Antagonism of gut, but not central effects of morphine with quaternary narcotic antagonists

Russell, James R.; Bass, Paul; Goldberg, Leon I.; Schuster, Charles R.; Merz, H.

doi:10.1016/0014-2999(82)90026-7

Cited by 224 publications

(91 citation statements)

References 7 publications

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“…Nevertheless, the dose of naloxone MeBr was probably adequate to produce significant peripheral opiatereceptor blockade because this dose has been demonstrated to abolish the A-receptor-mediated vaso-,u-receptor-mediated duodenal spike potentials produced by morphine. 10 Our results further show that although opiatereceptor antagonists significantly increased baroreflex sensitivity, they did not normalize the vagally mediated reflex slowing of heart rate in RHF. Our findings may suggest that the endogenous opioids play only a minor role in baroreflex control of heart rate in heart failure.…”

Section: D'iscussionmentioning

confidence: 45%

Opiate receptor inhibition improves the blunted baroreflex function in conscious dogs with right-sided congestive heart failure.

Sakamoto

Liang

1989

Circulation

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The endogenous opiate system is activated in congestive heart failure. Because endogenous opioids are known to depress the baroreflex function, we conducted studies to determine whether the increased endogenous opioids play a role in causing the reduced baroreflex function that occurs in heart failure. Right-sided congestive heart failure was produced in 16 dogs by tricuspid avulsion and progressive pulmonary artery constriction. Seven sham-operated dogs were included for comparison. Baroreflex function was measured in the conscious dogs after pretreatment with either normal saline or an opiate-receptor antagonist by bolus administration of phenylephrine. The slope of the regression line relating systolic blood pressure to cardiac cycle (R-R) interval was taken as an index of baroreflex sensitivity. Plasma js-endorphin was elevated in the dogs with heart failure (15.3+±2.5 pmol/l) compared with the sham-operated dogs (4.2+±0.4 pmol/1, p<0.001). The dogs with heart failure also exhibited a reduced baroreflex sensitivity (3.84+±0.19 msec/mm Hg) after saline pretreatment when compared with the sham-operated dogs (10.86±1.20 msec/mm Hg, p<0.001). Administration of naloxone hydrochloride increased the baroreflex sensitivity of dogs with heart failure to 5.16+±0.26 msec/ mm Hg (p<0.01) but produced no significant effects in sham-operated dogs (11.36±1.42 msec/mm Hg). To further study the site of action for the effect of naloxone, we measured baroreflex sensitivity in the dogs with heart failure after pretreatment with naloxonazine, a selective ,-receptor antagonist, with ICI 154,129, a selective A-receptor antagonist, or with naloxone methobromide, a quaternary analogue of naloxone that does not penetrate the blood-brain barrier. Like naloxone hydrochloride, naloxonazine increased baroreflex sensitivity (5.31+0.44 msec/mm Hg, p<0.01) in heart failure. However, this effect was not produced by ICI 154,129 or naloxone methobromide. The results indicate that the activated endogenous opiate system in heart failure plays a role in modulating the baroreflex. Naloxone probably exerts its effects on improving baroreflex function via an action on central g-opiate receptors. (Circulation 1989;80:1010-1015 D iminished baroreceptor reflexes have been well described in cases of congestive heart failure.1-4 However, the mechanisms by which this baroreflex dysfunction occurs are not

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Section: D'iscussionmentioning

confidence: 45%

Opiate receptor inhibition improves the blunted baroreflex function in conscious dogs with right-sided congestive heart failure.

