enkephalin--ala(2)-mephe(4)-gly(5)- and 3-7-dimethyl-1-propargylxanthine

Methylxanthines like caffeine and theophylline have long been used to treat apnea of prematurity. Despite their success in stimulating neonatal breathing, their mechanism of action remains poorly understood. Methylxanthines can act as both non-specific adenosine receptor antagonists and inhibitors of cAMP-dependent phosphodiesterases, sarcoplasmic/endoplasmic reticulum calcium ATPases or receptor-coupled anion channels, depending on the dose used. Though there is evidence for methylxanthine action at the level of the carotid body, the consensus is that methylxanthines stimulate the respiratory centers of the brainstem. Here we used the in situ neonatal rat working heart-brainstem preparation and the ex vivo neonatal rat carotid body preparation to test the hypothesis that methylxanthines act at the level of the carotid body. We conclude that although the neonatal carotid body has active adenosine receptors, the effects of methylxanthine therapy are likely mediated centrally, predominantly via inhibition of cAMP-dependent phosphodiesterase-4.

Topics: Adenosine A1 Receptor Antagonists; Adenosine A2 Receptor Antagonists; Animals; Animals, Newborn; Apnea; Brain Stem; Carotid Body; Central Nervous System Stimulants; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Phrenic Nerve; Quinazolines; Rats, Sprague-Dawley; Respiration; Theobromine; Theophylline; Tissue Culture Techniques; Triazoles; Xanthines

Relapse is the most serious limitation of effective medical treatment of opiate addiction. Opiate-related behaviors appear to be modulated by cannabinoid CB1 receptors (CB1) through poorly understood cross-talk mechanisms. Opiate and CB1 receptors are coexpressed in the nucleus accumbens (NAc) and dorsal striatum. These regions also have the highest density of adenosine A2a receptors (A2a) in the brain. We have been investigating the postsynaptic signaling mechanisms of mu-opiate receptors (MORs) and CB1 receptors in primary NAc/striatal neurons. In this article, we present evidence that MOR and CB1 act synergistically on cAMP/PKA signaling in NAc/striatal neurons. In addition, we find that synergy requires adenosine and A2a. Importantly, an A2a antagonist administered either directly into the NAc or indirectly by i.p. injection eliminates heroin-induced reinstatement in rats trained to self-administer heroin, a model of human craving and relapse. These findings suggest that A2a antagonists might be effective therapeutic agents in the management of abstinent heroin addicts.

Topics: Adenosine A2 Receptor Antagonists; Analgesics, Opioid; Animals; Arachidonic Acids; Behavior, Animal; Corpus Striatum; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Drug Synergism; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enzyme Activation; Gene Expression Regulation; Heroin Dependence; Humans; Male; Neurons; Nucleus Accumbens; Rats; Rats, Sprague-Dawley; Receptor, Adenosine A2A; Receptor, Cannabinoid, CB1; Receptors, Opioid, mu; Self Administration; Signal Transduction; Theobromine; Xanthines