UMLS:C0344307 - FACTA Search

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Query: UMLS:C0344307 (analgesia)
28,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This is the first report showing, in an in vivo study, that systemic morphine produced a marked (89%, P < 0.01) increase of the cholecystokinin octapeptide (CCK-8) immunoreactivity in the perfusate of the rat spinal cord, an effect completely reversed by naloxone. Since CCK-8 has been shown to possess potent anti-opioid activity at a spinal level, a blockade of the spinal cholecystokinin effect would be expected to potentiate opiate analgesia. With tail flick latency as a nociceptive index, it was found that intrathecal (i.t.) injection of a novel CCKB antagonist L-365,260 produced a marked potentiation of the analgesic effect induced by the mu-opioid agonists morphine (4 mg/kg s.c.) or ohmefentanyl (32 ng i.t.). Similar effects were obtained with the CCKA antagonist devazepide at a dose 40-50 times higher than that of L-365,260. Both devazepide and L-365,260 showed a bell-shaped dose-response curve. The results confirm the notion that an increased release of CCK-8 may constitute a self-limiting process for opioid effects at the spinal level, and that it is the CCKB receptor which mediates the anti-opioid effect of CCK-8 in the rat spinal cord.
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PMID:Increased release of immunoreactive cholecystokinin octapeptide by morphine and potentiation of mu-opioid analgesia by CCKB receptor antagonist L-365,260 in rat spinal cord. 838 8

Cholecystokinin octapeptide (CCK-8) in CNS has been shown to function as a neuropeptide with potent anti-opioid activity. It hinders opioid analgesia and facilitates opioid tolerance. The present study showed that electroacupuncture (EA) stimulation produced a marked increase of the CCK-8 immunoreactivity (ir) in the perfusate of the rat spinal cord. The increase of CCK-8-ir was most marked in response to EA of 100 Hz and 15 Hz, and less marked in response to EA of 2 Hz. Since CCK-8 has been shown to possess potent anti-opioid activity at the spinal level, blockade of the spinal CCK effect would be expected to potentiate EA-induced analgesia which is known to be opioid-mediated. Intrathecal (i.t.) administration of CCK-B antagonist L-365,260 per se did not affect tail flick latency (TFL) to any significant extent, yet it potentiated EA induced analgesia in a dose- and frequency-dependent manner. The potentiation was most marked at a dose range of 2.5-5.0 ng (i.t.) and at a frequency rank order of 100 Hz > 15 Hz > 2 Hz. The results suggest that an increased release of CCK-8 following EA may limit the effect of opioid peptides, and that the CCK-B receptor mediates the anti-opioid effect of CCK-8 in rat spinal cord.
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PMID:Increased release of immunoreactive CCK-8 by electroacupuncture and enhancement of electroacupuncture analgesia by CCK-B antagonist in rat spinal cord. 847 32

1. Cholecystokinin (CCK) has been shown to diminish opioid analgesia. Here we investigate whether changes in the physiological levels of spinal CCK are responsible for the enhanced potency of spinal morphine in animals following carrageenin inflammation, as compared with normal animals. 2. Single dorsal horn nociceptive neurones were recorded in intact halothane-anaesthetized rats in the presence and absence of carrageenin-induced inflammation and comparisons were made between the two groups of animals. Inflammation was induced by the injection of 100 microliters of 2% lambda-carrageenin into the hind paw. 3. The inhibitory effect of intrathecal morphine on the C-fibre-evoked responses of the neurones was enhanced in the carrageenin-treated animals such that the effects of 0.25 microgram and 10 micrograms of morphine in normal animals were comparable to those of 0.01 microgram and 2.5 micrograms in the carrageenin animals. The effect of 0.2 mg kg-1 of the CCKB antagonist, L-365,260, on the antinociceptive potency of intrathecal morphine was examined in both groups of animals. In normal animals, L-365,260 produced a significant enhancement in the effect of morphine indicating a tonic CCK modulation in these animals, but it had no effect on the inhibitions produced by either dose of morphine in the carrageenin animals. 4. The inhibition of the C-fibre-evoked response produced by intrathecal morphine in the presence of 1 microgram of CCK was examined in both groups of animals. CCK attenuated the effects of morphine only in animals with carrageenin inflammation, having no effect on the action of morphine in normal animals. 5. The effects of both CCK and L-365,260 were therefore dependent on the inflammatory state of the animal, with each drug being active in opposite situations.6. We propose that in normal animals, morphine may produce a maximal stimulation of the release of CCK such that exogenous CCK is unable to reduce further the analgesic effects under these conditions.However, the differential effects of the agonist and antagonist in the normal and inflamed rats points to a role of CCK in the enhanced opiate actions. This enhancement of the potency of spinal morphine in inflammation is best explained by a reduction in spinal CCK release by morphine in this state.
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PMID:Cholecystokinin as a factor in the enhanced potency of spinal morphine following carrageenin inflammation. 848 35

