Activation of Type 5 Metabotropic Glutamate Receptors and Diacylglycerol Lipase-  Initiates 2-Arachidonoylglycerol Formation and Endocannabinoid-Mediated Analgesia

Gregg, Laura C.; Jung, Kwang-Mook; Spradley, Jessica Marie; Nyilas, Rita; Suplita, Richard L.; Zimmer, Andreas; Watanabe, Masahiko; Mackie, Ken; Katona, István; Piomelli, Daniele; Hohmann, Andrea G.

doi:10.1523/jneurosci.0013-12.2012

Cited by 69 publications

(71 citation statements)

References 52 publications

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“…Detailed study of this effect revealed the mobilisation of both AEA and 2-AG in the periaqueductal grey matter (111) , and suggested that 2-AG acting at CB 1 receptors was the predominant mechanism. Additional work indicated that further enhancing stress-induced EC signalling via FAAH or MAGL inhibition produces still greater anti-nociceptive effects (112,113) , and confirmed the pivotal role of 2-AG signalling in the periaqueductal grey matter (114) . The involvement of stress in human pain responses and the presence of an EC-mediated mechanism are now being studied clinically (115) .…”

Section: Supra-spinal Mechanismsmentioning

confidence: 73%

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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Section: Supra-spinal Mechanismsmentioning

confidence: 73%

Endocannabinoid system and pain: an introduction

Burston

Woodhams

2013

Proc. Nutr. Soc.

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“…Low to moderate levels of CB 1 receptors have been found in the midbrain periaqueductal gray (PAG), where the ECS is involved in the control of pain sensation, including stress-induced analgesia Hohmann et al 2005;Gregg et al 2012). In contrast to opiate receptors on GABAergic aqueductal neurons, CB 1 receptors are preferentially, but not exclusively, localized in the dorsal portion of the PAG (Tsou et al 1998a;Azad et al 2001).…”

Section: Periaqueductal Graymentioning

confidence: 99%

Distribution of the Endocannabinoid System in the Central Nervous System

Mackie

2015

Handbook of Experimental Pharmacology

135

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The endocannabinoid system consists of endogenous cannabinoids (endocannabinoids), the enzymes that synthesize and degrade endocannabinoids, and the receptors that transduce the effects of endocannabinoids. Much of what we know about the function of endocannabinoids comes from studies that combine localization of endocannabinoid system components with physiological or behavioral approaches. This review will focus on the localization of the best-known components of the endocannabinoid system for which the strongest anatomical evidence exists.

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“…Stimulation of the DAP, particularly following stress, relies in part on cannabinoid receptor type-1 (CB 1 ) activation by the endocannabinoid 2-arachidonoylglycerol (2-AG), which disinhibits PAG output neurons through retrograde inhibition (Ohno-Shosaku and Kano, 2014) of GABA release from interneurons (Hohmann et al, 2005;Gregg et al, 2012). Orexinergic neurons of the lateral hypothalamus project to the vlPAG (Peyron et al, 1998;van den Pol et al, 1998), where activation of orexin type-1 receptors (OX1-R) by orexin-A (OX-A) stimulates 2-AG biosynthesis via the phospholipase C-diacylglycerol lipase α (DAGLα) route, thus potentially producing analgesia (Ho et al, 2011;Watanabe et al, 2005;Azhdari-Zarmehri et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Orexin-A and Endocannabinoid Activation of the Descending Antinociceptive Pathway Underlies Altered Pain Perception in Leptin Signaling Deficiency

Cristino

Luongo

Imperatore

et al. 2015

Neuropsychopharmacol

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Pain perception can become altered in individuals with eating disorders and obesity for reasons that have not been fully elucidated. We show that leptin deficiency in ob/ob mice, or leptin insensitivity in the arcuate nucleus of the hypothalamus in mice with high-fat diet (HFD)-induced obesity, are accompanied by elevated orexin-A (OX-A) levels and orexin receptor-1 (OX1-R)-dependent elevation of the levels of the endocannabinoid, 2-arachidonoylglycerol (2-AG), in the ventrolateral periaqueductal gray (vlPAG). In ob/ob mice, these alterations result in the following: (i) increased excitability of OX1-R-expressing vlPAG output neurons and subsequent increased OFF and decreased ON cell activity in the rostral ventromedial medulla, as assessed by patch clamp and in vivo electrophysiology; and (ii) analgesia, in both healthy and neuropathic mice. In HFD mice, instead, analgesia is only unmasked following leptin receptor antagonism. We propose that OX-A/endocannabinoid cross talk in the descending antinociceptive pathway might partly underlie increased pain thresholds in conditions associated with impaired leptin signaling.

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Activation of Type 5 Metabotropic Glutamate Receptors and Diacylglycerol Lipase- Initiates 2-Arachidonoylglycerol Formation and Endocannabinoid-Mediated Analgesia

Cited by 69 publications

References 52 publications

Endocannabinoid system and pain: an introduction

Endocannabinoid system and pain: an introduction

Distribution of the Endocannabinoid System in the Central Nervous System

Orexin-A and Endocannabinoid Activation of the Descending Antinociceptive Pathway Underlies Altered Pain Perception in Leptin Signaling Deficiency

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