Inhibition of fatty acid amide hydrolase produces PPAR‐α‐mediated analgesia in a rat model of inflammatory pain

Sagar, Devi Rani; Kendall, David A.; Chapman, Victoria

doi:10.1038/bjp.2008.335

Cited by 82 publications

(67 citation statements)

References 49 publications

(80 reference statements)

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“…In contrast, although this hypothesis could not be tested in the present study, the fact that the effects of URB597 were reversed by the CB 1 antagonist/inverse agonist rimonabant may indicate that selective activation of CB 1 receptors can produce synergistic effects with PPAR-a. These results are consistent with recent findings that joint stimulation of PPAR-a and CB 1 receptors produces synergistic antinociceptive effects on peripheral pain, that these effects are reversed by rimonabant (Russo et al 2007), and that antinociceptive effects of URB597 on peripheral pain can be blocked by PPAR-a antagonism (Sagar et al 2008). Further studies are needed to determine whether synergistic enhancement of learning and memory can be achieved with local coadministration of naturally occurring endogenous ligands for CB 1 receptors (anandamide) and PPAR-a (OEA and PEA), whose brain levels are all increased by FAAH inhibition.…”

supporting

confidence: 93%

Fatty acid amide hydrolase (FAAH) inhibition enhances memory acquisition through activation of PPAR-α nuclear receptors

Mazzola¹,

Medalie²,

Scherma³

et al. 2009

Learn. Mem.

117

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Inhibitors of fatty acid amide hydrolase (FAAH) increase endogenous levels of anandamide (a cannabinoid CB 1 -receptor ligand) and oleoylethanolamide and palmitoylethanolamide (OEA and PEA, ligands for a-type peroxisome proliferatoractivated nuclear receptors, PPAR-a) when and where they are naturally released in the brain. Using a passive-avoidance task in rats, we found that memory acquisition was enhanced by the FAAH inhibitor URB597 or by the PPAR-a agonist WY14643, and these enhancements were blocked by the PPAR-a antagonist MK886. These findings demonstrate novel mechanisms for memory enhancement by activation of PPAR-a, either directly by administering a PPAR-a agonist or indirectly by administering a FAAH inhibitor.Peroxisome proliferator-activated receptor-a (PPAR-a) is a ligandactivated transcriptional factor that regulates the expression of genes involved in lipid utilization, fatty acid oxidation, and inflammation (van Raalte et al. 2004;LoVerme et al. 2006). Immunolocalization studies of PPAR-a in the adult rat brain suggest that this nuclear receptor might have specific functions in regulating expression of genes involved in cholinergic neurotransmission and learning and memory processes (Moreno et al. 2004;Cimini et al. 2005). For example, there are high concentrations of PPAR-a receptors in the hippocampus and amygdala (Moreno et al. 2004). However, the potential involvement of PPAR-a in learning and memory processes has not been systematically investigated.Endogenous ligands for PPAR-a include the lipid mediators N-oleoylethanolamide (OEA) and N-palmitoylethanolamide (PEA). In addition, anandamide (N-arachidonoylethanolamine), which has primarily been studied as an endogenous ligand for G-proteincoupled cannabinoid CB 1 receptors that mediate the behavioral effects of cannabis and its active constituent D 9-tetrahydrocannabinol (THC) (Devane et al. 1992;Solinas et al. 2008), has recently begun to receive attention as a potential endogenous PPAR-a ligand (O'Sullivan 2000;Mackie and Stella 2006;Sun et al. 2007). OEA has primarily been studied as a satiety factor (Rodriguez de Fonseca et al. 2001;Fu et al. 2003) and PEA as an anti-inflammatory factor (Kuehl et al. 1957;Calignano et al. 1998;Jaggar et al. 1998). OEA and PEA are structurally similar to anandamide but do not bind to or activate cannabinoid CB 1 receptors. Anandamide, OEA, and PEA are all inactivated primarily by the intracellular serine enzyme, fatty acid amide hydrolase (FAAH) (Cravatt and Lichtman 2002;Fegley et al. 2005). Consequently, selective FAAH-inhibiting drugs such as cyclohexyl carbamic acid 39-carbamoyl-3-yl ester (URB597) increase endogenous levels of anandamide, OEA, and PEA in the brain (Fegley et al. 2005;Piomelli et al. 2006).In the present experiments, the effects of FAAH inhibition on learning and memory processes and the involvement of cannabinoid CB 1 receptors and PPAR-a nuclear receptors in those effects were studied using a passive-avoidance procedure in rats. FAAH inhibition was accomplished by administering U...

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supporting

confidence: 93%

Fatty acid amide hydrolase (FAAH) inhibition enhances memory acquisition through activation of PPAR-α nuclear receptors

Mazzola¹,

Medalie²,

Scherma³

et al. 2009

Learn. Mem.

