Biomaterial Database

Protein kinases modulate the cellular adaptations associated with opioid tolerance and dependence. 2001

J G Liu, and K J Anand

Department of Pharmacology, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA.

Prolonged opioid exposure occurs frequently as a result of clinical use or drug abuse. Research using different ligands, cell lines, and animal models in the past three decades has elucidated some correlation between the biochemical events and behavioral changes resulting from opioid tolerance, dependence and addiction. For the most part, opioid tolerance and dependence are associated with up-regulation of the cAMP pathway, mediated by the supersensitization of adenylyl cyclase and by the altered coupling of opioid receptors to stimulatory G proteins. Neuroadaptive changes in signal transduction following prolonged opioid exposure are mediated by protein kinase systems, such as protein kinase C (PKC), cyclic AMP-dependent protein kinase (PKA), Ca2+/camodulin-dependent protein kinase II (CaMKII), G protein-coupled receptor kinases (GRKs) and mitogen-activated protein kinases (MAPKs). Intermediate steps between opioid receptor activation and the second- or third-messenger cascades include GRK-mediated receptor endocytosis and intracellular trafficking, as well as interactions with excitatory amino acid receptors and regulation of nitric oxide synthesis. Thus, prolonged occupancy by opioid receptor agonists can have differential effects on opioid receptor internalization, down-regulation and desensitization, and in the supersensitization of adenylyl cyclase, which contribute to the development of opioid tolerance and dependence. We discuss the role of various protein kinases in the signaling mechanisms underlying these differences. Clearer understanding of the molecular mechanisms of opioid tolerance and dependence will help in the treatment of patients suffering from acute and chronic pain, or drug dependence and addiction.

UI	MeSH Term	Description	Entries
D009293	Opioid-Related Disorders	Disorders related to or resulting from abuse or misuse of OPIOIDS.	Opiate Addiction,Opiate Dependence,Opioid Misuse,Opioid Use Disorder,Prescription Opioid Abuse,Prescription Opioid Misuse,Addiction, Opioid,Dependence, Opioid,Opiate Abuse,Opioid Abuse,Opioid Addiction,Opioid Dependence,Abuse, Opiate,Abuse, Opioid,Abuse, Prescription Opioid,Addiction, Opiate,Dependence, Opiate,Disorder, Opioid Use,Misuse, Opioid,Misuse, Prescription Opioid,Opiate Abuses,Opioid Abuse, Prescription,Opioid Abuses,Opioid Addictions,Opioid Dependences,Opioid Misuses,Opioid Related Disorders,Opioid Use Disorders,Opioid-Related Disorder,Prescription Opioid Abuses,Prescription Opioid Misuses
D009294	Narcotics	Agents that induce NARCOSIS. Narcotics include agents that cause somnolence or induced sleep (STUPOR); natural or synthetic derivatives of OPIUM or MORPHINE or any substance that has such effects. They are potent inducers of ANALGESIA and OPIOID-RELATED DISORDERS.	Analgesics, Narcotic,Narcotic Analgesics,Narcotic,Narcotic Effect,Narcotic Effects,Effect, Narcotic,Effects, Narcotic
D011494	Protein Kinases	A family of enzymes that catalyze the conversion of ATP and a protein to ADP and a phosphoprotein.	Protein Kinase,Kinase, Protein,Kinases, Protein
D011957	Receptors, Opioid	Cell membrane proteins that bind opioids and trigger intracellular changes which influence the behavior of cells. The endogenous ligands for opioid receptors in mammals include three families of peptides, the enkephalins, endorphins, and dynorphins. The receptor classes include mu, delta, and kappa receptors. Sigma receptors bind several psychoactive substances, including certain opioids, but their endogenous ligands are not known.	Endorphin Receptors,Enkephalin Receptors,Narcotic Receptors,Opioid Receptors,Receptors, Endorphin,Receptors, Enkephalin,Receptors, Narcotic,Receptors, Opiate,Endorphin Receptor,Enkephalin Receptor,Normorphine Receptors,Opiate Receptor,Opiate Receptors,Opioid Receptor,Receptors, Normorphine,Receptors, beta-Endorphin,beta-Endorphin Receptor,Receptor, Endorphin,Receptor, Enkephalin,Receptor, Opiate,Receptor, Opioid,Receptor, beta-Endorphin,Receptors, beta Endorphin,beta Endorphin Receptor,beta-Endorphin Receptors
D004361	Drug Tolerance	Progressive diminution of the susceptibility of a human or animal to the effects of a drug, resulting from its continued administration. It should be differentiated from DRUG RESISTANCE wherein an organism, disease, or tissue fails to respond to the intended effectiveness of a chemical or drug. It should also be differentiated from MAXIMUM TOLERATED DOSE and NO-OBSERVED-ADVERSE-EFFECT LEVEL.	Drug Tolerances,Tolerance, Drug,Tolerances, Drug
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000222	Adaptation, Physiological	The non-genetic biological changes of an organism in response to challenges in its ENVIRONMENT.	Adaptation, Physiologic,Adaptations, Physiologic,Adaptations, Physiological,Adaptive Plasticity,Phenotypic Plasticity,Physiological Adaptation,Physiologic Adaptation,Physiologic Adaptations,Physiological Adaptations,Plasticity, Adaptive,Plasticity, Phenotypic
D000242	Cyclic AMP	An adenine nucleotide containing one phosphate group which is esterified to both the 3'- and 5'-positions of the sugar moiety. It is a second messenger and a key intracellular regulator, functioning as a mediator of activity for a number of hormones, including epinephrine, glucagon, and ACTH.	Adenosine Cyclic 3',5'-Monophosphate,Adenosine Cyclic 3,5 Monophosphate,Adenosine Cyclic Monophosphate,Adenosine Cyclic-3',5'-Monophosphate,Cyclic AMP, (R)-Isomer,Cyclic AMP, Disodium Salt,Cyclic AMP, Monoammonium Salt,Cyclic AMP, Monopotassium Salt,Cyclic AMP, Monosodium Salt,Cyclic AMP, Sodium Salt,3',5'-Monophosphate, Adenosine Cyclic,AMP, Cyclic,Adenosine Cyclic 3',5' Monophosphate,Cyclic 3',5'-Monophosphate, Adenosine,Cyclic Monophosphate, Adenosine,Cyclic-3',5'-Monophosphate, Adenosine,Monophosphate, Adenosine Cyclic
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D015398	Signal Transduction	The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway.	Cell Signaling,Receptor-Mediated Signal Transduction,Signal Pathways,Receptor Mediated Signal Transduction,Signal Transduction Pathways,Signal Transduction Systems,Pathway, Signal,Pathway, Signal Transduction,Pathways, Signal,Pathways, Signal Transduction,Receptor-Mediated Signal Transductions,Signal Pathway,Signal Transduction Pathway,Signal Transduction System,Signal Transduction, Receptor-Mediated,Signal Transductions,Signal Transductions, Receptor-Mediated,System, Signal Transduction,Systems, Signal Transduction,Transduction, Signal,Transductions, Signal