Restricted accessResearch articleFirst published online 2025
Cannabinoid 1 receptor occupancy and neurovascular responses induced by agonist,antagonist/inverse-agonist,and potential modulator in non-human primate brains: PET/fMRI study
The cannabinoid 1 receptor (CB1R) is a key pharmacological target in the central nervous system, modulating emotions, cognition, and memory. Functional interactions between CB1R and mu-opioid receptors (MOR) in analgesia have been reported. This study investigated CB1R occupancy and neuronal activation in non-human primate brains following acute administration of a CB1R agonist (CP55,940), an antagonist/inverse-agonist (rimonabant), an MOR agonist (morphine) using simultaneous positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). [11C]OMAR, a CB1R-selective radiotracer, PET scans were acquired using bolus or bolus-plus-infusion protocols. Rimonabant (1, 3 mg/kg, n = 1 for each) reduced [11C]OMAR non-displaceable binding potential by 25%–40% in CB1R-rich regions. To our knowledge, this is the first in vivo demonstration of CB1R occupancy by the agonist CP55,940 (0.05 mg/kg, n = 2), which displaced 15%–30% of [11C]OMAR volume of distribution (VT) in CB1R-rich regions. Although there was no clear dose–response relationship, CP55,940 increased cerebral blood volume (CBV), whereas rimonabant caused a biphasic response. Morphine administration (1 mg/kg, n = 2) reduced CBV in MOR-rich areas and modestly increased [11C]OMAR VT, suggesting a potential indirect modulation of CB1R availability. Given the small sample size and variability close to test–retest levels, these preliminary findings should be interpreted with caution.
LeoLMAboodME.CB1 cannabinoid receptor signaling and biased signaling. Molecules2021; 26(17): 5413.
2.
HerkenhamMLynnABLittleMD, et al. Cannabinoid receptor localization in brain. Proc Natl Acad Sci U S A1990; 87(5): 1932–1936.
3.
BloomfieldMAPHindochaCGreenSF, et al. The neuropsychopharmacology of Cannabis: a review of human imaging studies. Pharmacol Ther2019; 195: 132–161.
4.
SvíženskáIDubovýPŠulcováA.Cannabinoid receptors 1 and 2 (CB1 and CB2), their distribution, ligands and functional involvement in nervous system structures—a short review. Pharmacol Biochem Behav2008; 90(4): 501–511.
5.
BroydSJVan HellHHBealeC, et al. Acute and chronic effects of cannabinoids on human cognition—a systematic review. Biol Psychiatry2016; 79(7): 557–567.
6.
GaoniYMechoulamR.Isolation, structure, and partial synthesis of an active constituent of Hashish. J Am Chem Soc1964; 86(8): 1646–1647.
7.
LivnyACohenKTikN, et al. The effects of synthetic cannabinoids (SCs) on brain structure and function. Eur Neuropsychopharmacol2018; 28(9): 1047–1057.
8.
WhitingPFWolffRFDeshpandeS, et al. Cannabinoids for medical use: a systematic review and meta-analysis. JAMA2015; 313(24): 2456–2473.
9.
DevinskyOCrossJHLauxL, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med2017; 376(21): 2011–2020.
10.
ZajicekJFoxPSandersH, et al. Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial. Lancet2003; 362(9395): 1517–1526.
11.
PorcuAMelisMTurecekR, et al. Rimonabant, a potent CB1 cannabinoid receptor antagonist, is a Gαi/o protein inhibitor. Neuropharmacology2018; 133: 107–120.
12.
Bosquez-BergerTSzandaGStraikerA.Requiem for rimonabant: therapeutic potential for cannabinoid CB1 receptor antagonists after the fall. Drugs Drug Candidates2023; 2(3): 689–707.
13.
MurphyTLe FollB.Targeting the endocannabinoid CB1 receptor to treat body weight disorders: a preclinical and clinical review of the therapeutic potential of past and present CB1 drugs. Biomolecules2020; 10(6): 855.
14.
HeXHJordanCJVemuriK, et al. Cannabinoid CB1 receptor neutral antagonist AM4113 inhibits heroin self-administration without depressive side effects in rats. Acta Pharmacol Sin2019; 40(3): 365–373.
15.
Le FollBGoldbergSR. Cannabinoid CB1 receptor antagonists as promising new medications for drug dependence. J Pharmacol Exp Ther2005; 312(3): 875–883.
16.
DellazizzoLPotvinSGiguèreS, et al. Evidence on the acute and residual neurocognitive effects of Cannabis use in adolescents and adults: a systematic meta-review of meta-analyses. Addiction2022; 117(7): 1857–1870.
17.
