Effects of Cannabinoids and Cannabinoid-enriched Cannabis Extracts on TRP Channels and Endocannabinoid Metabolic Enzymes

Overview

Journal Br J Pharmacol

Publisher Wiley

Specialty Pharmacology

Date 2010 Dec 24

PMID 21175579

Citations 409

Authors

Luciano De Petrocellis

Alessia Ligresti

Aniello Schiano Moriello

Marco Allara

Tiziana Bisogno

Stefania Petrosino

Colin G Stott

Vincenzo Di Marzo

Affiliations

Soon will be listed here.

Abstract

Background And Purpose: Cannabidiol (CBD) and Δ(9) -tetrahydrocannabinol (THC) interact with transient receptor potential (TRP) channels and enzymes of the endocannabinoid system.

Experimental Approach: The effects of 11 pure cannabinoids and botanical extracts [botanical drug substance (BDS)] from Cannabis varieties selected to contain a more abundant cannabinoid, on TRPV1, TRPV2, TRPM8, TRPA1, human recombinant diacylglycerol lipase α (DAGLα), rat brain fatty acid amide hydrolase (FAAH), COS cell monoacylglycerol lipase (MAGL), human recombinant N-acylethanolamine acid amide hydrolase (NAAA) and anandamide cellular uptake (ACU) by RBL-2H3 cells, were studied using fluorescence-based calcium assays in transfected cells and radiolabelled substrate-based enzymatic assays. Cannabinol (CBN), cannabichromene (CBC), the acids (CBDA, CBGA, THCA) and propyl homologues (CBDV, CBGV, THCV) of CBD, cannabigerol (CBG) and THC, and tetrahydrocannabivarin acid (THCVA) were also tested.

Key Results: CBD, CBG, CBGV and THCV stimulated and desensitized human TRPV1. CBC, CBD and CBN were potent rat TRPA1 agonists and desensitizers, but THCV-BDS was the most potent compound at this target. CBG-BDS and THCV-BDS were the most potent rat TRPM8 antagonists. All non-acid cannabinoids, except CBC and CBN, potently activated and desensitized rat TRPV2. CBDV and all the acids inhibited DAGLα. Some BDS, but not the pure compounds, inhibited MAGL. CBD was the only compound to inhibit FAAH, whereas the BDS of CBC > CBG > CBGV inhibited NAAA. CBC = CBG > CBD inhibited ACU, as did the BDS of THCVA, CBGV, CBDA and THCA, but the latter extracts were more potent inhibitors.

Conclusions And Implications: These results are relevant to the analgesic, anti-inflammatory and anti-cancer effects of cannabinoids and Cannabis extracts.

Citing Articles

A systematic study of molecular targets of cannabidiol in Alzheimer's disease.

Patil N, Patil K, Jain M, Mohammed A, Yadav A, Dhanda P J Alzheimers Dis Rep. 2025; 8(1):1339-1360.

PMID: 40034365 PMC: 11863746. DOI: 10.1177/25424823241284464.

Extraction, GC-MS analysis, cytotoxic, anti-inflammatory and anticancer potential of female flower; , and .

Safir W, Malik A, Saadia H, Zahid A, Li J Front Pharmacol. 2025; 16:1546062.

PMID: 40008130 PMC: 11850312. DOI: 10.3389/fphar.2025.1546062.

The Endocannabinoid System: Implications in Gastrointestinal Physiology and Pathology.

Aloisio Caruso E, De Nunzio V, Tutino V, Notarnicola M Int J Mol Sci. 2025; 26(3).

PMID: 39941074 PMC: 11818434. DOI: 10.3390/ijms26031306.

Role of TRP Channels in Cancer-Induced Bone Pain.

Coluzzi F, Scerpa M, Alessandri E, Romualdi P, Rocco M Int J Mol Sci. 2025; 26(3).

PMID: 39940997 PMC: 11818569. DOI: 10.3390/ijms26031229.

Nav1.8, an analgesic target for nonpsychotomimetic phytocannabinoids.

Ghovanloo M, Tyagi S, Zhao P, Waxman S Proc Natl Acad Sci U S A. 2025; 122(4):e2416886122.

PMID: 39835903 PMC: 11789019. DOI: 10.1073/pnas.2416886122.

References

Bisogno T, Cascio M, Saha B, Mahadevan A, Urbani P, Minassi A . Development of the first potent and specific inhibitors of endocannabinoid biosynthesis. Biochim Biophys Acta. 2006; 1761(2):205-12. DOI: 10.1016/j.bbalip.2005.12.009. View

Izzo A, Borrelli F, Capasso R, Di Marzo V, Mechoulam R . Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol Sci. 2009; 30(10):515-27. DOI: 10.1016/j.tips.2009.07.006. View

Hayakawa K, Mishima K, Hazekawa M, Sano K, Irie K, Orito K . Cannabidiol potentiates pharmacological effects of Delta(9)-tetrahydrocannabinol via CB(1) receptor-dependent mechanism. Brain Res. 2007; 1188:157-64. DOI: 10.1016/j.brainres.2007.09.090. View

