha,beta-Me-ATP with suramin (120 microg/rat, i.t.) or TFG extract (1mg/rat, i.t.). Effective concentrations of TFG extract in the above mentioned experiments did not inhibit COX enzymes in EIA tests. In conclusion, these results indicate that the blocking of spinal purinoceptors may contribute in the analgesic effect of TFG leaves extract.
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PMID:Probable role of spinal purinoceptors in the analgesic effect of Trigonella foenum (TFG) leaves extract. 1629 92


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