VolkowNDSwansonJMEvinsAE, et al. Effects of Cannabis use on human behavior, including cognition, motivation, and psychosis: a review. JAMA Psychiatry2016; 73(3): 292–297.
18.
BudneyAJRoffmanRStephensRS, et al. Marijuana dependence and its treatment. Addict Sci Clin Pract2007; 4(1): 4–16.
19.
SamAHSalemVGhateiMA.Rimonabant: from RIO to ban. J Obes2011; 2011: 432607.
20.
HasinDWalshC.Trends over time in adult Cannabis use: a review of recent findings. Curr Opin Psychol2021; 38: 80–85.
21.
United Nations Office on Drugs and Crime. World Drug Report 2020 (United Nations publication, sales no. E.20.XI.6). New York, NY: United Nations, 2020.
22.
NielsenSSabioniPTrigoJM, et al. Opioid-sparing effect of cannabinoids: a systematic review and meta-analysis. Neuropsychopharmacology2017; 42(9): 1752–1765.
23.
LiJXKoekWFranceCP.Interactions between Δ9-tetrahydrocannabinol and heroin: self-administration in rhesus monkeys. Behav Pharmacol2012; 23(8): 754–761.
24.
MaguireDRGerakLRFranceCP.Delay discounting of food and remifentanil in rhesus monkeys. Psychopharmacology2013; 229(2): 42–54.
25.
WeedPFGerakLRFranceCP.Ventilatory-depressant effects of opioids alone and in combination with cannabinoids in rhesus monkeys. Eur J Pharmacol2018; 833(5): 120–132.
26.
GerakLRFranceCP.Combined treatment with morphine and Δ9-tetrahydrocannabinol in rhesus monkeys: antinociceptive tolerance and withdrawal. J Pharmacol Exp Ther2016; 357(2): 357–366.
27.
BabalonisSWalshSL.Therapeutic potential of opioid/cannabinoid combinations in humans: review of the evidence. Eur Neuropsychopharmacol2020; 36(4): 45–68.
28.
CooperZDBediGRameshD, et al. Impact of co-administration of oxycodone and smoked Cannabis on analgesia and abuse liability. Neuropsychopharmacology2018; 43(6): 54–72.
29.
DunnKEBergeriaCLHuhnAS, et al. Within-subject, double-blinded, randomized, and placebo-controlled evaluation of the combined effects of the cannabinoid dronabinol and the opioid hydromorphone in a human laboratory pain model. Neuropsychopharmacology2021; 46(8): 1451–1459.
30.
SchoffelmeerANMHogenboomFWardehG, et al. Interactions between CB1 cannabinoid and μ opioid receptors mediating inhibition of neurotransmitter release in rat nucleus accumbens core. Neuropharmacology2006; 51(4): 773–781.
31.
RiosCGomesIDeviLA.μ opioid and CB1 cannabinoid receptor interactions: reciprocal inhibition of receptor signaling and neuritogenesis. Br J Pharmacol2006; 148(4): 387–395.
32.
PorzionatoAStoccoEGuidolinD, et al. Receptor–receptor interactions of G protein-coupled receptors in the carotid body: a working hypothesis. Front Physiol2018; 9: 697.
33.
VayssePJJGardnerELZukinRS.Modulation of rat brain opioid receptors by cannabinoids. J Pharmacol Exp Ther1987; 241(2): 534–539.
34.
KathmannMFlauKRedmerA, et al. Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors. Naunyn Schmiedebergs Arch Pharmacol2006; 372(5): 354–361.
35.
MohammadkhaniABorglandSL.Cellular and behavioral basis of cannabinioid and opioid interactions: implications for opioid dependence and withdrawal. J Neurosci Res2022; 100(1): 278–296.
36.
LorenzettiVChyeYSilvaP, et al. Does regular Cannabis use affect neuroanatomy? An updated systematic review and meta-analysis of structural neuroimaging studies. Eur Arch Psychiatry Clin Neurosci2019; 269(1): 59–71.
37.
Martín-SantosRFagundoABCrippaJA, et al. Neuroimaging in Cannabis use: a systematic review of the literature. Psychol Med2010; 40(3): 383–398.
ArakawaRTakanoAHalldinC.PET technology for drug development in psychiatry. Neuropsychopharmacol Rep2020; 40(5): 232–256.
40.
TakamuraYKakutaH. In vivo receptor visualization and evaluation of receptor occupancy with positron emission tomography. J Med Chem2021(9): 5226–5251.
41.
PhelpsME.PET: the merging of biology and imaging into molecular imaging. J Nucl Med2000; 41(4): 661–681.
42.
HortiALaereK.Development of radioligands for in vivo imaging of type 1 cannabinoid receptors (CB1) in human brain. Curr Pharm Des2008; 14(31): 3363–3383.
