R-Flurbiprofen Reduces Neuropathic Pain in Rodents by Restoring Endogenous Cannabinoids

Abstract

BackgroundR-flurbiprofen, one of the enantiomers of flurbiprofen racemate, is inactive with respect to cyclooxygenase inhibition, but shows analgesic properties without relevant toxicity. Its mode of action is still unclear.Methodology/Principal FindingsWe show that R-flurbiprofen reduces glutamate release in the dorsal horn of the spinal cord evoked by sciatic nerve injury and thereby alleviates pain in sciatic nerve injury models of neuropathic pain in rats and mice. This is mediated by restoring the balance of endocannabinoids (eCB), which is disturbed following peripheral nerve injury in the DRGs, spinal cord and forebrain. The imbalance results from transcriptional adaptations of fatty acid amide hydrolase (FAAH) and NAPE-phospholipase D, i.e. the major enzymes involved in anandamide metabolism and synthesis, respectively. R-flurbiprofen inhibits FAAH activity and normalizes NAPE-PLD expression. As a consequence, R-Flurbiprofen improves endogenous cannabinoid mediated effects, indicated by the reduction of glutamate release, increased activity of the anti-inflammatory transcription factor PPARγ and attenuation of microglia activation. Antinociceptive effects are lost by combined inhibition of CB1 and CB2 receptors and partially abolished in CB1 receptor deficient mice. R-flurbiprofen does however not cause changes of core body temperature which is a typical indicator of central effects of cannabinoid-1 receptor agonists.ConclusionOur results suggest that R-flurbiprofen improves the endogenous mechanisms to regain stability after axonal injury and to fend off chronic neuropathic pain by modulating the endocannabinoid system and thus constitutes an attractive, novel therapeutic agent in the treatment of chronic, intractable pain.

Pharmacogenetics of new analgesics

“…Lack of FAAH has been associated with a cannabinoid related hypoalgesic phenotype in mice (Lichtman et al, 2004). Moreover, FAAH has been implicated in the antinociceptive effects of paracetamol (Högestätt et al, 2005;Mallet et al, 2008) and other analgesics such as R-flurbiprofen (Ates et al, 2003;Bishay et al, 2010) affecting prostaglandin production and therefore, its polymorphisms may modulate the action of classical and new analgesics.…”

Activation of Mas Oncogene-Related G Protein–Coupled Receptors Inhibits Neurochemical Alterations in the Spinal Dorsal Horn and Dorsal Root Ganglia Associated with Inflammatory Pain in Rats

“…Nociceptive inputs can also be modulated in dorsal root ganglia (DRG) before traveling to the central nervous system. For example, the activation of opioid (Ji et al, 1995), acetylcholine, GABA (Li et al, 2002), galanin (Holmes et al, 2003), and cannabinoid (Bishay et al, 2010) receptors in the DRG can limit nociceptive information transferred from the periphery to the spinal cord and effectively relieve pain (Gold and Gebhart, 2010).…”

R-flurbiprofen attenuates experimental autoimmune encephalomyelitis in mice

“…R-flurbiprofen itself is at least 100-fold less active as COX-inhibitor and has been considered as the inactive constituent of the racemate. However, R-flurbiprofen reduces pain and inflammation in humans (Lotsch et al, 1995) and Sprague-Dawley rats (Bishay et al, 2010;Geisslinger et al, 1993;Tegeder et al, 2001), species which do not essentially invert R-to S-flurbiprofen. R-flurbiprofen is almost free of the side-effects typical of classical NSAIDs, such as gastrointestinal or renal toxicity (Holzer et al, 2001).…”

“…R-flurbiprofen is almost free of the side-effects typical of classical NSAIDs, such as gastrointestinal or renal toxicity (Holzer et al, 2001). Its mechanisms of action involve inhibition of the transcription factors NF-jB and AP1 (Tegeder et al, 2001), inhibition of acid sensing ion channels (ASIC1) (Mishra et al, 2010) and inhibition of endocannabinoid hydrolysis or oxidation (Bishay et al, 2010;Duggan et al, 2011) with a resulting general facilitation of actions at cannabinoid CB1 and CB2 receptors on neurons, microglia and peripheral immune cells (Bishay et al, 2010). In particular, R-flurbiprofen treatment after peripheral nerve injury prevents microglia from adopting a phagocyte-like activated phenotype and thereby blocks the neuroinflammatory component of neuropathic pain (Bishay et al, 2010).…”

“…Its mechanisms of action involve inhibition of the transcription factors NF-jB and AP1 (Tegeder et al, 2001), inhibition of acid sensing ion channels (ASIC1) (Mishra et al, 2010) and inhibition of endocannabinoid hydrolysis or oxidation (Bishay et al, 2010;Duggan et al, 2011) with a resulting general facilitation of actions at cannabinoid CB1 and CB2 receptors on neurons, microglia and peripheral immune cells (Bishay et al, 2010). In particular, R-flurbiprofen treatment after peripheral nerve injury prevents microglia from adopting a phagocyte-like activated phenotype and thereby blocks the neuroinflammatory component of neuropathic pain (Bishay et al, 2010). Either as a consequence of the pro-endocannabinoid effects or possibly directly, R-flurbiprofen increases activation of the peroxisome proliferator activated receptors, PPARc and PPARa, contributing to anti-inflammatory and neuroprotective effects in the brain (Bernardo et al, 2005(Bernardo et al, , 2006Bishay et al, 2010).…”