Online citations, reference lists, and bibliographies.
← Back to Search

Local Interactions Between Anandamide, An Endocannabinoid, And Ibuprofen, A Nonsteroidal Anti-inflammatory Drug, In Acute And Inflammatory Pain

J. Guindon, A. D. Léan, P. Beaulieu
Published 2006 · Chemistry, Medicine

Save to my Library
Download PDF
Analyze on Scholarcy
Share
Abstract Anandamide, an endocannabinoid, is degraded by the enzyme fatty acid amide hydrolase which can be inhibited by nonsteroidal anti‐inflammatory drugs (NSAIDs). The present work was designed to study the peripheral interactions between anandamide and ibuprofen (a non‐specific cyclooxygenase inhibitor) in the rat formalin test. We first determined the ED50 for anandamide (0.018 &mgr;g ± 0.009), ibuprofen (0.18 &mgr;g ± 0.09), and their combination (0.006 &mgr;g ± 0.002). Drugs were given 15 min before a 2.5% formalin injection into the dorsal surface of the right hind paw. Results were analyzed using isobolographic analysis. The antinociceptive interaction between anandamide and ibuprofen was synergistic. To further investigate the mechanisms by which the combination of anandamide with ibuprofen produced their antinociceptive effects, we used specific antagonists for the cannabinoid CB1 (AM251; 80 &mgr;g) and CB2 (AM630; 25 &mgr;g) receptors. We demonstrated that the antinociceptive effects of ibuprofen were not antagonized by either AM251 or AM630 and that those of anandamide were antagonized by AM251 but not by AM630. The synergistic antinociceptive effects of the combination of anandamide with ibuprofen were completely antagonized by AM251 but only partially inhibited by AM630. In conclusion, locally (hind paw) injected anandamide, ibuprofen or combination thereof decreased pain behavior in the formalin test. The combination of anandamide with ibuprofen produced synergistic antinociceptive effects involving both cannabinoid CB1 and CB2 receptors. Comprehension of the mechanisms involved needs further investigation.
This paper references
Mice lacking fatty
AH 429041–9.Lichtman (2003)
10.1016/0006-8993(90)90389-S
Effects of cyclooxygenase products of arachidonic acid metabolism on cutaneous nociceptive threshold in the rat
Y. O. Taiwo (1990)
10.1021/BI034471K
Amino acid determinants in cyclooxygenase-2 oxygenation of the endocannabinoid anandamide.
K. Kozak (2003)
10.1016/S0024-3205(02)01491-1
Comparison of the antinociceptive effect of celecoxib, diclofenac and resveratrol in the formalin test.
J. E. Torres-López (2002)
10.1046/j.1460-9568.2003.02470.x
Intrathecally applied flurbiprofen produces an endocannabinoid‐dependent antinociception in the rat formalin test
M. Ates (2003)
10.1016/S0304-3959(98)00041-4
The anti-hyperalgesic actions of the cannabinoid anandamide and the putative CB2 receptor agonist palmitoylethanolamide in visceral and somatic inflammatory pain
S. Jaggar (1998)
10.1016/S0009-3084(02)00155-X
Inhibition of pain responses by activation of CB(2) cannabinoid receptors.
T. Malan (2002)
10.1016/S1056-8719(00)00047-2
Evidence for the participation of the nitric oxide-cyclic GMP pathway in the antinociceptive effect of nimesulide.
M. Islas-Cadena (1999)
10.1016/S0028-3908(03)00195-3
Intraplantar injection of anandamide inhibits mechanically-evoked responses of spinal neurones via activation of CB2 receptors in anaesthetised rats
D. M. Sokal (2003)
10.1016/S0024-3205(97)00690-5
Binding of the non-classical cannabinoid CP 55,940, and the diarylpyrazole AM251 to rodent brain cannabinoid receptors.
S. Gatley (1997)
Intraplantar injection of a cyclooxygenase
phenotypic hypoalgesia. Pain (2004)
10.1016/S0014-2999(00)00157-6
Evidence for the participation of the nitric oxide-cyclic GMP pathway in the antinociceptive action of meloxicam in the formalin test.
P. Aguirre-Bañuelos (2000)
10.1016/S0024-3205(97)01030-8
Efficient designs for studying synergistic drug combinations.
