Opinion
NSAIDs: eNdocannabinoid stimulating anti-inflammatory drugs?

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Read any pharmacology textbook and the message is clear: nonsteroidal anti-inflammatory drugs (NSAIDs) act by inhibiting the activity of cyclooxygenase (COX) and thereby the production of prostaglandins. However, evidence is accumulating that NSAIDs involve the endocannabinoid system in their actions, and that such effects may pave the way towards the design of new analgesics that are not plagued with the gastrointestinal and cardiovascular adverse actions that are associated with this class of drugs. In this Opinion article, our current understanding of the involvement of the endocannabinoid system in the actions of NSAIDs is described, and the ways in which this can lead to novel drug development is discussed.

Section snippets

Pharmacology of NSAIDs

Prostaglandin G/H synthases 1 and 2, commonly called COX -1 and -2, are homodimeric enzymes with COX and peroxidase activities that catalyse the production of prostaglandins from arachidonic acid [1]. COX-1 and -2 are the target of compounds such as ibuprofen and naproxen, whereas COX-2 is targeted by compounds such as celecoxib and L745337. Although blockade of prostaglandin production is inextricably associated with the antinociceptive, anti-inflammatory and antipyretic effects of NSAIDs [2],

The endocannabinoid system

The endocannabinoid system in its simplest form can be described as the endogenous ligands anandamide (arachidonoylethanolamide, AEA) and 2-arachidonoylglycerol (2-AG), their target G-protein-coupled CB1 and CB2 receptors [8], and their synthetic and catabolic enzymes. AEA is hydrolysed to arachidonic acid by the enzyme fatty acid amide hydrolase (FAAH), whereas several enzymes [monoacylglycerol lipase (MGL), α/β-hydrolase domains 6 and 12 as well as FAAH] are responsible for 2-AG hydrolysis 9,

NSAIDs involve the endocannabinoid system in their analgesic actions

In 2002, Gühring et al. [20] reported that the spinal administration of the NSAID indomethacin to mice produced antinociceptive activity in the formalin test of prolonged pain, and that the effect was blocked by the CB1 receptor antagonist/inverse agonist AM251. The antinociceptive activity of indomethacin in this model was also lost in CB1–/– mice [20]. Although in a different model (inflammation-evoked spinal hyperexcitation) spinally administered indomethacin had no effect by itself at the

Placebo analgesic responses and the endocannabinoid system

In an elegant study, Benedetti et al. [26] investigated the endocannabinoid component of the placebo response to the opioid analgesic morphine and to the NSAID ketorolac. In this double-blind study, volunteers were subjected to ischaemic forearm pain produced by hand exercise following application of a tourniquet. For four patient groups (n = 14–15/group) the tourniquet test was applied on five separate occasions in the following order of treatments: none, analgesic, analgesic, placebo (± the CB

NSAIDs affect endocannabinoid metabolism

In theory, NSAIDs could produce their endocannabinoid-mediated effects by increasing AEA and 2-AG levels, or alternatively by normalising deficient levels produced by the pain syndrome, parallel to their effects on prostaglandin production. In the spinal nerve ligation model of neuropathic pain, AEA levels in the dorsal root ganglia (DRG), the dorsal horn of the spinal cord and the forebrain cortex follow this pattern, with a decrease after the lesion, but with broadly normal levels seen in R

Paracetamol and dipyrone

Although not an NSAID, paracetamol can be of interest here, because it has also been suggested to involve the endocannabinoid system in its actions. In rodents, administration of paracetamol results in the formation of N-(4-hydroxyphenyl)arachidonylamide (AM404) via an FAAH-dependent pathway, as it is not found in FAAH–/– mice [54]. AM404 has a multiplicity of actions, including blockade of endocannabinoid uptake [55] and inhibition of COX-1 and -2 [54]. The importance of this pathway in the

Implications for drug discovery and treatment strategies

The toxicity associated with NSAID use 3, 4, 5 is problematic for many patients, and a reasonable question to be asked is whether the endocannabinoid-mediated effects of NSAIDs are useful in either designing new drugs or mitigating the unwanted effects of this class of compounds. With respect to the former, it has long been known that R-flurbiprofen has analgesic effects and a lower gastrointestinal toxicity than the S-enantiomer 61, 62, and the identification of a potential mechanism [42] to

