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)

Sulfated cholecystokinin octapeptide (CCK-8; Asp-Tyr-SO3H-Met-Gly-Trp-Met-Asp-Phe-NH2) produced analgesia in mice when administered i.c.v. and tested in the acetic acid-induced writhing assay. The ED50 was found to be 0.03 nmol/mouse which was about 3, 24 and 714 times more potent than morphine. [D-Pen2,D-Pen5]enkephalin and U50,488H [trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrolidinyl)cyclohexyl] benzeneacetamidel], respectively. When administered i.t., CCK-8 produced partial analgesia of up to 22 to 23% at low doses ranging from 15 to 60 ng/mouse and hyperalgesia at doses over 120 ng/mouse. Naloxone, an opioid antagonist, inhibited the analgesia induced by CCK-8 (i.c.v. and i.t.) but potentiated hyperalgesia induced by CCK-8 (i.t.). Apparent pA2 value for CCK-8 (i.c.v.) against naloxone (s.c.) was 5.88 which was significantly different from those for morphine-naloxone and U50,488H-naloxone but was not significantly different from that for [D-Pen2,D-Pen5]enkephalin-naloxone. Studies using highly selective opioid antagonists showed that CCK-8-induced analgesia was significantly antagonized by the delta receptor antagonist, ICI154,129 [(Allyl)2-Tyr-gly-gly-psi-(CH2S)-Phe-Leu] but not by beta-funaltrexamine, a highly selective mu receptor antagonist or nor-binaltorphimine, a highly selective kappa receptor antagonist. Opioid receptor binding study using [3H]-[D-Ala2,D-Leu5]enkephalin (+unlabeled [D-Ala2,MePhe4,Gly-ol5]enkephalin) in mouse brain membrane preparations revealed that there were no changes in the maximum binding or Kd of delta opioid binding sites in the presence of CCK-8 (1 microM) in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Indirect involvement of delta opioid receptors in cholecystokinin octapeptide-induced analgesia in mice. 255 28

The potential clinical utility of drug interactions between morphine and the cholecystokinin antagonist proglumide was examined in 80 postoperative patients suffering from moderate to severe pain. Four groups of ASA I-III patients (mean age 51 years, mean weight 72 kg) recovering from major abdominal or gynecological surgery (mean duration of surgery 141 minutes) performed under balanced anesthesia (midazolam, droperidol, fentanyl, N2O, enflurane) were randomly assigned to self-administer morphine-proglumide mixtures on the first postoperative day (ODAC; morphine demand dose 3 mg; infusion rate 0.36 mg/hr; lockout time 2 minutes; hourly maximum dose 15 mg/hr; proglumide doses per demand 0, 50 micrograms, 100 micrograms, or 50 mg). Morphine consumption, actual as well as retrospective pain scores (0-5) and side effects were evaluated. Mean duration of patient-controlled analgesia (PCA) in the subgroups was 17-19 hours, during which time 24.6 +/- 9.5 to 28.0 +/- 3.4 micrograms morphine.kg-1.hr-1 was given. There were no statistically significant differences between the groups either for drug consumption, pain scores, or side effects. It is therefore concluded that proglumide does not potentiate morphine analgesia in a clinical (postoperative) setting.
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PMID:Failure of proglumide, a cholecystokinin antagonist, to potentiate clinical morphine analgesia. A randomized double-blind postoperative study using patient-controlled analgesia (PCA). 264 68

Proglumide, an antagonist of cholecystokinin, has been shown to potentiate morphine analgesia in animal and human experimental pain models. This study was undertaken to determine whether proglumide enhances morphine analgesia for patients experiencing postoperative pain. At onset of pain after the removal of impacted third molars, patients (n = 60) received intravenously either 4 mg morphine, 8 mg morphine, or 4 mg morphine plus proglumide (0.05, 0.5, or 5 mg). The administration of 8 mg morphine significantly reduced pain, in comparison with baseline and 4 mg morphine, for the first 30 minutes. The addition of 0.05 mg proglumide resulted in a significant increase in the magnitude and duration of the analgesic activity of 4 mg morphine; 0.5 and 5.0 mg proglumide did not produce this effect. No difference was seen in respiratory rate or in the frequency of side effects among the various forms of treatment. These data indicate that a low dose of proglumide potentiates both the magnitude and the duration of morphine analgesia in a clinical model of acute pain, without any detectable increase in side effects.
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PMID:Proglumide potentiates morphine analgesia for acute postsurgical pain. 265 36