The interaction between morphine and L740,093, a newly developed highly potent antagonist of cholecystokinin-B receptors, was examined in electrophysiological and behavioural studies. Intravenous L740,093 at 0.01 mg/kg had no effect on its own, but significantly potentiated the depressive effect of 1 mg/kg morphine on the nociceptive flexor reflex in decerebrate, spinalized rats. Similarly, subcutaneous L740, 093 at 0.03 mg/kg significantly prolonged the duration of antinociception induced by 10 mg/kg morphine in the rat hotplate test. A bell shaped dose-response curve was noted in the behavioural studies with respect to the interaction between L740,094 and morphine. L740,093, which has excellent CNS penetration, may represent a new tool in studying the involvement of the endogenous cholecystokinin system in the modulation of opioid analgesia and in exploring novel analgesics.
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PMID:L-740,093, a new antagonist of the CCK-B receptor, potentiates the antinociceptive effect of morphine: electrophysiological and behavioural studies. 877 63

Discovery of the involvement of endogenous opiates in placebo analgesia represents an important step in understanding the mechanisms underlying placebo response. In the present study, we investigated the effects of the opiate antagonist naloxone and the cholecystokinin antagonist proglumide on placebo analgesia in a human model of experimentally induced ischemic pain. First, we found that part of the placebo response was reversed by naloxone, confirming previous studies on the role of opioids in the placebo phenomenon. Second, since it was demonstrated that the action of exogenous and endogenous opiates is potentiated by proglumide, we analysed the effects of this cholecystokinin antagonist on placebo response and found that it enhanced placebo analgesia. The placebo effect can thus be modulated in two opposite directions: it can be partially abolished by naloxone and potentiated by proglumide. The fact that placebo potentiation by proglumide occurred only in placebo responders, but not in non-responders, suggests that activation of an endogenous opiate system is a necessary condition for the action of proglumide. These results suggest an inhibitory role for cholecystokinin in placebo response, although the low affinity of proglumide for cholecystokinin receptors does not rule out the possibility of other mechanisms.
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PMID:The opposite effects of the opiate antagonist naloxone and the cholecystokinin antagonist proglumide on placebo analgesia. 878 19