R. Tallarida (1997)
10.1111/J.1432-1033.1995.TB20780.X
Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations.
S. Galiègue (1995)
10.1016/0304-3959(92)90003-T
The formalin test: an evaluation of the method
A. Tjølsen (1992)
10.1007/s002130050955
Local administration of Δ9-tetrahydrocannabinol attenuates capsaicin-induced thermal nociception in rhesus monkeys: a peripheral cannabinoid action
M.-C. Ko (1999)
10.1016/S0165-6147(00)01482-6
The endocannabinoid system as a target for therapeutic drugs.
D. Piomelli (2000)
10.1038/365061A0
Molecular characterization of a peripheral receptor for cannabinoids
S. Munro (1993)
10.1016/S0304-3959(01)00336-0
Cannabinoids attenuate capsaicin-evoked hyperalgesia through spinal and peripheral mechanisms
L. Johanek (2001)
10.1054/PLEF.2001.0362
Endocannabinoids and pain: spinal and peripheral analgesia in inflammation and neuropathy.
A. Rice (2002)
10.1016/S0014-2999(97)00047-2
AM630 antagonism of cannabinoid-stimulated [35S]GTPγS binding in the mouse brain
Y. Hosohata (1997)
10.1523/JNEUROSCI.5054-03.2004
Constitutive Spinal Cyclooxygenase-2 Participates in the Initiation of Tissue Injury-Induced Hyperalgesia
J. Ghilardi (2004)
The anti-hyperalgesic
SI 4287–92.Jaggar (1999)
10.1126/SCIENCE.1470919
Isolation and structure of a brain constituent that binds to the cannabinoid receptor.
W. Devane (1992)
10.1016/S0304-3940(02)01366-6
Flurbiprofen inhibits capsaicin induced calcitonin gene related peptide release from rat spinal cord via an endocannabinoid dependent mechanism
K. Seidel (2003)
10.1016/S0014-2999(02)02485-8
A role for endocannabinoids in indomethacin-induced spinal antinociception.
H. Gühring (2002)
10.1159/000136761
A new mechanical method for measuring rat paw edema.
M. Petricevic (1978)
Makriyannis A. 123 Ilabelled AM251: a radioiodinated ligand which binds in vivo to mouse brain cannabinoid CB1 receptors
S J Gatley (1996)
10.1038/sj.bjp.0704466
Antiinflammatory action of endocannabinoid palmitoylethanolamide and the synthetic cannabinoid nabilone in a model of acute inflammation in the rat
S. Conti (2002)
10.1016/S0304-3959(97)00213-3
Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors
J. D. Richardson (1998)
10.1006/ABBI.1998.1025
Inhibition of anandamide hydrolysis by the enantiomers of ibuprofen, ketorolac, and flurbiprofen.
C. Fowler (1999)
10.1124/JPET.105.096198
Response to Comments on “Isobolographic Analysis for Combinations of a Full and Partial Agonist: Curved Isoboles”
R. Tallarida (2006)
10.1002/0471458503.CH4
Statistical Principles in Experimental Design
R. Mason (2003)
10.1038/28393
Control of pain initiation by endogenous cannabinoids
A. Calignano (1998)
10.1038/346561A0
Structure of a cannabinoid receptor and functional expression of the cloned cDNA
L. Matsuda (1990)
10.1006/nbdi.1998.0221
Endogenous Cannabinoid Signaling
D. Piomelli (1998)
10.1152/AJPENDO.1978.235.2.E97
Simultaneous analysis of families of sigmoidal curves: application to bioassay, radioligand assay, and physiological dose-response curves.
A. Deléan (1978)
10.1038/sj.bjp.0704937
Selective inhibitors of cyclo‐oxygenase‐2 (COX‐2) induce hypoalgesia in a rat paw model of inflammation
J. Francischi (2002)
10.1016/S0009-3084(02)00154-8
Spinal and peripheral mechanisms of cannabinoid antinociception: behavioral, neurophysiological and neuroanatomical perspectives.
A. Hohmann (2002)
10.1038/384083A0
Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides
B. Cravatt (1996)
10.1073/PNAS.96.25.14228
HU-308: a specific agonist for CB(2), a peripheral cannabinoid receptor.
