Differential effects of cannabinoid receptor agonists on regional brain activity using pharmacological MRI.
OBJECTIVE
Activation of cannabinoid CB1 and/or CB2 receptors mediates analgesic effects across a broad spectrum of preclinical pain models. Selective activation of CB2 receptors may produce analgesia without the undesirable psychotropic side effects associated with modulation of CB1 receptors. To address selectivity in vivo, we describe non-invasive, non-ionizing, functional data that distinguish CB1 from CB2 receptor neural activity using pharmacological MRI (phMRI) in awake rats.


METHODS
Using a high field (7 T) MRI scanner, we examined and quantified the effects of non-selective CB1/CB2 (A-834735) and selective CB2 (AM1241) agonists on neural activity in awake rats. Pharmacological specificity was determined using selective CB1 (rimonabant) or CB2 (AM630) antagonists. Behavioural studies, plasma and brain exposures were used as benchmarks for activity in vivo.


RESULTS
The non-selective CB1/CB2 agonist produced a dose-related, region-specific activation of brain structures that agrees well with published autoradiographic CB1 receptor density binding maps. Pretreatment with a CB1 antagonist but not with a CB2 antagonist, abolished these activation patterns, suggesting an effect mediated by CB1 receptors alone. In contrast, no significant changes in brain activity were found with relevant doses of the CB2 selective agonist.


CONCLUSIONS
These results provide the first clear evidence for quantifying in vivo functional selectivity between CB1 and CB2 receptors using phMRI. Further, as the presence of CB2 receptors in the brain remains controversial, our data suggest that if CB2 receptors are expressed, they are not functional under normal physiological conditions.
Chin
C-L
CL
Advanced Technology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA.
Tovcimak
A E
AE
Hradil
V P
VP
Seifert
T R
TR
Hollingsworth
P R
PR
Chandran
P
P
Zhu
C Z
CZ
Gauvin
D
D
Pai
M
M
Wetter
J
J
Hsieh
G C
GC
Honore
P
P
Frost
J M
JM
Dart
M J
MJ
Meyer
M D
MD
Yao
B B
BB
Cox
B F
BF
Fox
G B
GB
D000465:Algorithms; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects*; D063386:Cannabinoid Receptor Agonists; D002478:Cells, Cultured; D002560:Cerebrovascular Circulation / Q000187:drug effects; D006801:Humans; D007090:Image Interpretation, Computer-Assisted; D007249:Inflammation / Q000150:complications; D008279:Magnetic Resonance Imaging; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010146:Pain / Q000188:drug therapy / Q000209:etiology; D010523:Peripheral Nervous System Diseases / Q000150:complications; D004856:Postural Balance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000037:antagonists & inhibitors
D063386:Cannabinoid Receptor Agonists; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2