Concluding remarks

The title of this article somewhat provocatively suggested that the ‘N’ in NSAID should be rebranded to recognise the endocannabinoid involvement of this class of drugs. Of course, this was an attention-grabbing exercise rather than a serious suggestion, and it is wise not to rule out other biological targets potentially contributing to the modus operandi of NSAIDs such as the prostanoid DP2 receptor [68], the multidrug resistance protein MRP4, which can transport prostaglandins [69], and

References (70)

  • J. Guindon

    Local interactions between anandamide, an endocannabinoid, and ibuprofen, a nonsteroidal anti-inflammatory drug, in acute and inflammatory pain

    Pain

    (2006)
  • K.R. Kozak

    Amino acid determinants in cyclooxygenase-2 oxygenation of the endocannabinoid 2-arachidonylglycerol

    J. Biol. Chem.

    (2001)
  • A.J. Vecchio et al.

    The structural basis of endocannabinoid oxygenation by cyclooxygenase-2

    J. Biol. Chem.

    (2011)
  • G.C. Brailoiu

    Intracellular cannabinoid type 1 (CB1) receptors are activated by anandamide

    J. Biol. Chem.

    (2011)
  • L. Jean-Gilles

    Interaction between cytokines, cannabinoids and the nervous system

    Immunobiology

    (2010)
  • A. Singh Tahim

    Inflammatory mediators convert anandamide into a potent activator of the vanilloid type 1 transient receptor potential receptor in nociceptive primary sensory neurons

    Neuroscience

    (2005)
  • G. Horvath

    The role of TRPV1 receptors in the antinociceptive effect of anandamide at spinal level

    Pain

    (2008)
  • E. Högestätt

    Conversion of acetaminophen to the bioactive N-acylphenolamine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system

    J. Biol. Chem.

    (2005)
  • C. Mallet

    Endocannabinoid and serotonergic systems are needed for acetaminophen-induced analgesia

    Pain

    (2008)
  • V. Haller

    Non-cannabinoid CB1, non-cannabinoid CB2 antinociceptive effects of several novel compounds in the PPQ stretch test in mice

    Eur. J. Pharmacol.

    (2006)
  • T. Rogosch

    Novel bioactive metabolites of dipyrone (metamizol)

    Bioorg. Med. Chem.

    (2012)
  • N.M. Davies

    Effect of the enantiomers of flurbiprofen, ibuprofen, and ketoprofen on intestinal permeability

    J. Pharm. Sci.

    (1996)
  • O. Sasso

    Peripheral FAAH inhibition causes profound antinociception and protects against indomethacin-induced gastric lesions

    Pharmacol. Res.

    (2012)
  • S. Holt

    Inhibition of fatty acid amide hydrolase, a key endocannabinoid metabolizing enzyme, by analogues of ibuprofen and indomethacin

    Eur. J. Pharmacol.

    (2007)
  • F. De Wael

    Chemistry around imidazopyrazine and ibuprofen: discovery of novel fatty acid amide hydrolase (FAAH) inhibitors

    Eur. J. Med. Chem.

    (2010)
  • J. Lehmann

    Peroxisome proliferator-activated receptors α and γ are activated by indomethacin and other non-steroidal anti-inflammatory drugs

    J. Biol. Chem.

    (1997)
  • J. Vane

    Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs

    Nat. New Biol.

    (1971)
  • S. Trelle

    Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis

    BMJ

    (2011)
  • J.L. Wallace

    NSAID gastropathy and enteropathy: distinct pathogenesis likely necessitates distinct prevention strategies

    Br. J. Pharmacol.

    (2012)
  • R.G. Pertwee

    International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB1 and CB2

    Pharmacol. Rev.

    (2010)
  • G. Labar et al.

    Fatty acid amide hydrolase: from characterization to therapeutics

    Chem. Biodivers.

    (2007)
  • N. Ueda

    Biosynthesis and degradation of the endocannabinoid 2-arachidonoylglycerol

    Biofactors

    (2011)
  • B.F. Cravatt

    Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase

    Proc. Natl. Acad. Sci. U.S.A.

    (2001)
  • S. Kathuria

    Modulation of anxiety through blockade of anandamide hydrolysis

    Nat. Med.

    (2003)
  • J.Z. Long

    Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects

    Nat. Chem. Biol.

    (2009)
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