43.
HouLRongJHaiderA, et al. Positron emission tomography imaging of the endocannabinoid system: opportunities and challenges in radiotracer development. J Med Chem2021; 64(1): 123–149.
44.
SloanMEGrantCWGowinJL, et al. Endocannabinoid signaling in psychiatric disorders: a review of positron emission tomography studies. Acta Pharmacol Sin2019; 40(3): 342–350.
45.
HjorthSKarlssonCJucaiteA, et al. A PET study comparing receptor occupancy by five selective cannabinoid 1 receptor antagonists in non-human primates. Neuropharmacology2016; 101: 519–530.
46.
ChenYIChoiJKXuH, et al. Pharmacologic neuroimaging of the ontogeny of dopamine receptor function. Dev Neurosci2010; 32(2): 125–138.
47.
JenkinsBG.Pharmacologic magnetic resonance imaging (phMRI): imaging drug action in the brain. Neuroimage2012; 62(2): 1072–1085.
48.
MandevilleJBLiuCHVanduffelW, et al. Data collection and analysis strategies for phMRI. Neuropharmacology2014; 84: 65–78.
49.
BorsookDBecerraLHargreavesR.A role for fMRI in optimizing CNS drug development. Nat Rev Drug Discov2006; 5(5): 411–424.
50.
ElphickMREgertováM.The neurobiology and evolution of cannabinoid signalling. Philos Trans R Soc Lond B Biol Sci2001; 356(1407): 381–408.
51.
BhattacharyyaSCrippaJMartin-SantosR, et al. Imaging the neural effects of cannabinoids: current status and future opportunities for psychopharmacology. Curr Pharm Des2009; 15(22): 2603–2614.
52.
AmpsonAJHRimaldiMGXelrodJA.Cannabidiol and (−)Delta9-tetrahydrocannabinol are neuroprotective antioxidants. Med Sci1998; 95(3): 52–72.
53.
PertweeRG.The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol2008; 153(2): 199–215.
54.
CatanaCDrzezgaAHeissWD, et al. PET/MRI for neurologic applications. J Nucl Med2012; 53(12): 1916–1925.
55.
SanderCYHansenHDWeyHY.Advances in simultaneous PET/MR for imaging neuroreceptor function. Journal of Cerebral Blood Flow and Metabolism2020; 40(6): 1148–1166.
56.
SanderCYHookerJMCatanaC, et al. Neurovascular coupling to D2/D3 dopamine receptor occupancy using simultaneous PET/functional MRI. Proc Natl Acad Sci U S A2013; 110(27): 11169–11174.
57.
MandevilleJBSanderCYMJenkinsBG, et al. A receptor-based model for dopamine-induced fMRI signal. Neuroimage2013; 75: 46–57.
58.
HansenXDMandevilleJBSanderCY, et al. Functional characterization of 5-HT1B receptor drugs in nonhuman primates using simultaneous PET–MR. J Neurosci2017; 37(44): 10671–10678.
59.
CarsonRE.PET physiological measurements using constant infusion. Nucl Med Biol2000; 27(7): 657–660.
60.
AlpertNMBadgaiyanRDLivniE, et al. A novel method for noninvasive detection of neuromodulatory changes in specific neurotransmitter systems. Neuroimage2003; 19(3): 1049–1060.
61.
RohlfingTKroenkeCDSullivanEV, et al. The INIA19 template and NeuroMaps atlas for primate brain image parcellation and spatial normalization. Front Neuroinform2012; 6: 27.
62.
YooC-HChenZRaniN, et al. Evaluation of [(18)F]PF-06455943 as a potential LRRK2 PET imaging agent in the brain of nonhuman primates. ACS Chem Neurosci2023; 14: 370–377.
63.
YooCHDuBoisJMWangL, et al. Preliminary exploration of pseudo-CT-based attenuation correction for simultaneous PET/MRI brain imaging in nonhuman primates. ACS Omega2023; 8(48): 45438–45446.
64.
HortiAGFanHKuwabaraH, et al. 11C-JHU75528: a radiotracer for PET imaging of CB1 cannabinoid receptors. J Nucl Med2006; 47(10): 1689–1696.
65.
NormandinMDZhengMQLinKS, et al. Imaging the cannabinoid CB1 receptor in humans with [11C] OMAR: assessment of kinetic analysis methods, test–retest reproducibility, and gender differences. J Cereb Blood Flow Metab2015; 35(8): 1313–1322.
66.
MandevilleJBWeigand-WhittierJWeyHY, et al. Amphetamine pretreatment blunts dopamine-induced D2/D3-receptor occupancy by an arrestin-mediated mechanism: a PET study in internalization compromised mice. Neuroimage2023; 283: 120416.
