Opioids exert their effects by binding to opioid receptors (that is, G-protein-coupled receptors) and triggering signaling transmission to several downstream effectors, including inhibition of adenylyl cyclase, activation of G-protein-activated inwardly rectifying potassium channels, and inhibition of voltage-gated Ca2+ channels.32, 33, 34 Inhibition of adenylyl cyclase inhibits the production of cAMP, thus decreasing the active form of protein kinase A, phosphorylating CREB, and decreasing gene expression in the nucleus related to the action of analgesia and reward.35, 36 Indeed, the administration of cAMP intracerebrally or intravenously antagonized morphine analgesia in nontolerant and tolerant mice.37 Moreover, all of the major behavioral effects of morphine, including analgesia, tolerance, reward, and physical dependence and withdrawal symptoms, were attenuated in mice that lacked adenylyl cyclase 5.38 Meanwhile, increased CREB function in the nucleus accumbens decreased the sensitivity to the rewarding effects of morphine and cocaine in animals, whereas decreased CREB function had the opposite effect.35, 36, 39 Although no change in opioid-binding sites or morphine-induced analgesia was observed in CREBαδ-deficient mice,40 alterations in dose-dependent morphine-induced reward were also reported in CREBαδ-deficient mice.41 Altogether, these reports
