Opioid and Cannabinoid Receptor Inhibition of Adenylyl Cyclase in Braina

Abstract

Both opioids and cannabinoids bind to G-protein-coupled receptors to inhibit adenylyl cyclase in neurons. These reactions were assayed in brain membranes, where maximal inhibitory activity occurred in the following regions: mu-opioid inhibition in rat thalamus, delta-opioid inhibition in rat striatum, kappa-opioid inhibition in guinea pig cerebellum, and cannabinoid inhibition in cerebellum. The inhibition of adenylyl cyclase by both cannabinoid and opioid agonists was typical of G-protein-linked receptors: they required GTP, they were not supported by non-hydrolyzable GTP analogs, and they were abolished (in primary neuronal cell culture) by pertussis toxin treatment. The immediate targets of this system were determined by assaying protein phosphorylation in the presence of receptor agonists and App(NH)p, a substrate for adenylyl cyclase. In striatal membranes, opioid agonists inhibited the phosphorylation of at least two bands of MW 85 and 63 kDa, which may be synapsins I and II, respectively. Other experiments determined the long-term effects of this second messenger system. In primary neuronal cultures, opioid-inhibited adenylyl cyclase attenuated forskolin-stimulated pro-enkephalin mRNA levels, thus providing a feedback regulation of opioid synthesis. Finally, in cerebellar granule cells, both cannabinoid and opioid receptors may exist on the same cells. In these cells, agonists which bind to different receptor types may produce similar biological responses.

GZ coupling to the rat κ‐opioid receptor

“…These results are consistent with the known pharmacological profile of the cloned Xl-opioid receptor [18]. Both p-and ~-opioid receptors are coupled to the PTXsensitive G~/Go proteins [19], and Gi-like proteins have also been implicated in the coupling of x-opioid receptors to their effectors [20]. We therefore examined the possible involvement of Gi proteins in xl-opioid receptor mediated inhibition of cAMP accumulation.…”

Cannabinoid Modulation of Opiate Reinforcement through the Ventral Striatopallidal Pathway

“…In addition, CB 1 receptor activation drastically reduces stimulated glutamate release in the NAC (Pistis et al, 2002) through the activation of presynaptic CB 1 receptors (Robbe et al, 2002;Robbe et al, 2003). Moreover, CB 1 receptors have been localized presynaptically on excitatory-type neurons that synapse with medium spiny neurons in the NAC (Pickel et al, 2004) whose postsynaptic activity can be suppressed by opiates (Childers et al, 1992). Thus, removal of the inhibitory influence of CB 1 receptors on these glutamate inputs (via SR 141716A administration) may serve to activate the VP GABA projection, thereby counteracting the morphine-induced decrease in VP GABA outflow.…”

“…For example, CB 1 and opiate receptors might interact at the level of their signal transduction pathways as both classes of receptors are coupled to Gi/Go-proteins and their stimulation modulates cAMP-dependent and MAP kinase pathways (Matsuda et al, 1990;Childers et al, 1992;Reisine et al, 1996). In addition, CB 1 receptor activation drastically reduces stimulated glutamate release in the NAC (Pistis et al, 2002) through the activation of presynaptic CB 1 receptors (Robbe et al, 2002;Robbe et al, 2003).…”

Chronic Morphine Modulates the Contents of the Endocannabinoid, 2-Arachidonoyl Glycerol, in Rat Brain

“…At the cellular level they activate different receptors, which are both coupled to Gi/Go GTP-binding proteins and inhibit adenylyl cyclase activity, block voltage-dependent calcium channels, and activate potassium channels. Receptors for these drugs are co-localized in the same neurons in various brain areas (caudate putamen, hippocampus, and substantia nigra) and might also compete for the same pool of Gi proteins (Childers et al, 1992).…”