Elevation of Endocannabinoid Levels in the Ventrolateral Periaqueductal Grey through Inhibition of Fatty Acid Amide Hydrolase Affects Descending Nociceptive Pathways via Both Cannabinoid Receptor Type 1 and Transient Receptor Potential Vanilloid Type-1 Receptors

Maione, Sabatino; Bisogno, Tiziana; Novellis, Vito de; Palazzo, Enza; Cristino, Luigia; Valenti, Marta; Petrosino, Stefania; Guglielmotti, Vittorio; Rossi, Francesco; Marzo, Vincenzo Di

doi:10.1124/jpet.105.093286

Cited by 264 publications

(265 citation statements)

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“…Research on mammalian models has provided evidence that TRPV-type receptors are activated by endocannabinoids in vitro and mediate in vivo effects of endocannabinoids [71,126]. Thus, Burrell and coworkers have investigated TRPV-type receptors as potential mediators of endocannabinoid-dependent LTD in the leech nervous system.…”

Section: Review Evolution and Comparative Neurobiology M R Elphickmentioning

confidence: 99%

The evolution and comparative neurobiology of endocannabinoid signalling

Elphick

2012

Phil. Trans. R. Soc. B

151

137

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CB 1 -and CB 2 -type cannabinoid receptors mediate effects of the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide in mammals. In canonical endocannabinoid-mediated synaptic plasticity, 2-AG is generated postsynaptically by diacylglycerol lipase alpha and acts via presynaptic CB 1 -type cannabinoid receptors to inhibit neurotransmitter release. