Activation of G-proteins in brain by endogenous and exogenous cannabinoids
Journal Title: The AAPS Journal - Year 2006, Vol 8, Issue 1
Abstract
The biological response to cannabinoid agonist begins when the agonist-bound receptor activates G-protein Gα subunits, thus initiating a cascade of signal transduction pathways. For this reason, information about cannabinoid receptors/G-protein coupling is critical to understand both the acute and chronic actions of cannabinoids. This review focuses on these mechanisms, predominantly examining the ability of cannabinoid agonists to activate G-proteins in brain with agonist-stimulated [35S]guanylyl-5′-O-(γ-thio)-triphosphate ([35S]GTPγS) binding. Acute efficacies of cannabinoid agonists at the level of G-protein activation depend not only on the ability of the agonist to induce a high affinity state in Gα for GTP, but also to induce a low affinity for GDP. When several agonists are compared, it is clear that cannabinoid agonists differ considerably in their efficacy. Both WIN 55212-2 and levonantradol are full agonists, while Δ9 is a weak partial agonist. Of interest, anandamide and its stable analog methanand amide are partial agonists. Chronic treatment in vivo with cannabinoids produces significant tolerance to the physiological and behavioral effects of these drugs, and several studies have shown that this is accompanied by a significant loss in the ability of cannabinoid receptors to couple to G-proteins in brain. These effects vary across different brain regions and are usually (but not always) accompanied by loss of cannabinoid receptor binding. Although the relationship between cannabinoid receptor desensitization and tolerance has not yet been established, these mechanisms may represent events that lead to a loss of cannabinoid agonist response and development of tolerance.
Authors and Affiliations
Steven R. Childers
Keywords
Related Articles
- EP ID EP681644
- DOI 10.1208/aapsj080113
- Views 91
- Downloads 0
An in vitro examination of the impact of polyethylene glycol 400, pluronic P85, and vitamin E d-a-tocopheryl polyethylene glycol 1000 succinate on P-glycoprotein efflux and enterocyte-based metabolism in excised rat intestine
Intranasal Delivery of Influenza Subunit Vaccine Formulated with GEM Particles as an Adjuvant
Nasal administration of influenza vaccine has the potential to facilitate influenza control and prevention. However, when administered intranasally (i.n.), commercially available inactivated vaccines only generate system...
Therapeutic Protein Drug–Drug Interactions: Navigating the Knowledge Gaps–Highlights from the 2012 AAPS NBC Roundtable and IQ Consortium/FDA Workshop
The investigation of therapeutic protein drug–drug interactions has proven to be challenging. In May 2012, a roundtable was held at the American Association of Pharmaceutical Scientists National Biotechnology Con...
Effects of Device and Formulation on In Vitro Performance of Dry Powder Inhalers
The study examined the sensitivity of DPI in vitro performance to formulation and device changes. Rotahaler/Rotacaps was selected as the reference DPI drug product, and Aerolizer was selected as the test device. Since th...
A Technique to Estimate In Vivo Dissolution Profiles Without Data from a Solution
Dissolution tests are expected to ensure adequate in vivo product performance. Given the recent progress in the ability to predict of human permeability, it is possible to synthesize the plasma drug concentration–...