Original ArticlesOpiate tolerance and dependence: receptors, G-proteins, and antiopiates
Section snippets
The discovery of opiate binding sites
The stereospecificity of narcotic analgesics led to the hypothesis that they act at specific receptors in the central nervous system (CNS) 77, 202. However, early attempts to demonstrate the “opiate receptor” biochemically were unsuccessful. One early paper described uptake of [3H]dihydromorphine into synaptosomes, but this did not necessarily represent specific binding (96). That same year, Goldstein et al. (77) proposed a method for determining specific binding by use of radioactive and
Opioid peptides
The initial discovery of opiate binding sites in the brain led to the speculation that there must be an endogenous ligand which acts at these sites. A search for this endogenous morphine-like ligand ensued. Two different approaches were used to screen brain extracts for opiate activity: (a) displacement of opiate alkaloids in binding assays and (b) bioassays consisting of guinea pig myenteric plexus or mouse vas deferens preparations. For either assay, reversibility of the response by naloxone
Opiate receptor-effector coupling
Opiate receptors belong to the superfamily of G-protein-coupled receptors. Opiate ligands bind to a membrane receptor, which transduces this signal into the cell via activation of a guanosine triphosphate (GTP)-binding protein and effectors such as AC and ion channels. The coupling of receptor to G-protein is a possible locus of specificity of action for different receptor subtypes and of regulation during chronic ligand exposure.
The cycle of G-protein activation and deactivation was initially
Opiate receptor localization
The cloning of opiate receptors has allowed for the use of molecular biologic techniques to localize the receptors in the CNS. Such techniques extend the anatomic detail with which the receptors can be studied beyond that revealed by autoradiographic studies of binding sites, the method of choice before the cloning of the receptor. For example, in situ hybridization (ISH) and immunocytochemistry (ICC) offer better resolution than autoradiography, enabling examination of single cells. Also, the
Opiate tolerance
One of the major limitations of the clinical use of opiates is their tendency to induce tolerance and dependence. As such, the possible mechanisms for these phenomena have been intensively studied in an attempt to understand and prevent them. Early studies focused on the obvious mechanisms of receptor down-regulation and desensitization (TABLE 1, TABLE 2 , ref. 247, and below). Because these mechanisms cannot fully explain the phenomena, more recent studies have investigated a possible role
Summary and conclusions
The studies outlined above indicate that a wealth of information exists about opiate receptors and peptides. Also, there has been extensive investigation of the effects of chronic opiates. However, a clear picture of the correlation between biochemical effects and behavioral tolerance has yet to emerge. A simple blunting of the response to opiates does not seem to be the sole mechanism of tolerance. Rather, the induction of a compensatory response, in addition to a decrease in response to
References (253)
- et al.
Cloning of kappa opioid receptors: functional significance and future directions
Prog. Brain Res.
(1994) - et al.
Autoradiographic distribution of receptors to FLFQPQPRFamide, a morphine-modulating peptide, in rat central nervous system
Neuroscience
(1992) - et al.
Characterization of rat spinal cord receptors to FLFQPQRFamide, a mammalian morphine modulating peptide: a binding study
Brain Res
(1989) - et al.
Neuropeptide FF in the VTA blocks the analgesic effects of both intra-VTA morphine and exposure to stress
Brain Res
(1997) - et al.
Evidence for multiple “kappa” binding sites by use of opioid peptides in the guinea-pig lumbro-sacral spinal cord
Neuropeptides
(1982) - et al.
Characterization of [3H]-etorphine binding in guinea-pig striatum after blockade of mu and delta sites
Life Sci
(1982) - et al.
κ-opioid receptor-transfected cell linesmodulation of adenylyl cyclase activity following acute and chronic morphine treatments
FEBS Lett
(1995) - et al.
Receptor-mediated stimulation of brain GTPase by opiates in normal and dependent rats
Biochem. Biophys. Res. Commun.
(1984) - et al.
Expression of two variants of the human μ opioid receptor mRNA in SK-N-SH cells and human brain
FEBS Lett
(1994) - et al.
Down-regulation of brain and spinal cord μ-opiate receptors in morphine tolerant-dependent rats
Eur. J. Pharmacol.
(1990)
Differential opioid agonist regulation of the mouse μ opioid receptor
J. Biol. Chem.
Opiate binding to membrane preparations of neuroblastoma x glioma hybrid cells NG108–15: effects of ions and nucleotides
Life Sci
Purification and properties of the inhibitory guanine nucleotide-binding regulatory component of adenylate cyclase
J. Biol. Chem.
Chronic morphine increases μ-opiate receptor binding in rat brain: a quantitative autoradiographic study
Brain Res
CNS levels of mu opioid receptor (MOR-1) mRNA during chronic treatment with morphine or naltrexone
Brain Res. Bull.
Catecholamine-stimulated GTPase activity in turkey erythrocyte membranes
Biochim. Biophys. Acta
Chronic morphine and naltrexone fail to modify μ-opioid receptor mRNA levels in the rat brain
Mol. Brain Res.