Using the mouse caudate-putamen, where delta-opioid receptor subtypes have been shown to regulate adenylyl cyclase activity, we show in this study that endogenous enkephalins inhibit enzyme activity through activation of delta 1- and delta 2-opioid receptors. Thus, naltriben or 7-benzylidenenaltrexone as well as the delta-selective antagonist naltrindole (mixed delta 1 and delta 2 antagonist) antagonized inhibition of adenylyl cyclase activity induced by methionine- or leucine-enkephalin, while the micro-antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) was without effect. Furthermore, we have previously shown that activation of delta-opioid receptors increases cholecystokinin release in the central nervous system, resulting in a potentiation of micro-opioid antinociceptive responses, and the respective role of delta 1- and delta 2-opioid receptors in this facilitatory effect has now been evaluated. Activation of delta 2-opioid receptors, either by endogenous enkephalins protected from catabolism by the complete enkephalin-degrading enzyme inhibitor N-((R,S)-2-benzyl-3((S)(2-amino-4-methyl-thio) butyldithio)-1-oxopropyl)-L-phenyl-alanine benzyl ester (RB 101), or by the delta 2-selective agonist Tyr-D-Ser(O-tert-butyl)-Gly-Phe-Leu-Thr(O-tert-butyl) (BUBU), potentiated micro-opioid antinociceptive responses in the hot-plate test in mice. This effect was antagonized by a selective cholecystokinin-A antagonist. Activation of delta 1-opioid receptors by endogenous opioid peptides decreased the micro-opioid responses. These results suggest that stimulation of delta 2-opioid receptors potentiates micro-opioid analgesia in the hot-plate test in mice through an increase in endogenous cholecystokinin release, while activation of delta 1-opioid receptors could decrease it. Thus, the pre-existing physiological balance between opioid and cholecystokinin systems seems to be modulated in opposite directions depending on whether delta 1- or delta 2-opioid receptors are selectively activated. This is the first demonstration that endogenous enkephalins, methionine- and leucine-enkephalin, are the natural ligands of delta-opioid receptor subtypes, and that delta 2-opioid receptor activation may facilitate the endogenous cholecystokinin-related modulation of micro-opioid analgesia, while the delta 1-opioid receptors may have an inhibitory role. These results could have important applications for the characterization of opioid delta 1 and delta 2 as subtypes or subsites and in pain alleviation.
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PMID:Opposite role of delta 1- and delta 2-opioid receptors activated by endogenous or exogenous opioid agonists on the endogenous cholecystokinin system: further evidence for delta-opioid receptor heterogeneity. 895 84

After suffering some setbacks since its introduction in 1967, stimulation of the spinal and peripheral nervous systems has undergone rapid development in the last ten years. Based on principles enunciated in the Gate Control Hypothesis that was published in 1968, stimulation-produced analgesia [SPA] has been subjected to intensive laboratory and clinical investigation. Historically, most new clinical ideas in medicine have tended to follow a three-tiered course. Initial enthusiasm gives way to a reappraisal of the treatment or modality as side-effects or unanticipated problems arise. The last and third phase proceeds at a more measured pace as the treatment is refined by experience. This review is divided into three parts as it traces the progress of spinal cord stimulation [SCS] and peripheral nerve stimulation [PNS]. The review commences with a discussion of the theory of SCS and PNS, and is followed by early reports during which it became apparent that the modality is essentially only effective in the treatment of neuropathic pain. The last section describes the modern experience including efficacy in specific types of pain and concludes with recent accomplishments that dramatize the relief of pain which can be achieved in nonoperable peripheral vascular disease or myocardial ischemia. Over the years, a search for those transmitters that might be influenced by spinal cord stimulation focused on somatostatin, cholecystokinin (CCK), vasoactive intestinal polypeptide (VIP), neurotensin and other amines, although only substance "P" was implicated. More recently, in animal studies, evidence that GABA-ergic systems are affected may explain the frequent successful suppression of allodynia that follows spinal cord stimulation. During the past eight years, much attention has been directed to studies that use a chronic neuropathic pain model. While PNS held significant promise as a pain relieving modality, early electrode systems and their surgical implantation yielded variable results due to evolving technical and surgical skills. These results dramatically reduced the continued development of PNS, which then gave way to a preoccupation with SCS. Modern development of SCS with outcome studies, particularly in relation to failed back surgery syndrome [FBSS] and the outcome of peripheral nerve surgery for chronic regional pain syndromes, has earned both modalities a place in the ongoing management of patients with intractable neuropathic pain. The last section, dealing with pain of peripheral vascular and myocardial ischemia, is perhaps one of the more exciting developments in stimulation produced analgesia and as the papers discussed demonstrate, can provide a level of analgesia and efficacy that is unattainable by other treatment modalities. SCS and PNS has an important role to play in the management of conditions that are otherwise refractory to conservative or other conventional management.
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PMID:Stimulation of the central and peripheral nervous system for the control of pain. 901 59

