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, 153 (2), 367-79

Differential Effects of Cannabinoid Receptor Agonists on Regional Brain Activity Using Pharmacological MRI

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Differential Effects of Cannabinoid Receptor Agonists on Regional Brain Activity Using Pharmacological MRI

C-L Chin et al. Br J Pharmacol.

Abstract

Background and purpose: 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.

Experimental approach: 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.

Key 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.

Conclusion and implications: 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.

Figures

Figure 1
Figure 1
Group average phMRI activation maps (z-score; threshold: z>2.58, P<0.01) obtained from awake rats following acute i.v. administration of (a) vehicle (PEG400, n=6), (b) A-834735 at 0.3, 1 or 3 μmol kg−1 (n=5 per dose), or (c) AM1241 30 μmol kg−1 (n=5). No significant activation was found from rats treated with vehicle (a) or AM1241 (c). In contrast, A-834735 elicited dose-related, region-specific increases in brain activation in awake rats. At the lowest dose, A-834735 affected only prefrontal, cingulate, motor and somatosensory cortices, whereas the nucleus accumbens, striatum, hippocampus, PAG and cerebellum were activated at higher doses. Data are shown for 6 of 13 slices for clarity. PAG, periaqueductal grey; phMRI, pharmacological magnetic resonance imaging.
Figure 2
Figure 2
Results of selective antagonist blockade experiments. Group average phMRI activation maps (z-score; threshold: z>2.58, P<0.01) obtained from awake rats treated with (a) rimonabant 13 μmol kg−1i.v. (n=5), (b) pretreatment with rimonabant 13 μmol kg−1i.p., ∼40 min prior to infusing A-834735 1 μmol kg−1i.v. (n=5 per dose), (c) AM630 6 μmol kg−1i.v. (n=5) and (d) pretreatment with AM630 6 μmol kg−1i.p., ∼40 min prior to infusing A-834735 1 μmol kg−1i.v. (n=5 per dose). Our data show that rats pretreated with rimonabant, but not with AM630, abolished the effects of 1 μmol kg−1 A-834735, indicating a CB1 mechanism. CB1, cannabinoid 1; phMRI, pharmacological magnetic resonance imaging.
Figure 3
Figure 3
Group average phMRI activation maps (z-score; threshold: z>2.58, P<0.01) obtained from awake rats pretreated with AM1241 30 μmol kg−1 i.p., ∼40 min prior to infusing A-834735 1 μmol kg−1i.v. (n=5). Activation patterns were similar to those obtained from rats infused with A-834735 1 μmol kg−1i.v. (n=5, Figure 1b), indicating that AM1241 did not function as a CB1 antagonist in vivo under these conditions. CB1, cannabinoid 1; phMRI, pharmacological magnetic resonance imaging.
Figure 4
Figure 4
Quantitative ROI analysis of rCBV changes obtained from vehicle, A-834735 1 μmol kg−1, and antagonist blockade (rimonabant or AM630) treatment groups. (a) Anatomical images indicating the ROIs analysed: 1-prefrontal cortex, 2-cingulate cortex, 3-motor cortex, 4-nucleus accumbens, 5-striatum, 6-somatosensory cortex, 7-hippocampus, 8-PAG, 9-cerebellum. (b–f) Regional mean rCBV changes calculated from cingulate cortex, motor cortex, somatosensory cortex, hippocampus and PAG, respectively. The data show that increases in rCBV induced by A-834735 are abolished by the pretreatment with rimonabant, but not by AM630 (data shown are means±s.e. mean; **P<0.01, vs the vehicle group). PAG, periaqueductal grey; ROI, region of interest; rCBV, relative cerebral blood volume.
Figure 5
Figure 5
Regional temporal response of A-834735-induced rCBV changes (means±s.e. mean, n=5 per region) from (a) somatosensory cortex and (b) hippocampus. For both brain regions, the rCBV temporal response varied in a dose-related manner. The drug was infused from t=0 over a period of 5 min. Interestingly, compared to hippocampus, the onset and magnitude of rCBV changes in somatosensory cortex were earlier and greater, respectively. rCBV, relative cerebral blood volume.
Figure 6
Figure 6
Effects of A-834735 (injected i.p. 30 min before testing and 48 h after CFA) on CFA-induced chronic inflammatory thermal hyperalgesia (a) and effects of A-834735 (injected 30 min prior to testing) on tactile allodynia in a rat neuropathic pain model of sciatic nerve chronic constriction injury (CCI). Data represent mean±s.e. mean. *P<0.05, *P<0.01 compared to vehicle-treated rats (n=12 per group). A-834735 dose-dependently attenuated thermal hyperalgesia (a) and neuropathic pain (b) as reflected by increased paw withdrawal threshold and latencies, respectively.
Figure 7
Figure 7
Effects of A-834735 (i.p.) on rotorod performance (a) and spontaneous horizontal locomotor activity (b). A-834735 impaired rotorod performance and decreased exploratory locomotor behaviour at higher doses, reaching statistical significance at the highest dose tested in each case. Data are mean±s.e. mean, n=7 rats/group for rotorod and n=8 rats/group for locomotor activity. **P<0.001 vs vehicle control.

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