Separation of Opioid Analgesia from Respiratory Depression

Ling, Geoffrey; Spiegel, Katharyn; Lockhart, Stephen H.; Pasternak, G. W.

doi:10.1097/00132586-198604000-00006

Cited by 60 publications

(97 citation statements)

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“…As in Experiment 1, morphine produced a dose-dependent decrease in mean respirations. This finding is consistent with earlier research that demonstrated mu-mediation of morphine-induced respiratory depression (Green, 1959;Ling et al, 1985;McGilliard & Takemori, 1978, PfcQueen, 1983.…”

Section: Methodssupporting

confidence: 92%

“…Consistent with the notion that morphine-induced respiratory depression involves the activation of mu receptors (Green, 1959;Ling et al, 1985;McGilliard & Takemori, 1978, McXSueen, 1983, selective kappa antagonism failed to attenuate this morphine effect. The present results suggest that morphine-induced respiratory depression involves systems not dependent upon kappa activation.…”

Section: Resultssupporting

confidence: 65%

“…Morphine is known to decrease respiration (Green, 1959;Ling et al, 1985;MoGilliard & Takemori, 1978;McQueen, 1983) and body temperature (Tarn, 1989) (Green, 1959;Ling et al, 1985;MoGilliard & Takemori, 1978;McQueen, 1983).…”

Section: Methodsmentioning

confidence: 99%

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Effects of selective opiate antagonists on morphine-induced hyperalgesia in domestic fowl

Sufka

Hughes

Giordano

1991

Pharmacology Biochemistry and Behavior

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Sufka, Kenneth Joseph, "Effects of selective opiate antagonists on morphine-induced hyperalgesia in domestic fowl " (1990 INFORMATION TO USERSThe most advanced technology has been used to photograph and reproduce this manuscript from the microfilm master. UMI films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter face, while others may be from any type of computer printer.The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleedthrough, substandard margins, and improper alignment can adversely affect reproduction.In the unlikely event that the author did not send UMI a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicate the deletion.Oversize materials (e.g., maps, drawings, charts) are reproduced by sectioning the original, beginning at the upper left-hand corner and continuing from left to right in equal sections with small overlaps. Each original is also photographed in one exposure and is included in reduced form at the back of the book.Photographs included in the original manuscript have been reproduced xerographically in this copy. Higher quality 6" x 9" black and white photographic prints are available for any photographs or illustrations appearing in this copy for an additional charge. Contact UMI directly to order.

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Section: Methodssupporting

confidence: 92%

Section: Resultssupporting

confidence: 65%

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Effects of selective opiate antagonists on morphine-induced hyperalgesia in domestic fowl

Sufka

Hughes

Giordano

1991

Pharmacology Biochemistry and Behavior

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“…(1989). As it is the mu 2 receptor which is thought to be responsible for principally mediating the lethal effects of morphine (Wolozin & Pasternak, 1981), particularly respiratory depression (Ling et al, 1983;Ling et al, 1985), this study provides a possible explanation for the significantly lower degree of respiratory depression, nausea and vomiting and sedation observed in man after M6G than after morphine (Thompson et al, 1990). The difference in binding affinity also takes on more significance when considering the observation that M6G has approximately three times the systemic analgesic potency of morphine (Shimomura et al, 1971;Pasternak et al, 1987;Abbot & Palmour, 1988, Thompson et al, 1990.…”

mentioning

confidence: 68%

Explanation at the opioid receptor level for differing toxicity of morphine and morphine 6-glucuronide

