Molecular pharmacology of the opioid receptors

doi:10.1016/0163-7258(95)02011-X

Pharmacology & Therapeutics

Volume 68, Issue 3, 1995, Pages 343-364

https://doi.org/10.1016/0163-7258(95)02011-X Get rights and content

Abstract

Opioid receptors are the primary sites of actions of opiates and endogenous opioid peptides, which have a wide variety of pharmacological and physiological effects. The opioid receptors are classified into at least three subtypes, μ, δ, and χ, and their cDNAs have been cloned. In this review, we describe the molecular cloning of opioid receptor gene family and studies of the structure-function relationships, modes of coupling to second messenger systems, pharmacological effects of antisense oligonucleotides, and anatomical distribution of opioid receptor mRNAs.

References (158)

L.D. Aimone et al.
Opioid modulation of capsaicin-evoked release of substance P from rat spinal cprd in vivo
Peptides
(1989)
L.A. Bare et al.
Expression of two variants of the human μ opioid receptor mRNA in SK-N-SH cells and human brain
FEBS Lett.
(1994)
K. Befort et al.
Chromosomal localization of the delta opioid receptor gene to human 1P34.3–36.1 and mouse 4D bands by in situ hybridization
Genomics
(1994)
J.R. Bunzow et al.
Molecular cloning and tissue distribution of a putative member of the rat opioid receptor gene family that is not a μ, δ or χ opioid receptor type
FEBS Lett.
(1994)
D.L. Burns et al.
Pertussis toxin inhibits enkephalin stimulation of GTPase of NG108-15 cells
J. Biol. Chem.
(1983)
Y. Chen et al.
Differential regulation by cAMP-dependent protein kinase and protein kinase C of the μ opioid receptor coupling to a G protein-activated K⁺ channel
J. Biol. Chem.
(1994)
Y. Chen et al.
Molecular cloning, tissue distribution and chromosomal localization of a novel member of the opioid receptor gene family
FEBS Lett.
(1994)
C.C. Chien et al.
Blockade of U50,488H analgesia by antisense oligodeoxynucleotides to a χ-opioid receptor
Eur. J. Pharmacol.
(1994)
A.M. DePaoli et al.
Distribution of χ opioid receptor mRNA in adult mouse brain: an in situ hybridization histochemistry study
Mol. Cell. Neurosci.
(1994)
A.W. Duggan et al.
Morphine, naloxone and the responses of medial thalamic neurons of the cat
Brain Res.
(1977)

J.P. Fedynyshyn et al.

Mu type opioid receptors in rat periaqueductal gray-enriched P2 membrane are coupled to G-protein-mediated inhibition of adenylyl cyclase

Brain Res.

(1989)

K. Fukuda et al.

Primary structures and expression from cDNAs of rat opioid receptor δ- and μ-subtypes

FEBS Lett.

(1993)

K. Fukuda et al.

cDNA cloning and regional distribution of a novel member of the opioid receptor family

FEBS Lett.

(1994)

N. Hirota et al.

Met-enkephalin and morphine but not dynorphin inhibit noxious stimuli-induced release of substance P from rabbit dorsal horn in situ

Neuropharmacology

(1985)

S. Kaneko et al.

Mobilization of intracellular Ca²⁺ and stimulation of cAMP production by χ opioid receptors expressed in Xenopus oocytes

Mol. Brain Res.

(1994)

G.A. Kevetter et al.

Spinothalamic cells in the rat lumbar cord with collaterals to the medullary reticular formation

Brain Res.

(1982)

R.J. Knapp et al.

Identification of a human delta opioid receptor: cloning and expression

Life Sci.

(1994)

H. Kong et al.

A single residue, aspartic acid 95, in the δ opioid receptor specifies selective high affinity agonist binding

J. Biol. Chem.

(1993)

Y. Kuraishi et al.

Evidence that substance P and somatostatin transmit separate information related to pain in the spinal dorsal horn

Brain Res.

(1985)

Y. Kuraishi et al.

Stimulus specificity of peripherally evoked substance P release from the rabbit dorsal horn in situ

Neuroscience

(1989)

R.A. Lahti et al.

³H-U-69,593 a highly selective ligand for the opioid χ receptor

Eur. J. Pharmacol.

(1985)

F. Lembeck et al.

Opioid control of the function of primary afferent substance P fibers

Eur. J. Pharmacol.

(1985)

C. LeMoine et al.

Delta-opioid receptor gene expression in the mouse forebrain: localization in cholinergic neurons on the striatum

Neuroscience

(1994)

A.R. Light et al.

Differential termination of large-diameter and small-diameter primary afferent fibers in the spinal dorsal gray matter as indicated by labeling with horseradish peroxidase

Neurosci. Lett.

(1977)

K. Maekawa et al.

In situ hybridization study of μ- and χ-opioid receptor mRNAs in the rat spinal cord and dorsal root ganglia

Neurosci. Lett.

(1994)

A. Mansour et al.

Delta opioid receptor mRNA distribution in the brain: comparison to delta receptor binding and proenkephalin mRNA

J. Chem. Neuroanat.

(1993)

A. Mansour et al.

χ1 Receptor mRNA distribution in the rat CNS: comparison to χ receptor binding and prodynorphin mRNA

Mol. Cell. Neurosci.