117

View full text Add to dashboard Cite

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“…The demonstration that, at least in cells, 15-LOX is capable of metabolizing 2-AG to 15-HETE-G (see references in Vandevoorde & Lambert [112]), which is a ligand for the antiinflammatory nuclear receptor PPARa [28], suggests that changes in LOX expression and metabolism of endocannabinoids via this pathway may also influence nociceptive processing. Indeed, we and others have shown that PPARa ligands can have marked inhibitory effects on inflammatory pain responses (see references in [113][114][115][116]). …”

Section: Effects Of Novel Biological Metabolites Of 2-ag and Anandamidementioning

confidence: 91%

Dynamic changes to the endocannabinoid system in models of chronic pain

Sagar

Burston

Woodhams

et al. 2012

Phil. Trans. R. Soc. B

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The analgesic effects of cannabinoid ligands, mediated by CB1 receptors are well established. However, the side-effect profile of CB1 receptor ligands has necessitated the search for alternative cannabinoid-based approaches to analgesia. Herein, we review the current literature describing the impact of chronic pain states on the key components of the endocannabinoid receptor system, in terms of regionally restricted changes in receptor expression and levels of key metabolic enzymes that influence the local levels of the endocannabinoids. The evidence that spinal CB2 receptors have a novel role in the modulation of nociceptive processing in models of neuropathic pain, as well as in models of cancer pain and arthritis is discussed. Recent advances in our understanding of the spinal location of the key enzymes that regulate the levels of the endocannabinoid 2-AG are discussed alongside the outcomes of recent studies of the effects of inhibiting the catabolism of 2-AG in models of pain. The complexities of the enzymes capable of metabolizing both anandamide (AEA) and 2-AG have become increasingly apparent. More recently, it has come to light that some of the metabolites of AEA and 2-AG generated by cyclooxygenase-2, lipoxygenases and cytochrome P450 are biologically active and can either exacerbate or inhibit nociceptive signalling.

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“…Systemic inactivation of FAAH via compounds such as URB597, OL135 and PF-3845 has been shown to be anti-nociceptive in models of acute and inflammatory pain (75)(76)(77)(78)(79)(80) . Elevations in both AEA and 2-AG have been shown, as well as reduced carrageenan-induced hyperalgesia (81) and expansion of peripheral receptive field size of wide dynamic range neurons (a marker of central sensitisation) following intra-plantar URB597 (82) . Similarly, capsaicin-induced pain behaviour and thermal hypersensitivity were attenuated following blockade of peripheral MAGL via JZL184 (83) , and peripheral administration of JZL184 produces local inhibition of MAGL activity, increased levels of 2-AG and anti-nociceptive effects in both phases of the formalin model through mechanisms involving both CB 1 and CB 2 ( 84) .…”

Section: Peripheral Mechanismsmentioning

confidence: 99%

Endocannabinoid system and pain: an introduction

Burston

Woodhams

2013

Proc. Nutr. Soc.

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The endocannabinoid (EC) system consists of two main receptors: cannabinoid type 1 receptor cannabinoid receptors are found in both the central nervous system (CNS) and periphery, whereas the cannabinoid type 2 receptor cannabinoid receptor is found principally in the immune system and to a lesser extent in the CNS. The EC family consists of two classes of well characterised ligands; the N-acyl ethanolamines, such as N-arachidonoyl ethanolamide or anandamide (AEA), and the monoacylglycerols, such as 2-arachidonoyl glycerol. The various synthetic and catabolic pathways for these enzymes have been (with the exception of AEA synthesis) elucidated. To date, much work has examined the role of EC in nociceptive processing and the potential of targeting the EC system to produce analgesia. Cannabinoid receptors and ligands are found at almost every level of the pain pathway from peripheral sites, such as peripheral nerves and immune cells, to central integration sites such as the spinal cord, and higher brain regions such as the periaqueductal grey and the rostral ventrolateral medulla associated with descending control of pain. EC have been shown to induce analgesia in preclinical models of acute nociception and chronic pain states. The purpose of this review is to critically evaluate the evidence for the role of EC in the pain pathway and the therapeutic potential of EC to produce analgesia. We also review the present clinical work conducted with EC, and examine whether targeting the EC system might offer a novel target for analgesics, and also potentially disease-modifying interventions for pathophysiological pain states. Pain: Endocannabinoid: AnalgesiaFrom an evolutionary standpoint, pain can be considered a necessary evil, providing a potent warning system to protect an individual from present and future harm. However, not all pain is part of this adaptive response, e.g. persistent pain after injury healing (chronic pain) or pain arising from damage to nerve tissue (neuropathic pain). Pain is the most common complaint in those seeking a physician, and a recent study suggests that pain represents the greatest economic burden of any pathological condition in the USA, with an estimated annual cost of $565-635 billion (1) . Many chronic pain states are refractory to standard analgesics, and even in those which do respond, pain control can be incomplete or only short-term in nature. Of the imperfect currently available analgesics, the most efficacious are the opioids which exploit an endogenous pain control pathway within the central nervous system. However, opioids have significant issues with tolerance, dependence, respiratory depression and opioid-induced hyperalgesia (2) . Over the past few decades, the existence of a second endogenous anti-nociceptive pathway has been revealed: the endocannabinoid (EC) system. *Corresponding author: J. J. Burston, fax +44 (0)115 823 0142, email james.burston@nottingham.ac.uk Abbreviations: 2-AG, 2-arachidonoylglycerol; ACC, anterior cingulate cortex; AEA, anandamide; CB 1 , cannab...

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Inhibition of fatty acid amide hydrolase produces PPAR‐α‐mediated analgesia in a rat model of inflammatory pain

Cited by 82 publications

References 49 publications

Fatty acid amide hydrolase (FAAH) inhibition enhances memory acquisition through activation of PPAR-α nuclear receptors

Fatty acid amide hydrolase (FAAH) inhibition enhances memory acquisition through activation of PPAR-α nuclear receptors

Dynamic changes to the endocannabinoid system in models of chronic pain

Endocannabinoid system and pain: an introduction

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