Trends in Pharmacological Sciences
OpinionNSAIDs: eNdocannabinoid stimulating anti-inflammatory drugs?
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)
- et al.
Cyclooxygenases: structural and functional insights
J. Lipid Res.
(2009) Precaution, cyclooxygenation, and cardiovascular risk
Trends Pharmacol. Sci.
(2009)Cyclooxygenase-inhibiting nitric oxide donators for osteoarthritis
Trends Pharmacol. Sci.
(2009)Dual COXIB/TP antagonists: a possible new twist in NSAID pharmacology and cardiovascular risk
Trends Pharmacol. Sci.
(2010)- et al.
Oxidative metabolism of endocannabinoids
Prostaglandins Leukot. Essent. Fatty Acids
(2002) - et al.
Cannabinoids as pharmacotherapies for neuropathic pain: from the bench to the bedside
Neurotherapeutics
(2009) A role for endocannabinoids in indomethacin-induced spinal antinociception
Eur. J. Pharmacol.
(2002)Spinal antinociceptive effects of cyclooxygenase inhibition during inflammation: involvement of prostaglandins and endocannabinoids
Pain
(2010)Changes in spinal and supraspinal endocannabinoid levels in neuropathic rats
Neuropharmacology
(2007)Inhibition of anandamide hydrolysis by the enantiomers of ibuprofen, ketorolac, and flurbiprofen
Arch. Biochem. Biophys.
(1999)