L. Hanuš (1999)
10.1038/sj.bjp.0702351
Agonist‐inverse agonist characterization at CB1 and CB2 cannabinoid receptors of L759633, L759656 and AM630
R. Ross (1999)
10.1016/0014-2999(96)00015-5
N-(2-hydroxyethyl)hexadecanamide is orally active in reducing edema formation and inflammatory hyperalgesia by down-modulating mast cell activation.
S. Mazzari (1996)
10.1016/S0306-4522(03)00497-4
Intraplantar injection of a cyclooxygenase inhibitor ketorolac reduces immunoreactivities of substance p, calcitonin gene-related peptide, and dynorphin in the dorsal horn of rats with nerve injury or inflammation
W. Ma (2003)
10.1016/j.pain.2004.01.022
Mice lacking fatty acid amide hydrolase exhibit a cannabinoid receptor-mediated phenotypic hypoalgesia
A. Lichtman (2004)
10.1016/0024-3205(95)00175-6
AM630, a competitive cannabinoid receptor antagonist.
R. Pertwee (1995)
10.1016/S0304-3959(96)03299-X
Optimal scoring strategies and weights for the formalin test in rats
G. Watson (1997)
10.1016/S0014-2999(01)00988-8
Antinociceptive activity of the endogenous fatty acid amide, palmitylethanolamide.
A. Calignano (2001)
10.1016/J.LFS.2004.10.025
Inverse agonism and neutral antagonism at cannabinoid CB1 receptors.
R. Pertwee (2005)
10.1016/S0306-4522(02)00870-9
A peripheral cannabinoid mechanism suppresses spinal fos protein expression and pain behavior in a rat model of inflammation
A. Nackley (2003)
10.1016/0014-2999(96)00279-8
123I-labeled AM251: a radioiodinated ligand which binds in vivo to mouse brain cannabinoid CB1 receptors.
S. Gatley (1996)
10.1111/J.1600-0773.1997.TB00291.X
Ibuprofen inhibits the metabolism of the endogenous cannabimimetic agent anandamide.
C. Fowler (1997)
Antinociceptive actions of spinal nonsteroidal anti-inflammatory agents on the formalin test in the rat.
A. Malmberg (1992)
10.1016/S0304-3959(01)00321-9
CB2 cannabinoid receptor-mediated peripheral antinociception
T. Malan (2001)
N-(2hydroxyethyl)hexadecanamide is orally active in reducing edema formation and inflammatory hyperalgesia by downmodulating mast cell activation
S Mazzari (1996)
10.1038/sj.bjp.0703850
Structure‐activity relationship for the endogenous cannabinoid, anandamide, and certain of its analogues at vanilloid receptors in transfected cells and vas deferens
R. Ross (2001)
10.2307/2004561
Applied Regression Analysis
Nathan Jaspen (1968)



This paper is referenced by
Title The antinociceptive effects of local injections of propofol in rats are mediated in part by cannabinoid CB 1 and CB 2 receptors
J. Guindon (2007)
THEMED ISSUE: CANNABINOIDS RESEARCH PAPER Biochanin A, a naturally occurring inhibitor of fatty
L. Thors (2010)
10.5772/INTECHOPEN.79673
Modulation of Pain by Endocannabinoids in the Periphery
M. Uhelski (2018)
10.1007/978-3-642-42014-6_11
PET Imaging of Endocannabinoid System
A. Horti (2014)
10.1186/1744-8069-10-56
Optimization of a cisplatin model of chemotherapy-induced peripheral neuropathy in mice: use of vitamin C and sodium bicarbonate pretreatments to reduce nephrotoxicity and improve animal health status
J. Guindon (2014)
10.1098/rstb.2011.0381
Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities
R. Pertwee (2012)
10.1038/sj.bjp.0707531
Cannabinoid CB2 receptors: a therapeutic target for the treatment of inflammatory and neuropathic pain
J. Guindon (2008)
10.1016/j.molmed.2019.04.009
Endocannabinoid and Prostanoid Crosstalk in Pain.
Baptiste Buisseret (2019)
10.1016/j.tips.2014.04.006
Substrate-selective COX-2 inhibition as a novel strategy for therapeutic endocannabinoid augmentation.