Sakamoto

Liang

1989

Circulation

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“…The dose of QN chosen was based on reported differences in potency between naltrexone and QN, and on the reported thresh old for selective peripheral action (1,11,12). Rats were tested at both levels of the Agonist factor in a balanced design.…”

Section: Methodsmentioning

confidence: 99%

Amniotic-fluid ingestion enhances the central analgesic effect of morphine

Pirro¹,

Thompson²,

Kristal³

1991

Brain Research Bulletin

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fluid ingestion enhances the central analgesic effect of morphine. BRAIN RES BULL 26(6) 851-855, 1991.-Amniotic fluid and placenta contain a substance (POEF) that when in gested enhances opioid-mediated analgesia produced by several agents (morphine injection, vaginal/cervical stimulation, late preg nancy, footshock) , but not that produced by aspirin injection. The present series of experiments employed quaternary naltrexone, an opioid antagonist that does not readily cross the blood-brain barrier, in conjunction with either peripheral or central administra tion of morphine, to determine whether amniotic-fluid ingestion (and therefore POEF ingestion) enhances opioid-mediated analge sia by affecting the central and/or peripheral actions of morphine. The results suggest that POEF affects only the central analgesic effects of morphine.

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“…The addition of the methyl group at the amine in its ring forms a compound with greater polarity and lower lipid solubility. Thus, methylnaltrexone does not cross the blood-brain barrier in humans (Russell et al, 1982;Brown and Goldberg, 1985). These properties provide methylnaltrexone with the potential to block undesired side effects of opioid pain medications predominantly mediated by peripherally located receptors (Tavani et al, 1980;Manara et al, 1986), while sparing centrally mediated analgesic effect.…”

mentioning

confidence: 99%

Effects of Subcutaneous Methylnaltrexone on Morphine-Induced Peripherally Mediated Side Effects: A Double-Blind Randomized Placebo-Controlled Trial

Yuan¹,

Wei²,

Foss³

et al. 2002

J Pharmacol Exp Ther

110

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Methylnaltrexone, the first peripheral opioid receptor antagonist, has the potential to prevent or reverse opioid-induced peripherally mediated side effects without affecting analgesia. In previous human trials, we demonstrated that intravenous methylnaltrexone prevented morphine-induced delay in gastrointestinal transit time. We also observed that the compound decreased some of the morphine-induced troublesome subjective effects. However, the effects of subcutaneous methylnaltrexone, a more convenient route of administration, have not been evaluated. In this controlled trial, we evaluated the efficacy of subcutanous methylnaltrexone in antagonizing morphine-induced delay in oral-cecal transit time. In addition, opioid-induced unpleasant subjective effects and pharmacokinetics were studied. We observed that in the first group (n ϭ 6) morphine (0.05 mg/kg intravenously) increased the transit time from a baseline level of 85 Ϯ 20.5 min to 155 Ϯ 27.9 min (mean Ϯ S.D., P Ͻ 0.01). After 0.1 mg/kg subcutaneous methylnaltrexone plus morphine, the transit time reduced to 110 Ϯ 41.0 min. In the second group (n ϭ 6), morphine increased the transit time from a baseline level of 98 Ϯ 49.1 min to 140 Ϯ 58.2 min (P Ͻ 0.01). After 0.3 mg/kg subcutaneous methylnaltrexone plus morphine, the transit time reduced to 108 Ϯ 59.6 min (P Ͻ 0.05 compared with placebo plus morphine). In addition, subcutaneous methylnaltrexone significantly decreased morphineinduced subjective rating changes. Pharmacokinetic data after subcutaneous drug injection were compared to the data obtained from previous intravenous and oral administrations. Our results suggest that subcutaneous methylnaltrexone may have clinical utility in treating opioid-induced constipation and reducing opioid-induced unpleasant subjective symptoms.

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Antagonism of gut, but not central effects of morphine with quaternary narcotic antagonists

Cited by 224 publications

References 7 publications

Opiate receptor inhibition improves the blunted baroreflex function in conscious dogs with right-sided congestive heart failure.

Opiate receptor inhibition improves the blunted baroreflex function in conscious dogs with right-sided congestive heart failure.

Amniotic-fluid ingestion enhances the central analgesic effect of morphine

Effects of Subcutaneous Methylnaltrexone on Morphine-Induced Peripherally Mediated Side Effects: A Double-Blind Randomized Placebo-Controlled Trial

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