Hucks

Thompson²,

McLoughlin³

et al. 1992

Br J Cancer

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Summary The radiolabelled opioid receptor binding affinities of morphine and its active metabolite morphine 6-glucuronide at the total mu, mu 1, mu 2 and delta receptors were determined. Morphine 6-glucuronide was found to have a 4-fold lower affinity for the mu 2 receptor (IC50 17 nm and 82 nm for morphine and morphine 6-glucuronide respectively, P = 0.01), the receptor postulated to be responsible for mediating the respiratory depression and gastrointestinal effects after morphine. This provides a possible explanation for the reduced respiratory depression and vomiting seen following morphine 6-glucuronide in man. A similar reduction in affinity of morphine 6-glucuronide was seen at the total mu receptor whilst there was no significant difference seen at the mu or delta receptor. Hence the increased analgesic potency of morphine 6-glucuronide over morphine remains unexplained.Morphine is one of the commonest drugs prescribed by cancer physicians and is an effective potent analgesic. However one or more of the side effects of constipation, nausea and vomiting, and sedation are encountered frequently (Jaffe & Martin, 1991). Respiratory depression is a less common problem but is the most potentially dangerous toxicity. An analgesic with equivalent potency but lower toxicity would therefore be of particular use.The major metabolic products of morphine are morphine 3-glucuronide (M3G) and morphine 6-glucuronide (M6G). Although M3G is devoid of analgesic activity, M6G is now thought to play a major role in mediating the analgesic effect of morphine (Osborne et al., 1986;Hanks et al., 1987;Hoskin & Hanks, 1990 Pasternak, 1981). This model suggests there is a common receptor labelled by either a prototypic delta agonist such as DADLE (D-Ala2, D-Leu5-enkephalin) or with a mu agonist such as morphine which has high affinity for morphine. This they termed the mu 1 receptor. The receptor labelled with a mu agonist which possessed a lower affinity they termed the mu 2 receptor. Similarly the receptor labelled with a delta agonist possessing lower affinity for morphine they termed the true delta receptor.It has been postulated that several of the adverse affects including respiratory depression of morphine are due to activation of the mu 2 or lower affinity mu opioid receptor (Pasternak & Wood, 1986). Using this classification it was therefore hypothesised that M6G has a lower affinity for the mu 2 receptor than morphine at least partially explaining the lower apparent toxicity seen in man. The aim of the current study was

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“…Supporting such a view, Hucks et al (1992) found that M6G had a 4 to 5 fold lower binding affinity for the t2 receptor subtype than morphine. The ,.2 receptor is believed to mediate, e.g., respiratory depression (Ling et al, 1985). In line with this, spinal and/or supraspinal t2 receptors may be involved also in the inhibitory action of M6G on micturition.…”

Section: Discussionmentioning

confidence: 83%

Effects of morphine metabolites on micturition in normal, unanaesthetized rats

Igawa

Westerling

Mattiasson

et al. 1993

British J Pharmacology

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1 By means of continuous cystometry in normal, unanaesthetized rats, the effects on micturition of intrathecally (i.t.) administered morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), the two main metabolites of morphine, were studied and compared with those of i.t. morphine.2 Both M6G (0.01, 0.1, and 0.5 lg) and M3G (5 pg) were found to have significant effects on micturition. Like morphine (0.1, 0.5, and 10pg), M6G was able to inhibit the micturition reflex, and produce urinary retention and dribbling incontinence in a dose-dependent manner. The potency of M6G for inhibiting micturition was approximately 10 times higher than that of morphine, and the duration of its effect was longer. All effects of M6G could be reversed by naloxone.3 M3G (5 jig) facilitated the micturition reflex, resulting in decreases in bladder capacity and micturition volume, and an increase in spontaneous contractile activity. Pretreatment with naloxone (10 fig), which by itself had no effect on micturition, enhanced the facilitatory effects of M3G. In addition, M3G tended to counteract the inhibitory effects of both morphine and M6G on micturition. M3G (5 jg) also produced an excitatory behavioural syndrome. 4 It is concluded that in rats, i.t. M3G has excitatory effects on micturition and behaviour, probably not mediated via opioid receptors. I.t M6G has a potent inhibitory effect on micturition mediated by stimulation of opioid receptors. It may have effects on somatosensory afferent input in lower doses than those required for effects on micturition.

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Separation of Opioid Analgesia from Respiratory Depression

Cited by 60 publications

References 0 publications

Effects of selective opiate antagonists on morphine-induced hyperalgesia in domestic fowl

Effects of selective opiate antagonists on morphine-induced hyperalgesia in domestic fowl

Explanation at the opioid receptor level for differing toxicity of morphine and morphine 6-glucuronide

Effects of morphine metabolites on micturition in normal, unanaesthetized rats

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