D. J. Hermanson (2014)
10.4274/balkanmedj.galenos.2020.2020.6.66
Non-opioid Analgesics and the Endocannabinoid System
R. D. Topuz (2020)
10.1021/jm4005626
Therapeutic utility of cannabinoid receptor type 2 (CB(2)) selective agonists.
Sangdon Han (2013)
Endocannabinoids and N-acylethanolamines in translational pain research : from monoacylglycerol lipase to muscle pain
Nazdar Ghafouri (2013)
10.1016/j.lfs.2010.02.006
The antinociceptive effect of acetylsalicylic acid is differently affected by a CB1 agonist or antagonist and involves the serotonergic system in rats.
V. Ruggieri (2010)
10.1371/journal.pone.0103589
Inhibition of Endocannabinoid Metabolism by the Metabolites of Ibuprofen and Flurbiprofen
Jessica Karlsson (2014)
Investigating the antinociceptive effects of N-docosahexaenoyl ethanolamine and novel kappa opioid receptor agonists
K. Paton (2018)
10.1111/j.1476-5381.2008.00029.x
The case for the development of novel analgesic agents targeting both fatty acid amide hydrolase and either cyclooxygenase or TRPV1
C. Fowler (2009)
Modulation of pain sensitivity by endogenous and exogenous ligands and by social isolation
G. Tuboly (2010)
10.1002/cmdc.201500395
A Double Whammy: Targeting Both Fatty Acid Amide Hydrolase (FAAH) and Cyclooxygenase (COX) To Treat Pain and Inflammation
R. Scarpelli (2016)
10.2174/187152709789824660
The endocannabinoid system and pain.
J. Guindon (2009)
10.3928/02793695-20150422-01
Synthetic cannabinoids: the dangers of spicing it up.
Deborah A Salani (2015)
10.1213/ANE.0000000000000070
The Endocannabinoid Anandamide Inhibits Voltage-Gated Sodium Channels Nav1.2, Nav1.6, Nav1.7, and Nav1.8 in Xenopus Oocytes
Dan Okura (2014)
10.2174/1874467210902010134
The Role of the Endogenous Cannabinoid System in Peripheral Analgesia
Josée Guindon (2009)
LOS ENDOCANNABINOIDES COMO UNA FUTURA HERRAMIENTA PARA EL TRATAMIENTO DE CÁNCER
Fabio Mayorga Niño (2014)
10.1016/B978-0-323-31696-5.00024-3
Chapter 24 – Prostaglandins, Leukotrienes, and Related Compounds
R. Zurier (2017)
10.1111/j.1476-5381.2010.00974.x
Inhibition of monoacylglycerol lipase by troglitazone, N‐arachidonoyl dopamine and the irreversible inhibitor JZL184: comparison of two different assays
E. Björklund (2010)
10.1111/j.1476-5381.2010.00716.x
Biochanin A, a naturally occurring inhibitor of fatty acid amide hydrolase
L. Thors (2010)
ENDOCANNABINOID MODULATION OF CAPSAICIN-INDUCED BEHAVIORAL HYPERSENSITIVITY by JESSICA MARIE SPRADLEY
Andrea Hohmann (2010)
10.1371/journal.pone.0152913
A Randomized Placebo Controlled Trial of Ibuprofen for Respiratory Syncytial Virus Infection in a Bovine Model
P. Walsh (2016)
10.1152/jn.90809.2008
Cannabinoid modulation of cutaneous Adelta nociceptors during inflammation.
Carl Potenzieri (2008)
10.1016/j.pain.2007.01.015
Blockade of central cyclooxygenase (COX) pathways enhances the cannabinoid-induced antinociceptive effects on inflammatory temporomandibular joint (TMJ) nociception
D. K. Ahn (2007)
BIOWAIVER MONOGRAGHS OF DEXIBUPROFEN
R. Sivakumar (2013)
10.1159/000156485
Effect of Cannabinoid Receptor Agonists on Streptozotocin-Induced Hyperalgesia in Diabetic Neuropathy
M. Bujalska (2008)
See more
Semantic Scholar Logo Some data provided by SemanticScholar