Biomaterial Database

Role of cAMP-dependent protein kinase (PKA) in opioid agonist-induced mu-opioid receptor downregulation and tolerance in mice. 2000

J Shen, and A Benedict Gomes, and A Gallagher, and K Stafford, and B C Yoburn

Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Queens, New York 11439, USA.

Studies suggest that acute and chronic opioids can regulate the cAMP-dependent protein kinase (PKA) signaling pathway and that changes in this pathway may be involved in opioid tolerance. In the present study, we examined the role of cAMP-PKA on mu-opioid receptor downregulation and tolerance in mice. Mice were injected intracerebroventricular (i.c.v.) and intrathecal (i.t.) once a day with an antisense oligodeoxynucleotide directed at the mRNA for the alpha catalytic subunit of mouse PKA. Controls were treated with saline or a mismatch oligodeoxynucleotide. On day 2 of treatment, mice were implanted s.c. with a 25-mg morphine pellet and an osmotic minipump infusing morphine (40 mg/kg/day) for 3 days. Other mice were implanted with an osmotic minipump infusing etorphine (125, 250 microg/kg/day) for 2 days. Control mice were implanted s.c. with inert placebo pellets. At the end of treatment, pumps and pellets were removed and mice tested for morphine or etorphine analgesia. Other mice were sacrificed and mu-opioid receptor binding assays conducted in whole brain. Both infusion doses of etorphine produced significant tolerance (ED(50) shift = 3.6 and 6.3-fold). The higher etorphine infusion produced downregulation of mu-receptor density ( approximately 30%) while the lower infusion dose of etorphine did not. Morphine treatment also produced significant tolerance in mice (ED(50) shift = 4.5-fold), but no receptor downregulation. Antisense to PKA partially blocked tolerance induced by the higher dose of etorphine, but had no effect on receptor downregulation. On the other hand, antisense to PKA completely blocked tolerance induced by morphine and the lower infusion dose of etorphine. The mismatch oligodeoxynucleotide had no effect on any measure. These results suggest that PKA has a limited role in opioid agonist-induced receptor downregulation. However, the partial block of tolerance for the high infusion dose of etorphine and the complete block of tolerance for morphine and the low infusion dose of etorphine suggests that PKA may play a critical role in tolerance that is "receptor-regulation-independent."

UI	MeSH Term	Description	Entries
D008297	Male		Males
D009020	Morphine	The principal alkaloid in opium and the prototype opiate analgesic and narcotic. Morphine has widespread effects in the central nervous system and on smooth muscle.	Morphine Sulfate,Duramorph,MS Contin,Morphia,Morphine Chloride,Morphine Sulfate (2:1), Anhydrous,Morphine Sulfate (2:1), Pentahydrate,Oramorph SR,SDZ 202-250,SDZ202-250,Chloride, Morphine,Contin, MS,SDZ 202 250,SDZ 202250,SDZ202 250,SDZ202250,Sulfate, Morphine
D010147	Pain Measurement	Scales, questionnaires, tests, and other methods used to assess pain severity and duration in patients or experimental animals to aid in diagnosis, therapy, and physiological studies.	Analgesia Tests,Analogue Pain Scale,Formalin Test,McGill Pain Questionnaire,Nociception Tests,Pain Assessment,Pain Intensity,Pain Severity,Tourniquet Pain Test,Visual Analogue Pain Scale,Analog Pain Scale,Assessment, Pain,McGill Pain Scale,Visual Analog Pain Scale,Analgesia Test,Analog Pain Scales,Analogue Pain Scales,Formalin Tests,Intensity, Pain,Measurement, Pain,Nociception Test,Pain Assessments,Pain Intensities,Pain Measurements,Pain Questionnaire, McGill,Pain Scale, Analog,Pain Scale, Analogue,Pain Scale, McGill,Pain Severities,Pain Test, Tourniquet,Questionnaire, McGill Pain,Scale, Analog Pain,Scale, Analogue Pain,Scale, McGill Pain,Severity, Pain,Test, Analgesia,Test, Formalin,Test, Nociception,Test, Tourniquet Pain,Tests, Nociception,Tourniquet Pain Tests
D001921	Brain	The part of CENTRAL NERVOUS SYSTEM that is contained within the skull (CRANIUM). Arising from the NEURAL TUBE, the embryonic brain is comprised of three major parts including PROSENCEPHALON (the forebrain); MESENCEPHALON (the midbrain); and RHOMBENCEPHALON (the hindbrain). The developed brain consists of CEREBRUM; CEREBELLUM; and other structures in the BRAIN STEM.	Encephalon
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
D005048	Etorphine	A narcotic analgesic morphinan used as a sedative in veterinary practice.	Ethorphine,M99
D000701	Analgesics, Opioid	Compounds with activity like OPIATE ALKALOIDS, acting at OPIOID RECEPTORS. Properties include induction of ANALGESIA or NARCOSIS.	Opioid,Opioid Analgesic,Opioid Analgesics,Opioids,Full Opioid Agonists,Opioid Full Agonists,Opioid Mixed Agonist-Antagonists,Opioid Partial Agonists,Partial Opioid Agonists,Agonist-Antagonists, Opioid Mixed,Agonists, Full Opioid,Agonists, Opioid Full,Agonists, Opioid Partial,Agonists, Partial Opioid,Analgesic, Opioid,Full Agonists, Opioid,Mixed Agonist-Antagonists, Opioid,Opioid Agonists, Full,Opioid Agonists, Partial,Opioid Mixed Agonist Antagonists,Partial Agonists, Opioid
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
D015536	Down-Regulation	A negative regulatory effect on physiological processes at the molecular, cellular, or systemic level. At the molecular level, the major regulatory sites include membrane receptors, genes (GENE EXPRESSION REGULATION), mRNAs (RNA, MESSENGER), and proteins.	Receptor Down-Regulation,Down-Regulation (Physiology),Downregulation,Down Regulation,Down-Regulation, Receptor
D016376	Oligonucleotides, Antisense	Short fragments of DNA or RNA that are used to alter the function of target RNAs or DNAs to which they hybridize.	Anti-Sense Oligonucleotide,Antisense Oligonucleotide,Antisense Oligonucleotides,Anti-Sense Oligonucleotides,Anti Sense Oligonucleotide,Anti Sense Oligonucleotides,Oligonucleotide, Anti-Sense,Oligonucleotide, Antisense,Oligonucleotides, Anti-Sense