The use of quaternary narcotic antagonists in opiate research

Brown, David R.; Goldberg, Leon I.

doi:10.1016/0028-3908(85)90072-3

Cited by 237 publications

(126 citation statements)

References 44 publications

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“…First, its antitussive action (at 2.5 mg kg-') was reduced significantly by N-methylnalorphine, which being a quaternary salt of nalorphine, was designed not to penetrate the blood-brain barrier, and which has been shown in mice and guinea-pigs to be excluded from the CNS (Parsons et al, 1986; see also Brown & Goldberg, 1985). Second, whole body radiographic studies in the rat, have shown (Parsons, personal communication) that there was little BW443C in the brain compared to plasma levels within 45 min of an intravenous injection of 7.8 mg kg-'.…”

Section: Discussionmentioning

confidence: 99%

Effects of codeine, morphine and a novel opioid pentapeptide BW443C, on cough, nociception and ventilation in the unanaesthetized guinea‐pig

Adcock

Schneider

Smith

1988

British J Pharmacology

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1 Antitussive, antinociceptive and respiratory depressant effects of codeine, morphine and H.Tyr.DArg.Gly.Phe(4-NO2) Pro.NH2 (compound BW443C) were investigated in unanaesthetized guineapigs. Antagonism of the antitussive and antinociceptive effects was investigated by the use of nalorphine and N-methylnalorphine. Naloxone was used to antagonize respiratory depression.2 Antitussive ED50s (with 95% confidence limits) for inhibition of cough induced by citric acid vapour were for codeine, morphine and BW443C respectively, 9.1(5.8-15), 1.3(0.7-2.4) and 1.2(0.6-2.6) mg kg-' s.c. and 8.7(4.2-12), 1.6(1.2-1.9) and 0.67(0.002-3.3) mg kg-', i.v. The antitussive effects of subcutaneous codeine (25mg kg-') morphine (8.1 mg kg-') and BW443C (2.5mg kg-') were significantly antagonized by subcutaneous nalorphine (3.0 mg kg-') and N-methylnalorphine (3.0mg kg-').3 In the multiple toe-pinch test, the antinociceptive ED5s (with 95% confidence limits) of codeine and morphine were 18(16-22) and 2.3(0.4-4.3) mg kg-', s.c., respectively. Compound BW443C was ineffective in doses of 2.5 and 10 mg kg-' s.c., a result consistent with its lacking penetration into the CNS. Subcutaneous nalorphine (3.0mg kg-') antagonized the antinociceptive action of codeine (25mg kg-') and morphine (8.1 mg kg-'). In contrast, N-methylnalorphine (3.0mg kg-') had no significant effect on the antinociceptive action of codeine and morphine, suggesting lack of penetration of the CNS by N-methylnalorphine.4 At doses near to the i.v. ED50 values for the antitussive activity, morphine (1.5 mg kg-', i.v.) and codeine (10mg kg-', i.v.) caused small but significant depressions of ventilation (7.0 ± 2.3% and 16.5 ± 8.4% respectively). Higher doses of morphine (10, 30 and 60mg kg-',i.v.) caused further doserelated depression of ventilation (9.6 ± 5.3%, 22.4 ± 6.2% and 36.2 ± 9.6% respectively) whereas codeine (30 and 60 mg kg-' i.v.) caused stimulation of ventilation which was marked (191.3 ± 43.9%) at 60 mg kg-'. 5 Compound BW443C in doses of 1 or 10mgkg-',i.v. (approximately equal to, and 10 times the EDo for antitussive activity) did not cause significant depression of ventilation. Only at higher doses of 30 and 60mg kg-', i.v. was there a significant decrease in minute volume (13.1 ± 6.8% and 15.9 ± 1.89% respectively). The depression of ventilation caused by either BW443C (60mg kg- ', i.v.) or morphine (60mg kg-', i.v.) was prevented by pretreatment with naloxone (3mg kg- ', i.v.) administered 15 min before morphine or BW443C. 6 These results in the guinea-pig support the hypothesis that the antitussive action of the opiates codeine and morphine and the opioid pentapeptide BW443C do not require penetration of these drugs into the CNS.

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Section: Discussionmentioning

confidence: 99%

Effects of codeine, morphine and a novel opioid pentapeptide BW443C, on cough, nociception and ventilation in the unanaesthetized guinea‐pig

Adcock

Schneider

Smith

1988

British J Pharmacology

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“…Forty minutes after parturition, mothers whose pups had been removed at delivery were injected with the quaternary opioid antago nist naltrexone methobromide (QN) bilaterally into the VTA. QN has been shown to diffuse slowly from the site of injection in the eNS, and to be resistant to crossing the blood-brain barrier [6,11,78]. Thirty minutes after the test rat was injected, foster stimulus pups were introduced into the cage and the development of maternal behavior was observed.…”

Section: Methodsmentioning

confidence: 99%

Opioid stimulation in the ventral tegmental area facilitates the onset of maternal behavior in rats

Thompson

Kristal

1996

Brain Research

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This research investigated the effect of an increase or decrease in opioid activity in the ventral tegmental area (VTA) on the onset of maternal behavior in rats. In Experiment 1, the latency to show maternal behavior toward foster rat pups (sensitization latency) was determined in maternally naive female rats given either nothing or a unilateral intra-VTA injection of morphine sulfate (MS) (0.0, 0.01, 0.03, 0.1 or 0.3 J.Lg), on the first three days of a lO-day period' of constant exposure to pups. Rats treated with 0.03 J.Lg MS had significantly shorter sensitization latencies than did rats treated with 0,0 J.Lg MS, 0.01 J.Lg MS, or receiving no treatment (higher doses of morphine produced intermediate results). The facilitating effect of intra-VTA MS on the onset of maternal behavior was blocked by pretreatment with naltrexone hydrochloride and was found to have a specific site of action in the VTA (MS injections dorsal to the VTA were ineffective). In Experiment 2, sensitization latencies were determined in periparturitional rats given a bilateral intra-VTA injection of either the opioid antagonist naltrexone methobromide (quaternary naltrexone), its vehicle, a sham injection, or left untreated 40 min after delivery of the last pup. The mothers' own pups were removed at delivery; mothers were nonmaternal at the time of testing. Quaternary naltrexone treatment produced significantly slower sensitization to foster pups than did control conditions. Total activity and pup-directed activity did not differ significantly with treatment. The results demonstrate that increased opioid activity in the VTA facilitates the onset of maternal behavior in inexperienced nonpregnant female rats, and decreased opioid activity in the VTA disrupts the rapid onset of maternal behavior at parturition.

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“…In order to localize the action of POEF, we used a quaternary derivative of the opiate antagonist naltrex one, naltrexone methobromide (QN). QN penetrates the blood brain barrier less readily than its tertiary counterpart and can thus be used to discriminate peripheral from central opioid action (2,12). Morphine has both peripheral and central actions, al though the more important locus, for analgesia, is central (9,13).…”

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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 use of quaternary narcotic antagonists in opiate research

Cited by 237 publications

References 44 publications

Effects of codeine, morphine and a novel opioid pentapeptide BW443C, on cough, nociception and ventilation in the unanaesthetized guinea‐pig

Effects of codeine, morphine and a novel opioid pentapeptide BW443C, on cough, nociception and ventilation in the unanaesthetized guinea‐pig

Opioid stimulation in the ventral tegmental area facilitates the onset of maternal behavior in rats

Amniotic-fluid ingestion enhances the central analgesic effect of morphine

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