Adenylyl cyclase type 5 (AC5) is an essential mediator of morphine action

Abstract

Opioid drugs produce their pharmacological effects by activating inhibitory guanine nucleotide-binding regulatory protein-linked , ␦, and opioid receptors. One major effector for these receptors is adenylyl cyclase, which is inhibited upon receptor activation. However, little is known about which of the ten known forms of adenylyl cyclase are involved in mediating opioid actions. Here we show that all of the major behavioral effects of morphine, including locomotor activation, analgesia, tolerance, reward, and physical dependence and withdrawal symptoms, are attenuated in mice lacking adenylyl cyclase type 5 (AC5), a form of adenylyl cyclase that is highly enriched in striatum. Furthermore, the behavioral effects of selective or ␦ opioid receptor agonists are lost in AC5 ؊/؊ mice, whereas the behavioral effects of selective opioid receptor agonists are unaffected. These behavioral data are consistent with the observation that the ability of a or ␦ opioid receptor agonist to suppress adenylyl cyclase activity was absent in striatum of AC5 ؊/؊ mice. Together, these results establish AC5 as an important component of and ␦ opioid receptor signal transduction mechanisms in vivo and provide further support for the importance of the cAMP pathway as a critical mediator of opioid action. striatum ͉ opioid receptors ͉ analgesia ͉ addiction ͉ cAMP M orphine and most other opioid drugs are widely used clinically because of their potent analgesic effects, but this use is limited by their addiction liability. Both the analgesic and addicting actions of morphine and related drugs are initiated by their binding to , and to a lesser extent, ␦ opioid receptors (1-5). In contrast, other opioid drugs, such as U69593 and U50488H, activate opioid receptors, which generally produce distinct, and in some cases opposite, behavioral effects (6-8).Activation of all three types of opioid receptors is translated into physiological responses via coupling to inhibitory guanine nucleotide-binding regulatory protein, which then acts through several effectors, including most prominently inhibition of adenylyl cyclase, activation of G protein-linked inwardly rectifying K ϩ channels (GIRKs), and inhibition of voltage-gated Ca 2ϩ channels (2, 9). Regulation of G protein-linked inwardly rectifying K ϩ channels has been most closely related to the acute electrophysiological effects of , ␦, and opioid receptor activation of target cells (10, 11), whereas inhibition of adenylyl cyclase, and subsequent inhibition of the cAMP pathway, has been implicated mostly in longer term adaptations to repeated opiate administration (12, 13). Thus, up-regulation of adenylyl cyclase and other components of the cAMP pathway within specific regions of the central and peripheral nervous system has been shown to contribute to tolerance and dependence, and to changes in reward mechanisms, after repeated opioid administration.Despite the important role for adenylyl cyclase in mediating the actions of opioid drugs, little information is available concerning which type of th...

Sphingosine 1-Phosphate Modulates Spinal Nociceptive Processing

“…Moreover, agents that decrease cAMP levels, such as opioids and adenosine, inhibit hyperalgesia (30,31). In accordance with these findings, adenylyl cyclase knock-out mice show reduced behavioral responses in several pain models (44,45) as well as a reduced response to opioids (46,47). At the cellular and molecular level the hyperalgesic effect of cAMP is mainly mediated by PKA (32).…”

Molecular Changes in Opioid Addiction: The Role of Adenylyl Cyclase and cAMP/PKA System

“…17 It was further established that AC V mediates the effects of MOP and DOP but not KOP agonists. 16 In wild-type mice, the administration of MOP agonist, DAMGO (D-Ala 2 , NME-Phe 4 , Gly-ol 5 ]-enkephalin) or DOP agonist, DPDPE ([D-Pen 2,5 ]Enkephalin), both reduced forskolin-stimulated AC activity in striatal tissues. Following acute administration of opioids, the activity of AC isoforms I, V, VI, and VIII were reduced due to MOP activation.…”

“…AC V is involved in the mediation of morphine analgesia. 16 High densities of AC V are expressed in the striatum along with MOP, KOP, and DOP receptors. 17 It was further established that AC V mediates the effects of MOP and DOP but not KOP agonists.…”

“…26,27 Withdrawal symptoms associated with morphine dependence are reduced in AC V knockout mice. 16 The locus coeruleus (LC) plays a central role in opiate dependence and withdrawal and its activity is regulated by opioids. 28 While neuronal firing in the LC is reduced with acute opioid administration, AC activity and cAMP levels return toward basal levels during chronic opiate exposure.…”

Age-Dependent Neurodegeneration Accompanying Memory Loss in Transgenic Mice Defective in Mitochondrial Aldehyde Dehydrogenase 2 Activity

“…Locomotor activity was measured using an open-field apparatus (45 ϫ 45 ϫ 65 cm) (Kim et al, 2006). Animals were placed in the center of the apparatus in standard indoor-lighting conditions and total distance traveled for 10 min was recorded.…”