The effects of cholecystokinin octapeptide sulphated (CCK) and the potent CCK antagonist MK-329 (L-364, 718) on analgesia induced by morphine in the paw pressure test in the rat were examined. Both CCK (4-16 micrograms/kg) and MK-329 (0.1-8.0 mg/kg) had no significant effect on thresholds for pain when given alone, whereas morphine (2-16 mg/kg) induced dose-dependent analgesia. Cholecystokinin (4-16 micrograms/kg) abolished the analgesia induced by 8 mg/kg morphine. In contrast, doses of 1 and 2 mg/kg MK-329 enhanced the analgesia induced by 8 and 4 mg/kg morphine, respectively. The present data are consistent with previous reports that CCK blocks, and CCK antagonists enhance, opiate-induced analgesia in response to thermal pain stimuli. In addition, the results show that CCK/opiate interactions extend to mechanical pain stimuli. Recent ligand binding studies have shown that CCK receptors in the spinal cord of the rat (where CCK/opiate interactions are thought to occur) are predominantly of the CCK-B subtype. The drug MK-329 has a relatively weak (micromolar) affinity for CCK-B receptors and a high affinity (nanomolar) for CCK-A receptors. As relatively large doses (1-2 mg/kg) of MK-329 are required to enhance opiate-induced analgesia in the paw pressure test and tail flick test in rats it appears that CCK/opiate interactions in this species involve CCK-B receptors.
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PMID:Morphine-induced analgesia in the rat paw pressure test is blocked by CCK and enhanced by the CCK antagonist MK-329. 272 51

Intraperitoneally administered benzodiazepines, chlordiazepoxide (2-5 mg/kg), diazepam (1 mg/kg), flurazepam (1 mg/kg) and a benzodiazepine antagonist, Ro 15-1788 (0.5 mg/kg), reversed the antinociceptive effect in mice which was induced by intracisternal administration of 1 microgram of sulfated cholecystokinin octapeptide. The antinociceptive effect of cholecystokinin was reversed by naloxone, suggesting that the antinociceptive action involves endogenous opioid peptides in its production. On the other hand, morphine-induced analgesia was not reversed by diazepam and Ro 15-1788. These facts rule out opioid receptors as the site of the antagonism between the benzodiazepines or Ro 15-1788 and cholecystokinin on the antinociceptive effect. Benzodiazepines and Ro 15-1788 seem to inhibit the release of opioid peptides induced by cholecystokinin.
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PMID:Reversal of antinociceptive effect of cholecystokinin by benzodiazepines and a benzodiazepine antagonist, Ro 15-1788. 285 82

The recent discovery that cholecystokinin (CCK) is present in the nervous system has prompted studies that have nearly proven its neurotransmitter status. Pain modulation appears to be a major effect of CCK and proglumide, its antagonist. CCK's inhibitory effect and proglumide's potentiating effect on opiate analgesia may have clinical application; proglumide's inhibitory effect on opiate tolerance may help in management of chronic pain. More research is required before the CCK/opiate interaction can be exploited on a large scale to relieve pain.
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PMID:Cholecystokinin and pain: a review. 287 41

