Deletion of mu opioid receptors reduces palatable solution intake in a mouse model of binge eating.

Binge eating in humans is driven by hedonic properties of food, suggesting that brain reward systems may contribute to this behaviour. We examined the role of mu opioid receptors (MOP) in binge eating by examining sweet solution intake in mice with genetic deletion of the MOP. Wildtype and MOP knockout mice had 4 hours access to food in the home cage combined with limited (4 hours) access to sucrose (17.1% w/v) or saccharin (0.09% w/v), or continuous (24 hours) access to sucrose. Only limited access groups exhibited binge intake, measured as increased solution consumption during the first hour. Knockout mice consumed less solution and food during the first hour as well as less food each day compared with wildtype mice. Limited access groups consumed more food and gained more weight than continuous access groups, and the effect was magnified in saccharin-consuming mice. Indeed, the increased food consumption in animals given limited access to saccharin was so excessive that caloric intake of this group was significantly higher than either of the sucrose groups (limited or continuous access). Within this group, females consumed more food per bodyweight than males, highlighting important sex differences in feeding behaviours under restricted access schedules.

CB1 Agonism Alters Addiction-Related Behaviors in Mice Lacking Mu or Delta Opioid Receptors.

Opioids are powerful analgesics but the clinical utility of these compounds is reduced by aversive outcomes, including the development of affective and substance use disorders. Opioid systems do not function in isolation so understanding how these interact with other neuropharmacological systems could lead to novel therapeutics that minimize withdrawal, tolerance, and emotional dysregulation. The cannabinoid system is an obvious candidate as anatomical, pharmacological, and behavioral studies point to opioid-cannabinoid interactions in the mediation of these processes. The aim of our study is to uncover the role of specific cannabinoid and opioid receptors in addiction-related behaviors, specifically nociception, withdrawal, anxiety, and depression. To do so, we tested the effects of a selective CB1 agonist, arachidonyl-2-chloroethylamide (ACEA), on mouse behavior in tail immersion, naloxone-precipitated withdrawal, light-dark, and splash tests. We examined cannabinoid-opioid interactions in these tests by comparing responses of wildtype (WT) mice to mutant lines lacking either Mu or Delta opioid receptors. ACEA, both acute or repeated injections, had no effect on nociceptive thresholds in WT or Mu knockout (KO) mice suggesting that analgesic properties of CB1 agonists may be restricted to chronic pain conditions. The opioid antagonist, naloxone, induced similar levels of withdrawal in all three genotypes following ACEA treatment, confirming an opioidergic contribution to cannabinoid withdrawal. Anxiety-like responses in the light-dark test were similar across WT and KO lines; neither acute nor repeated ACEA injections modified this behavior. Similarly, administration of the Delta opioid receptor antagonist, naltrindole, alone or in combination with ACEA, did not alter responses of WT mice in the light-dark test. Thus, there may be a dissociation in the effect of pharmacological blockade vs. genetic deletion of Delta opioid receptors on anxiety-like behavior in mice. Finally, our study revealed a biphasic effect of ACEA on depressive-like behavior in the splash test, with a prodepressive state induced by acute exposure, followed by a shift to an anti-depressive state with repeated injections. The initial pro-depressive effect of ACEA was absent in Mu KO mice. In sum, our findings confirm interactions between opioid and cannabinoid systems in withdrawal and reveal reduced depressive-like symptoms with repeated CB1 receptor activation.

Morphine-induced hyperalgesia involves mu opioid receptors and the metabolite morphine-3-glucuronide.

Opiates are potent analgesics but their clinical use is limited by side effects including analgesic tolerance and opioid-induced hyperalgesia (OIH). The Opiates produce analgesia and other adverse effects through activation of the mu opioid receptor (MOR) encoded by the Oprm1 gene. However, MOR and morphine metabolism involvement in OIH have been little explored. Hence, we examined MOR contribution to OIH by comparing morphine-induced hyperalgesia in wild type (WT) and MOR knockout (KO) mice. We found that repeated morphine administration led to analgesic tolerance and hyperalgesia in WT mice but not in MOR KO mice. The absence of OIH in MOR KO mice was found in both sexes, in two KO global mutant lines, and for mechanical, heat and cold pain modalities. In addition, the morphine metabolite morphine-3beta-D-glucuronide (M3G) elicited hyperalgesia in WT but not in MOR KO animals, as well as in both MOR flox and MOR-Nav1.8 sensory neuron conditional KO mice. M3G displayed significant binding to MOR and G-protein activation when using membranes from MOR-transfected cells or WT mice but not from MOR KO mice. Collectively our results show that MOR is involved in hyperalgesia induced by chronic morphine and its metabolite M3G.

Opioid-induced hyperalgesia: Cellular and molecular mechanisms.

Opioids produce strong analgesia but their use is limited by a paradoxical hypersensitivity named opioid-induced hyperalgesia (OIH) that may be associated to analgesic tolerance. In the last decades, a significant number of preclinical studies have investigated the factors that modulate OIH development as well as the cellular and molecular mechanisms underlying OIH. Several factors have been shown to influence OIH including the genetic background and sex differences of experimental animals as well as the opioid regimen. Mu opioid receptor (MOR) variants and interactions of MOR with different proteins were shown important. Furthermore, at the cellular level, both neurons and glia play a major role in OIH development. Several neuronal processes contribute to OIH, like activation of neuroexcitatory mechanisms, long-term potentiation (LTP) and descending pain facilitation. Increased nociception is also mediated by neuroinflammation induced by the activation of microglia and astrocytes. Neurons and glial cells exert synergistic effects, which contribute to OIH. The molecular actors identified include the Toll-like receptor 4 and the anti-opioid systems as well as some other excitatory molecules, receptors, channels, chemokines, pro-inflammatory cytokines or lipids. This review summarizes the intracellular and intercellular pathways involved in OIH and highlights some mechanisms that may be challenged to limit OIH in the future.