(1994)

A. Mansour et al.

μ-Opioid receptor mRNA expression in the rat CNS: comparison to μ-receptor binding

Brain Res.

(1994)

A. Mansour et al.

Opioid-receptor mRNA expression in the rat CNS: anatomical and functional implications

Trends Neurosci.

(1995)

E. Mansson et al.

Isolation of a human χ opioid receptor cDNA from placenta

Biochem. Biophys. Res. Commun.

(1994)

G. McAllister et al.

Characterization of a chimeric hD3/D2 dopamine receptor expressed in CHO cells

FEBS Lett.

(1993)

I. Merchenthaler et al.

Immunocytochemical localization of proenkephalin-derived peptides in the central nervous system of the rat

Neuroscience

(1986)

M.J. Millan et al.

A model of chronic pain in the rat: highresolution neuroanatomical approach identifies alterations in multiple opioid systems in the periaqueductal grey

Brain Res.

(1987)

M. Minami et al.

In situ hybridization study of χ-opioid receptor mRNA in the rat brain

Neurosci. Lett.

(1993)

M. Minami et al.

Cloning and expression of a cDNA for the rat χ-opioid recptor

FEBS Lett.

(1993)

M. Minami et al.

Molecular cloning and in situ hybridization histochemistry for rat μ-opioid receptor

Neurosci. Res.

(1994)

M. Minami et al.

Double in situ hybridization study on coexistence of μ-, δ- and χ-opioid receptor mRNAs with preprotachykinin A mRNA in the rat dorsal root ganglia

Mol. Brain Res.

(1995)

T. Miyamae et al.

δ Opioid receptor mediates phospholipase C activation via Gi in Xenopus oocytes

FEBS Lett.

(1993)

C. Mollereau et al.

ORL1, a novel member of the opioid receptor family: cloning, functional expression and localization

FEBS Lett.

(1994)

H. Nakahama et al.

Antinociceptive action of morphine and pentazocine on unit activity in the nucleus centralis lateralis and nearby structures of the cat

Pain

(1981)

M. Nishi et al.

cDNA cloning and pharmacological characterization of an opioid receptor with high affinities for χ subtype-selective ligands

FEBS Lett.

(1993)

Y. Nomura et al.

Inositol phosphate formation and chloride current responses induced by acetylcholine and serotonin through GTP-binding proteins in Xenopus oocyte after injection of rat brain messenger RNA

Mol. Brain Res.

(1987)

D. Albe-Fessard et al.

Duality of unit discharges from cat centrum medianum in response to natural and electrical stimulation

J. Neurophysiol.

(1962)

O.G. Amaral et al.

The locus coeruleus: neurobiology of a central noradrenergic nucleus

Prog. Neurobiol.

(1977)

B. Attali et al.

Kappa-opiate agonists inhibit adenylate cyclase and produce heterologous desensitization in rat spinal cord

J. Neurochem.

(1989)

A.I. Basbaum et al.

Endogenous pain control systems: brainstem spinal pathways and endorphin circuitry

Annu. Rev. Neurosci.

(1984)

L.J. Botticelli et al.

Immunoreactive dynorphin in mammalian spinal cord and dorsal root ganglia

T. Bzdega et al.

Regional expression and chromosomal localization of the δ opiate receptor gene

M. Camps et al.

Isozyme-sensitive stimulation of phospholipase C-β2 by G protein βγ-subunits

Nature

(1992)

K.J. Chang et al.

Interaction of ligands with morphine and enkephalin receptors are differentially affected by guanine nucleotides

Mol. Pharmacol.

(1981)

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Molecular pharmacology of the opioid receptors

Abstract

Peptides

FEBS Lett.

Genomics

FEBS Lett.

J. Biol. Chem.

J. Biol. Chem.

FEBS Lett.

Eur. J. Pharmacol.

Mol. Cell. Neurosci.

Brain Res.

Brain Res.

FEBS Lett.

FEBS Lett.

Neuropharmacology

Mol. Brain Res.

Brain Res.

Life Sci.

J. Biol. Chem.

Brain Res.

Neuroscience

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Neuroscience

Neurosci. Lett.

Neurosci. Lett.

J. Chem. Neuroanat.

Mol. Cell. Neurosci.

Brain Res.

Trends Neurosci.

Biochem. Biophys. Res. Commun.

FEBS Lett.

Neuroscience

Brain Res.

Neurosci. Lett.

FEBS Lett.

Neurosci. Res.

Mol. Brain Res.

FEBS Lett.

FEBS Lett.

Pain

FEBS Lett.

Mol. Brain Res.

Duality of unit discharges from cat centrum medianum in response to natural and electrical stimulation

J. Neurophysiol.

The locus coeruleus: neurobiology of a central noradrenergic nucleus

Prog. Neurobiol.

Kappa-opiate agonists inhibit adenylate cyclase and produce heterologous desensitization in rat spinal cord

J. Neurochem.

Endogenous pain control systems: brainstem spinal pathways and endorphin circuitry

Annu. Rev. Neurosci.

Immunoreactive dynorphin in mammalian spinal cord and dorsal root ganglia

Regional expression and chromosomal localization of the δ opiate receptor gene

Isozyme-sensitive stimulation of phospholipase C-β2 by G protein βγ-subunits

Nature

Interaction of ligands with morphine and enkephalin receptors are differentially affected by guanine nucleotides

Mol. Pharmacol.