The central mechanism responsible for the potentiation by antidepressant drugs of analgesia induced by morphine, was explored by measuring the levels of various neuropeptides (met-enkephalin, leu-enkephalin, dynorphin, substance P and cholecystokinin-like materials) and the density of delta and mu opioid binding sites in the spinal cord of rats treated for 14 days with amoxapine (10 mg/kg i.p., daily) or amitriptyline (10 mg/kg i.p., daily). Similar measurements were made in the hypothalamus and cerebral cortex for comparison. Chronic treatment with amoxapine or amitriptyline did not affect the levels of dynorphin, substance P and cholecystokinin, but markedly enhanced the levels of leu-enkephalin in the three structures examined. The levels of met-enkephalin were also increased after treatment with amitriptyline but only in the spinal cord and hypothalamus. No changes in opioid receptors were found in the cerebral cortex, but the densities of delta and mu opioid binding sites were increased in the spinal cord, and decreased in the hypothalamus of rats treated with amoxapine or amitriptyline. These changes induced by antidepressants in opioidergic markers at the spinal level might account for the potentiation of the action of morphine in amoxapine- or amitriptyline-treated rats. In addition, the observed alterations in the same markers in the hypothalamus could be associated with changes induced by antidepressants in neuroendocrine regulation.
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PMID:Opioid receptors and neuropeptides in the CNS in rats treated chronically with amoxapine or amitriptyline. 303 21

Since the mid-1970s, evidence has accumulated that cholecystokinin (CCK) has a role as a neuromodulator or neurotransmitter in the central nervous system as well as in the periphery. CCK has been shown to have a variety of effects on gastrointestinal functions and is one of the main candidates for a role as a peripheral negative feedback signal to stop feeding behavior. CCK produces satiety not only in animals but also in man: it reduces appetite and activation arising from the preparation of a meal and inhibits intake of liquid and solid food in both lean and obese subjects. The closely related peptide caerulein has similar effects. The site of action of peripherally administered CCK seems to be on an abdominal organ innervated by gastric vagal branches and relayed to the brain by afferent vagal fibres, since selective gastric vagotomy blocks the satiety effect, but pharmacological antagonism of vagal motor effects or lesions of the ventromedial hypothalamus do not. CCK also may have a role in the regulation of pain perception. In mice, CCK and caerulein were shown to produce a decrement in response to noxious stimulation after peripheral and central administration. In man, caerulein was demonstrated to relieve pain originating from biliary and renal colic as well as from cancer and ischemia. A series of studies in healthy man revealed that caerulein also alleviates experimentally induced cutaneous pain. Data from animal studies suggest that CCK-like peptides not only are able to produce analgesic effects on their own, but also are involved in the modulation of opioid systems mediating analgesia. Further study of these effects of CCK should elucidate the regulatory connections between the life-sustaining functions of feeding and pain sensation.
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PMID:Effects of cholecystokinin and caerulein on human eating behavior and pain sensation: a review. 308 29

The effects of proglumide, a cholecystokinin (CCK) receptor antagonist, on the analgesia and catalepsy induced by beta-endorphin were investigated in rats. Proglumide itself produced a slight analgesia but no catalepsy. Combined intracerebroventricular administration of beta-endorphin and proglumide produced marked potentiation of the analgesic and cataleptic effects of beta-endorphin. The results suggest that endogenous CCK may have an antagonistic effect on the actions of beta-endorphin in the brain.
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PMID:Potentiation of beta-endorphin effects by proglumide in rats. 315 51

In adult mammals, cholecystokinin (CCK)-opiate interactions are complex and task dependent. Specifically, CCK antagonizes opiate effects in some cases, yet acts similarly to opiate agonists in others. The present study used behavioral measures to determine how CCK interacts with opiates in neonatal rats. CCK, at doses of 1 microgram/kg and higher, markedly reduced isolation-induced distress vocalization in rat pups. Moreover, CCK selectively prevented naltrexone antagonism of opiate-mediated reduction in distress vocalization in 3- and 11-day-old rats. Yet CCK did not affect opiate-induced analgesia, as measured by the hot-plate paw-lift response. Thus CCK either did not interact with opiates or did so agonistically, with the same (low) dose range, and within subjects. These findings suggest independence of stress and pain systems in neonatal rats and demonstrate a functional interaction between CCK and opioid systems.
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PMID:Behavioral evidence for cholecystokinin-opiate interactions in neonatal rats. 320 24


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