67.
KobayashiMJiangTTeluS, et al. 11C-DPA-713 has much greater specific binding to translocator protein 18 kDa (TSPO) in human brain than 11C-(R)-PK11195. J Cereb Blood Flow Metab2018; 38(3): 393–403.
68.
LassenNABartensteinPALammertsmaAA, et al. Benzodiazepine receptor quantification in vivo in humans using [11C]flumazenil and PET: application of the steady-state principle. J Cereb Blood Flow Metab1995; 15: 152–165.
69.
WongDFKuwabaraHHortiAG, et al. Quantification of cerebral cannabinoid receptors subtype 1 (CB1) in healthy subjects and schizophrenia by the novel PET radioligand [11C]OMAR. Neuroimage2010; 52(4): 1505–1513.
70.
TerryGLiowJSChernetE, et al. Positron emission tomography imaging using an inverse agonist radioligand to assess cannabinoid CB1 receptors in rodents. Neuroimage2008; 41(3): 690–698.
71.
YasunoFBrownAKZoghbiSS, et al. The PET radioligand [11C]MePPEP binds reversibly and with high specific signal to cannabinoid CB1 receptors in nonhuman primate brain. Neuropsychopharmacology2008; 33(2): 259–269.
72.
MiedererIMausSZwienerI, et al. Evaluation of cannabinoid type 1 receptor expression in the rat brain using [18F]MK-9470 microPET. Eur J Nucl Med Mol Imaging2013; 40(5): 65–78.
73.
GaddeKMAllisonDB.Cannabinoid-1 receptor antagonist, rimonabant, for management of obesity and related risks. Circulation2006; 114(9): 974–984.
74.
GullapalliSAmrutkarDGuptaS, et al. Characterization of active and inactive states of CB1 receptor and the differential binding state modulation by cannabinoid agonists, antagonists and inverse agonists. Neuropharmacology2010; 58(8): 1215–1219.
75.
ColomMVidalBZimmerL.Is there a role for GPCR agonist radiotracers in PET neuroimaging?Front Mol Neurosci2019; 12: 255.
76.
ZimmerL.Pharmacological agonists for more-targeted CNS radio-pharmaceuticals. Oncotarget2016; 7(49): 80111–80112.
77.
SpindleTRKuwabaraHEversoleA, et al. Brain imaging of cannabinoid type I (CB1) receptors in women with Cannabis use disorder and male and female healthy controls. Addict Biol2021; 26(6): e13061.
78.
D’SouzaDCCortes-BrionesJARanganathanM, et al. Rapid changes in cannabinoid 1 receptor availability in Cannabis-dependent male subjects after abstinence fromCannabis. Biol Psychiatry Cogn Neurosci Neuroimaging2016; 1(1): 60–67.
79.
SalamoneJDMcLaughlinPJSinkK, et al. Cannabinoid CB1 receptor inverse agonists and neutral antagonists: effects on food intake, food-reinforced behavior and food aversions. Physiol Behav2007; 91(4): 383–388.
80.
OgunbiyiMOHindochaCFreemanTP, et al. Acute and chronic effects of Δ9-tetrahydrocannabinol (THC) on cerebral blood flow: a systematic review. Prog Neuropsychopharmacol Biol Psychiatry2020; 101: 109900.
81.
HorderJHarmerCJCowenPJ, et al. Reduced neural response to reward following 7 days treatment with the cannabinoid CB 1 antagonist rimonabant in healthy volunteers. Int J Neuropsychopharmacol2010; 13(8): 1103–1113.
82.
BreivogelCSSimLJChildersSR.Regional differences in cannabinoid receptor/G-protein coupling in rat brain. J Pharmacol Exp Ther1997; 282(3): 1632–1642.
83.
BreivogelCSChildersSR.Cannabinoid agonist signal transduction in rat brain: comparison of cannabinoid agonists in receptor binding, G-protein activation, and adenylyl cyclase inhibition. J Pharmacol Exp Ther2000; 295(1): 328–336.
84.
HsiehC-JHouCLeeH, et al. Total-body imaging of mu-opioid receptors with [11C]carfentanil in non-human primates. Eur J Nucl Med Mol Imaging2024; 51: 3273–3283.
85.
MaguireDRFranceCP.Impact of efficacy at the μ-opioid receptor on antinociceptive effects of combinations of μ-opioid receptor agonists and cannabinoid receptor agonists. J Pharmacol Exp Ther2014; 351(2): 383–389.
86.
HojoMSudoYAndoY, et al. μ-Opioid receptor forms a functional heterodimer with cannabinoid CB1 receptor: electrophysiological and FRET assay analysis. J Pharmacol Sci2008; 108(3): 308–319.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
