Differential effects of cannabinoid receptor agonists on regional brain activity using pharmacological MRI

Abstract

Background and purpose: Activation of cannabinoid CB 1 and/or CB 2 receptors mediates analgesic effects across a broad spectrum of preclinical pain models. Selective activation of CB 2 receptors may produce analgesia without the undesirable psychotropic side effects associated with modulation of CB 1 receptors. To address selectivity in vivo, we describe non-invasive, non-ionizing, functional data that distinguish CB 1 from CB 2 receptor neural activity using pharmacological MRI (phMRI) in awake rats. Experimental approach: Using a high field (7 T) MRI scanner, we examined and quantified the effects of non-selective CB 1 / CB 2 (A-834735) and selective CB 2 (AM1241) agonists on neural activity in awake rats. Pharmacological specificity was determined using selective CB 1 (rimonabant) or CB 2 (AM630) antagonists. Behavioural studies, plasma and brain exposures were used as benchmarks for activity in vivo. Key results: The non-selective CB 1 /CB 2 agonist produced a dose-related, region-specific activation of brain structures that agrees well with published autoradiographic CB 1 receptor density binding maps. Pretreatment with a CB 1 antagonist but not with a CB 2 antagonist, abolished these activation patterns, suggesting an effect mediated by CB 1 receptors alone. In contrast, no significant changes in brain activity were found with relevant doses of the CB 2 selective agonist. Conclusion and implications: These results provide the first clear evidence for quantifying in vivo functional selectivity between CB 1 and CB 2

Selective CB2 Receptor Agonism Protects Central Neurons from Remote Axotomy-Induced Apoptosis through the PI3K/Akt Pathway

“…Furthermore, our study of CB2R signaling indicates that CB2R-related neuroprotection involves the PI3K/Akt pathway. The presence of CB2R in the brain is controversial, particularly with regard to its expression in central neurons (Van Sickle et al, 2005;Chin et al, 2008). Our immunohistochemistry and qPCR data confirmed the absence or low expression of CB2R in the brain under normal conditions, at least for the two structures that we considered-the IO and Pn.…”

“…Moreover, the expression and function of CB2R in the brain remain controversial. A recent pharmacological MRI study concluded, however, that CB2R is not functionally active in the brain under physiological conditions (Chin et al, 2008).…”

Xanomeline Modulation of the Blood Oxygenation Level-Dependent Signal in Awake Rats: Development of Pharmacological Magnetic Resonance Imaging as a Translatable Pharmacodynamic Biomarker for Central Activity and Dose Selection

“…The uptake of phMRI in research and development has gathered some momentum in recent years as reflected by some elegant, powerful, and thought-provoking work that has been conducted on a variety of targets. Moreover, many of these studies conducted early in the discovery process have afforded enriched translational approaches on disease-relevant central effects of existing and novel experimental therapeutics such as dopamine 3 receptors (D3), 5-hydroxytryptamine 2c, glycine transporter inhibitors, nicotinics, cannabinoid receptor 2/1, and mGluR2/3 (Schwarz et al, 2004(Schwarz et al, , 2007Chin et al, 2008Chin et al, , 2011Gozzi et al, 2008;Beaver et al, 2011;McKie et al, 2011).…”

Role of Multifunctional FADD (Fas-Associated Death Domain) Adaptor in Drug Addiction

“…This contrasts with brain CB 2 receptors, which pharmacological activation has been questioned in conscious rats (Chin et al, 2008) and, therefore, the presence of any receptor constitutive activity is uncertain. Similarly to δ-opioid receptors (see Fig.…”