Mu opioid receptor: a gateway to drug addiction

Opioids remain the most effective analgesics despite their potential adverse effects such as tolerance and addiction. Mechanisms underlying these opiate-mediated processes remain the subject of much debate. Here we describe opioid-induced behaviors of Lmx1b conditional knockout mice (Lmx1b f/f/p ), which lack central serotonergic neurons, and we report that opioid analgesia is differentially dependent on the central serotonergic system. Analgesia induced by a opioid receptor agonist administered at the supraspinal level was abolished in Lmx1b f/f/p mice compared with their wild-type littermates. Furthermore, compared with their wild-type littermates Lmx1b f/f/p mice exhibited significantly reduced analgesic effects of and ␦ opioid receptor agonists at both spinal and supraspinal sites. In contrast to the attenuation in opioid analgesia, Lmx1b f/f/p mice developed tolerance to morphine analgesia and displayed normal morphine reward behavior as measured by conditioned place preference. Our results provide genetic evidence supporting the view that the central serotonergic system is a key component of supraspinal pain modulatory circuitry mediating opioid analgesia. Furthermore, our data suggest that the mechanisms of morphine tolerance and morphine reward are independent of the central serotonergic system. serotonin ͉ pain ͉ conditioned place preference ͉ behavior ͉ mouse

Section: Discussionsupporting

confidence: 88%

Central serotonergic neurons are differentially required for opioid analgesia but not for morphine tolerance or morphine reward

Zhao¹,

Gao²,

Sun³

et al. 2007

“…In agreement with these results, the behavioral features of AC5 Ϫ/Ϫ mice with respect to morphine action are very similar to those of receptor knockout (MOR Ϫ/Ϫ ) mice. Thus, MOR Ϫ/Ϫ mice, like AC5 Ϫ/Ϫ mice, show a dramatic reduction in morphine-induced locomotion, analgesia, conditioned place preference, and physical dependence and withdrawal symptoms (4,5,20,21). In addition, although the ␦ receptor is much less important for morphine's behavioral effects, compared with the receptor, ␦ receptor knockout mice (DOR Ϫ/Ϫ ) do show some deficits in behavioral responses to morphine (22,23).…”

Section: Discussionmentioning

confidence: 99%

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

Kim

Lee

et al. 2006

102

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...

“…␦-opioid receptors (DORs) are promising targets for the treatment of chronic pain (5) and emotional disorders (6). This opioid receptor type has fostered tremendous interest for the development of therapeutic compounds without abuse liability (7), considered a hallmark of -opioid agonists (8). Previously, we used the DOR as a model receptor to study mechanisms of GPCR activation (9).…”

mentioning

confidence: 99%

Knockin mice expressing fluorescent δ-opioid receptors uncover G protein-coupled receptor dynamics in vivo

Scherrer

Tryoen-Tóth

Filliol

et al. 2006

223

275

The combination of fluorescent genetically encoded proteins with mouse engineering provides a fascinating means to study dynamic biological processes in mammals. At present, green fluorescent protein (GFP) mice were mainly developed to study gene expression patterns or cell morphology and migration. Here we used enhanced GFP (EGFP) to achieve functional imaging of a G proteincoupled receptor (GPCR) in vivo. We created mice where the ␦-opioid receptor (DOR) is replaced by an active DOR-EGFP fusion. Confocal imaging revealed detailed receptor neuroanatomy throughout the nervous system of knockin mice. Real-time imaging in primary neurons allowed dynamic visualization of drug-induced receptor trafficking. In DOR-EGFP animals, drug treatment triggered receptor endocytosis that correlated with the behavioral response. Mice with internalized receptors were insensitive to subsequent agonist administration, providing evidence that receptor sequestration limits drug efficacy in vivo. Direct receptor visualization in mice is a unique approach to receptor biology and drug design.behavioral desensitization ͉ green fluorescent protein ͉ neuroanatomy ͉ real-time imaging ͉ receptor internalization