Neuroblastoma Neuro2A cells stably expressing a cloned μ-opioid receptora specific cellular model to study acute and chronic effects of morphine
Mol. Brain Res.
Multiple opiate receptors: enkephalins and morphine bind to receptors of different specificity
J. Biol. Chem.
Opioid receptor-coupled second messenger systems
Life Sci
Ns and Ni, the stimulatory and inhibitory regulatory components of adenylyl cyclase. Purification of the human erythrocyte proteins without the use of activating regulatory ligands
J. Biol. Chem.
A peptide-like substance from pituitary that acts like morphine. 2. Purification
Life Sci
Opioids can evoke direct receptor-mediated excitatory effects on sensory neurons
Trends Pharmacol. Sci.
After chronic opioid exposure sensory neurons become supersensitive to the excitatory effects of opioid agonists and antagonists as occurs after acute elevation of GM1 ganglioside
Brain Res
Thr353, located within the COOH-terminal of the δ opiate receptor, is involved in receptor down-regulation
J. Biol. Chem.
Chronic administration of morphine and naltrexone up-regulates [3H][d-Ala2,d-Leu5]enkephalin binding sites by different mechanisms
Neuropharmacology
Simultaneous activation of spinal antiopioid system (neuropeptide FF) and pain facilitory circuitry by stimulation of opioid receptors in rats
Brain Res
The novel neuropeptide orphanin FQ fails to produce conditioned place preference or aversion
Brain Res
Isolation of a novel tetrapeptide with opiate and antiopiate activity from human cortexTyr-Pro-Trp-Gly-NH2 (Tyr-W-MIF-1)
Peptides
Existence of antiopiate systems as illustrated by MIF-1/Tyr-MIF-1
Life Sci
Distinct distributions of mu, delta and kappa opioid receptor mRNA in rat brain
Biochem. Biophys. Res. Commun.
Intrathecal Tyr-W-MIF-1 produces potent, naloxone-reversible analgesia modulated by alpha2-adrenoceptors
Eur. J. Pharmacol.
Analgesic effects of Tyr-W-MIF-1: a mixed mu2-opioid receptor agonist/mu1-opioid receptor antagonist
Eur. J. Pharmacol.
Downregulation of mu-opioid binding sites following chronic administration of neuropeptide FF (NPFF) and morphine
Peptides
Benzomorphan binding sites in rat lumbro-sacral spinal cord
Eur. J. Pharmacol.
Presence of neuropeptide FF receptors in primary afferent fibres of the rat spinal cord
Neuroscience
Isolation of relatively large amounts of endomorphin-1 and endomorphin-2 from human brain cortex
Peptides
Lack of cross-tolerance between the antinociceptive effect of intrathecal orphanin FQ and morphine in the rat
Neurosci. Lett.
Differential effects of endomorphin-1, endomorphin-2, and Tyr-W-MIF-1 on activation of G-proteins in SH-SY5Y human neuroblastoma membranes
Peptides
The orphan opioid receptor and its endogenous ligand—nociceptin/orphanin FQ
Trends Pharmacol. Sci.
Comparison of in vivo and in vitro parameters of receptor binding in naive and tolerant/dependent rats
Life Sci
Uptake of dihydromorphine-3H by synaptosomes
Life Sci
Isolation of an endogenous compound from the brain with pharmacological properties similar to morphine
Brain Res
Purification and properties of enkephalin—the possible endogenous ligand for the opiate receptor
Life Sci
Effects of kappa opiate agonists on neurochemical and neuroendocrine indicesevidence for kappa receptor subtypes
Life Sci
Assessment of delta opioid antinociception and receptor mRNA levels in mouse after chronic naltrexone treatment
Brain Res
Phosphorylation and agonist-specific intracellular trafficking of an epitope-tagged mu-opioid receptor expressed in HEK 293 cells
J. Neurochem.
δ-opioid receptor immunoreactivitydistribution in brainstem and spinal cord, and relationship to biogenic amines and enkephalin
J. Neurosci.
Distribution and targeting of a μ-opioid receptor (MOR1) in brain and spinal cord
J. Neurosci.
The κ-opioid receptor is primarily postsynaptic: combined immunohistochemical localization of the receptor and endogenous opioids
Proc. Natl. Acad. Sci. USA
Cited by (177)
Frontiers in Neuroscience Imaging: Whole-Body PET
2021, PET ClinicsKisspeptin modulates pain sensitivity of CFLP mice
2018, PeptidesInvolvement of the N/OFQ-NOP system in rat morphine antinociceptive tolerance: Are astrocytes the crossroad?
2018, European Journal of PharmacologyBinding mode analyses of NAP derivatives as mu opioid receptor selective ligands through docking studies and molecular dynamics simulation
2017, Bioorganic and Medicinal ChemistryNeurobiology of opioid withdrawal: Role of the endothelin system
2016, Life Sciences
- 1
Present Address: Department of Physiology and Pharmacology, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland OR 97201.