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Hypnotic and analgesic effects of the alpha 2-adrenergic agonist dexmedetomidine in morphine-tolerant rats. 1996

Y Hayashi, and T Z Guo, and M Maze
Department of Anesthesia, Stanford University, California, USA.

Combinations of alpha 2 agonists and opiates are used in the clinical management of pain to harness their potential synergistic interaction for analgesia while limiting their side-effects. To better predict the clinical consequences of this combination, we studied the behavioral effects of dexmedetomidine, a highly selective alpha 2 agonist with analgesic and hypnotic properties, during the development of, and recovery from, morphine tolerance. Rats were implanted with morphine pellets (or placebo), daily for 5 days. The analgesic response to morphine, dexmedetomidine, or the combination of the two drugs was assessed with the tail-flick latency response. The hypnotic response to dexmedetomidine, and to the combination of dexmedetomidine and morphine, was measured by the duration of the loss of righting reflex (sleep-time). One day after the last morphine pellet implantation, alpha 2 adrenoceptor binding was assessed in vitro in the locus coeruleus (LC) and the spinal cord (SC). Data were analyzed by analysis of variance (ANOVA), t-test, or Mann-Whitney test. The morphine tolerance was present after 1 day of morphine administration. At Days 1 and 3 of morphine administration, the hypnotic and analgesic responses to dexmedetomidine were significantly increased. After 5 days of morphine treatment, the analgesic response to dexmedetomidine was unaltered, while the hypnotic response to dexmedetomidine was now significantly decreased. The kd for the alpha 2 adrenoceptors was unaffected while the Bmax was significantly decreased only in the SC. Acutely administered morphine significantly enhanced the hypnotic and analgesic effects of dexmedetomidine in naive rats but not in morphine-tolerant rats. During morphine withdrawal, the hypnotic response to dexmedetomidine normalized; however, the analgesic response to dexmedetomidine was significantly decreased 5 days after withdrawal before returning to normal at Day 10 after withdrawal. We conclude that in the development of, and recovery from, the morphine-tolerant state, the hypnotic and analgesic responses to alpha 2 agonists are asynchronous.

UI MeSH Term Description Entries
D006993 Hypnotics and Sedatives Drugs used to induce drowsiness or sleep or to reduce psychological excitement or anxiety. Hypnotic,Sedative,Sedative and Hypnotic,Sedatives,Hypnotic Effect,Hypnotic Effects,Hypnotics,Sedative Effect,Sedative Effects,Sedatives and Hypnotics,Effect, Hypnotic,Effect, Sedative,Effects, Hypnotic,Effects, Sedative,Hypnotic and Sedative
D007093 Imidazoles Compounds containing 1,3-diazole, a five membered aromatic ring containing two nitrogen atoms separated by one of the carbons. Chemically reduced ones include IMIDAZOLINES and IMIDAZOLIDINES. Distinguish from 1,2-diazole (PYRAZOLES).
D008125 Locus Coeruleus Bluish-colored region in the superior angle of the FOURTH VENTRICLE floor, corresponding to melanin-like pigmented nerve cells which lie lateral to the PERIAQUEDUCTAL GRAY. Locus Caeruleus Complex,Locus Caeruleus,Locus Ceruleus,Locus Ceruleus Complex,Locus Coeruleus Complex,Nucleus Pigmentosus Pontis,Caeruleus Complex, Locus,Complex, Locus Caeruleus,Complex, Locus Ceruleus,Complex, Locus Coeruleus,Pontis, Nucleus Pigmentosus
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
D004357 Drug Synergism The action of a drug in promoting or enhancing the effectiveness of another drug. Drug Potentiation,Drug Augmentation,Augmentation, Drug,Augmentations, Drug,Drug Augmentations,Drug Potentiations,Drug Synergisms,Potentiation, Drug,Potentiations, Drug,Synergism, Drug,Synergisms, Drug
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
D000316 Adrenergic alpha-Agonists Drugs that selectively bind to and activate alpha adrenergic receptors. Adrenergic alpha-Receptor Agonists,alpha-Adrenergic Receptor Agonists,Adrenergic alpha-Agonist,Adrenergic alpha-Receptor Agonist,Receptor Agonists, Adrenergic alpha,Receptor Agonists, alpha-Adrenergic,alpha-Adrenergic Agonist,alpha-Adrenergic Agonists,alpha-Adrenergic Receptor Agonist,Adrenergic alpha Agonist,Adrenergic alpha Agonists,Adrenergic alpha Receptor Agonist,Adrenergic alpha Receptor Agonists,Agonist, Adrenergic alpha-Receptor,Agonist, alpha-Adrenergic,Agonist, alpha-Adrenergic Receptor,Agonists, Adrenergic alpha-Receptor,Agonists, alpha-Adrenergic,Agonists, alpha-Adrenergic Receptor,Receptor Agonist, alpha-Adrenergic,Receptor Agonists, alpha Adrenergic,alpha Adrenergic Agonist,alpha Adrenergic Agonists,alpha Adrenergic Receptor Agonist,alpha Adrenergic Receptor Agonists,alpha-Agonist, Adrenergic,alpha-Agonists, Adrenergic,alpha-Receptor Agonist, Adrenergic,alpha-Receptor Agonists, Adrenergic
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

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