Mechoulam R, Shvo Y . Hashish. I. The structure of cannabidiol. Tetrahedron. 1963; 19(12):2073-8. DOI: 10.1016/0040-4020(63)85022-x. View

Thomas A, Baillie G, Phillips A, Razdan R, Ross R, Pertwee R . Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. Br J Pharmacol. 2007; 150(5):613-23. PMC: 2189767. DOI: 10.1038/sj.bjp.0707133. View

Ueda N, Yamanaka K, Yamamoto S . Purification and characterization of an acid amidase selective for N-palmitoylethanolamine, a putative endogenous anti-inflammatory substance. J Biol Chem. 2001; 276(38):35552-7. DOI: 10.1074/jbc.M106261200. View

Resstel L, Tavares R, Lisboa S, Joca S, Correa F, Guimaraes F . 5-HT1A receptors are involved in the cannabidiol-induced attenuation of behavioural and cardiovascular responses to acute restraint stress in rats. Br J Pharmacol. 2009; 156(1):181-8. PMC: 2697769. DOI: 10.1111/j.1476-5381.2008.00046.x. View

Gong J, Onaivi E, Ishiguro H, Liu Q, Tagliaferro P, Brusco A . Cannabinoid CB2 receptors: immunohistochemical localization in rat brain. Brain Res. 2006; 1071(1):10-23. DOI: 10.1016/j.brainres.2005.11.035. View

Russo E, Guy G . A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. Med Hypotheses. 2005; 66(2):234-46. DOI: 10.1016/j.mehy.2005.08.026. View

10.

Capasso R, Borrelli F, Aviello G, Romano B, Scalisi C, Capasso F . Cannabidiol, extracted from Cannabis sativa, selectively inhibits inflammatory hypermotility in mice. Br J Pharmacol. 2008; 154(5):1001-8. PMC: 2451037. DOI: 10.1038/bjp.2008.177. View

11.

Comelli F, Giagnoni G, Bettoni I, Colleoni M, Costa B . The inhibition of monoacylglycerol lipase by URB602 showed an anti-inflammatory and anti-nociceptive effect in a murine model of acute inflammation. Br J Pharmacol. 2007; 152(5):787-94. PMC: 2190015. DOI: 10.1038/sj.bjp.0707425. View

12.

Monet M, Gkika D, Lehenkyi V, Pourtier A, Vanden Abeele F, Bidaux G . Lysophospholipids stimulate prostate cancer cell migration via TRPV2 channel activation. Biochim Biophys Acta. 2009; 1793(3):528-39. DOI: 10.1016/j.bbamcr.2009.01.003. View

13.

Solorzano C, Zhu C, Battista N, Astarita G, Lodola A, Rivara S . Selective N-acylethanolamine-hydrolyzing acid amidase inhibition reveals a key role for endogenous palmitoylethanolamide in inflammation. Proc Natl Acad Sci U S A. 2009; 106(49):20966-71. PMC: 2791595. DOI: 10.1073/pnas.0907417106. View

14.

Hohmann A, Suplita R, Bolton N, Neely M, Fegley D, Mangieri R . An endocannabinoid mechanism for stress-induced analgesia. Nature. 2005; 435(7045):1108-12. DOI: 10.1038/nature03658. View

15.

Sofia R, Nalepa S, Vassar H, Knobloch L . Comparative anti-phlogistic activity of delta 9-tetrahydrocannabinol, hydrocortisone and aspirin in various rat paw edema models. Life Sci. 1974; 15(2):251-60. DOI: 10.1016/0024-3205(74)90214-8. View

16.

King A, Dotsey E, Lodola A, Jung K, Ghomian A, Qiu Y . Discovery of potent and reversible monoacylglycerol lipase inhibitors. Chem Biol. 2009; 16(10):1045-52. PMC: 3034734. DOI: 10.1016/j.chembiol.2009.09.012. View

17.

De Petrocellis L, Vellani V, Schiano-Moriello A, Marini P, Magherini P, Orlando P . Plant-derived cannabinoids modulate the activity of transient receptor potential channels of ankyrin type-1 and melastatin type-8. J Pharmacol Exp Ther. 2008; 325(3):1007-15. DOI: 10.1124/jpet.107.134809. View

18.

Bisogno T, Howell F, Williams G, Minassi A, Cascio M, Ligresti A . Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain. J Cell Biol. 2003; 163(3):463-8. PMC: 2173631. DOI: 10.1083/jcb.200305129. View

19.

Iuvone T, Esposito G, De Filippis D, Scuderi C, Steardo L . Cannabidiol: a promising drug for neurodegenerative disorders?. CNS Neurosci Ther. 2009; 15(1):65-75. PMC: 6494021. DOI: 10.1111/j.1755-5949.2008.00065.x. View

20.

Pertwee R . The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol. 2007; 153(2):199-215. PMC: 2219532. DOI: 10.1038/sj.bjp.0707442. View