Minireview: Multiple MU opiate receptors

Pasternak, Gavril W.; Wood, Paul

doi:10.1016/0024-3205(86)90217-1

Cited by 324 publications

(64 citation statements)

References 44 publications

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“…For that purpose, CTOP (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Phe-Thr-NH 2 ), a mu-opioid receptor antagonist, together with EM-2 or EM-1 was locally infused into the NAc. In order to investigate the putative involvement of mu1-opioid receptors on the EM-1-induced accumbal dopamine efflux, the effects of the systemically administered mu1-opioid receptor antagonist naloxonazine (Pasternak and Wood, 1986) were also studied. Given the finding that CTOP did not antagonize the effects of EM-2, it became necessary to establish the opioid nature of the effects of EM-2.…”

Section: Introductionmentioning

confidence: 99%

Endomorphin-2 and Endomorphin-1 Promote the Extracellular Amount of Accumbal Dopamine via Nonopioid and Mu-Opioid Receptors, Respectively

Okutsu

Watanabe

Takahashi

et al. 2005

Neuropsychopharmacol

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Activation of mu-opioid receptors in the nucleus accumbens (NAc) is known to increase accumbal dopamine efflux in rats. Endomorphin-2 (Tyr-Pro-Phe-Phe-NH 2 ; EM-2) and endomorphin-1 (Tyr-Pro-Trp-Phe-NH 2 ; EM-1) are suggested to be the endogenous ligands for the mu-opioid receptor. As the ability of EM-2 and EM-1 to alter the accumbal extracellular dopamine level has not yet been studied in freely moving rats, the present study was performed, using a microdialysis technique that allows on-line monitoring of the extracellular dopamine with a temporal resolution of 5 min. A 25 min infusion of either EM-2 or EM-1 into the NAc (5, 25, and 50 nmol) produced a dose-dependent increase of the accumbal dopamine level. The EM-2 (50 nmol)-and EM-1 (25 and 50 nmol)-induced dopamine efflux were abolished by intra-accumbal perfusion of tetrodotoxin (2 mM). Intra-accumbal perfusion of the mu-opioid receptor antagonist CTOP (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Phe-Thr-NH 2 ; 3 nmol) failed to affect the EM-2 (50 nmol)-induced dopamine release, whereas it significantly inhibited the EM-1 (25 and 50 nmol)-induced dopamine release. The EM-1 (50 nmol)-induced accumbal dopamine efflux was significantly reduced by the systemic administration of the putative mu1-opioid receptor antagonist naloxonazine (15 mg/kg, intraperitoneally (i.p.), given 24 h before starting the perfusion). Systemic administration of the aspecific opioid receptor antagonist naloxone (1 mg/kg, i.p., given 10 or 20 min before starting the perfusion) also failed to affect the EM-2 (50 nmol)-induced dopamine efflux, whereas it significantly inhibited the EM-1 (25 and 50 nmol)-induced dopamine efflux. The present study shows that the intra-accumbal infusion of EM-2 and EM-1 increases accumbal dopamine efflux by mechanisms that fully differ. It is concluded that the effects of EM-2 are not mediated via opioid receptors in contrast to the effects of EM-1 that are mediated via mu1-opioid receptors in the NAc.

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Section: Introductionmentioning

confidence: 99%

Endomorphin-2 and Endomorphin-1 Promote the Extracellular Amount of Accumbal Dopamine via Nonopioid and Mu-Opioid Receptors, Respectively

Okutsu

Watanabe

Takahashi

et al. 2005

Neuropsychopharmacol

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“…The 4-to 5-fold higher affinity of morphine for the mu 2 receptor was also seen over the total mu receptor population. This is not surprising as approximately 70% of mu receptors are mu 2 receptors (Chang & Cuatrecasas, 1979;Wolozin & Pasternak, 1981) (Wolozin & Pasternak, 1981;Pasternak et al, 1986 (Paul et al, 1989). There are several reasons why this apparent inconsistency may exist.…”

mentioning

confidence: 98%

“…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.…”

mentioning

confidence: 99%

“…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 (Goldstein et al, 1971) Assay procedure The list of synthetic enkephalin ligands used with their assumed receptor specifities is displayed in Table I. All assays for specific binding were performed in triplicate in 10 ml plastic test tubes and assays for total binding and nonspecific binding performed in quadruplicate using the following experimental procedure:…”

mentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

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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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Multiple Morphine and Enkephalin Receptors and the Relief of Pain

Pasternak

1988

JAMA

169

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Minireview: Multiple MU opiate receptors

Cited by 324 publications

References 44 publications

Endomorphin-2 and Endomorphin-1 Promote the Extracellular Amount of Accumbal Dopamine via Nonopioid and Mu-Opioid Receptors, Respectively

Endomorphin-2 and Endomorphin-1 Promote the Extracellular Amount of Accumbal Dopamine via Nonopioid and Mu-Opioid Receptors, Respectively

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

Multiple Morphine and Enkephalin Receptors and the Relief of Pain

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