Using the P77PMC strain of rat, which is genetically prone to audiogenic seizures, and also has decreased levels of cholecystokinin (CCK), we examined the analgesic response to peripheral electrical stimulation, which is, in part, opiate-mediated. A number of studies have suggested that CCK may function as an antagonist to endogenous opiate effects. Therefore, we hypothesized that the P77PMC animals would show an enhanced analgesic response based on their decreased CCK levels producing a diminished endogenous opiate antagonism. We found that the analgesic effect on tail flick latency produced by 100 Hz peripheral electrical stimulation was more potent and longer lasting in P77PMC rats than in control rats. Moreover, the potency of the stimulation-produced analgesia correlated with the vulnerability to audiogenic seizures in these rats. We were able to block the peripheral electrical stimulation-induced analgesia (PSIA) using a cholecystokinin octapeptide (CCK-8) administered parenterally. Radioimmunoassay showed that the content of CCK-8 in cerebral cortex, hippocampus and periaqueductal gray was much lower in P77PMC rat than in controls. These results suggest that low CCK-8 content in the central nervous system of the P77PMC rats may be related to the high analgesic response to peripheral electrical stimulation, and further support the notion that CCK may be endogenous opiate antagonist.
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PMID:Rats with decreased brain cholecystokinin levels show increased responsiveness to peripheral electrical stimulation-induced analgesia. 903 5

To evaluate the potential for lipofectin-mediated central nervous system gene transfer, the plasmid coding for cholecystokinin was administered intracerebroventricularly to rats, which have congenital audiogenic seizures and high responses to peripheral electric stimulation-induced analgesia. Previous studies had shown that low brain cholecystokinin levels may be the neurochemical variable of rat's audiogenic seizure and high responses to the analgesia because cholecystokinin is an anticonvulsant and anti-opioid neuropeptide. Gene transfer of cholecystokinin corrected the increased susceptibility to audiogenic seizures and the high responses to analgesia for about one week. Similar administration of plasmid expressing beta-galactosidase indicated that the vector mainly transfected ependymal cells lining the ventricle and pia mater cells. The increased cholecystokinin messenger RNA and immunoreactivity in the hippocampus following stereotactic intrahippocampal administration of cholecystokinin plasmid was also demonstrated with in situ hybridization and immunohistochemistry techniques. These results suggest that lipofectin-mediated gene transfer will be useful for studies of brain function, the modification of behavior and gene therapy for central nervous system disorders.
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PMID:Lipofectin-facilitated transfer of cholecystokinin gene corrects behavioral abnormalities of rats with audiogenic seizures. 904 70

Certain types of cancer pain fail to respond well either to systemic drug therapy or to spinal opioids because of the occurrence of intolerable adverse effects. In addition to spinal opioids other drugs may produce an antinociceptive effect when administered by the spinal route, such as local anesthetics, NSAID, alpha 2-agonists, calcium-channel blockers, NMDA antagonists, cholinergic drugs, peptides such as somatostatin, octreotide or calcitonin, adenosine agonists, benzodiazepines, neurokinin and cholecystokinin antagonists, nitric oxide synthase inhibitors, corticosteroids, and enkephalinase inhibitors. All these drugs may be administered in combination between them, realising the so called balanced spinal analgesia. The aim of this study is to analyse: the available methods for the evaluation of pharmacological interactions, the types of interaction between different spinal antinociceptive drugs and the role of balanced spinal analgesia in the treatment of cancer pain. Analysis of the presented data shows that the spinal synergism between opioids-local anesthetics and opioids-alpha 2-agonists can be useful in the treatment of opioid refractory cancer pain. Furthermore, the use of cholinergic drugs combined with opioids and alpha 2-agonists may be promising. Finally, even if the synergism between NSAID or NMDA antagonists with opioids or alpha 2-agonists have been proved, at the moment their use in man by the spinal route is not advisable because of the absence of adequate studies on their neurotoxicity and adverse effects.
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PMID:[Balanced spinal analgesia in the treatment of oncologic pain. Review of the literature]. 910 86

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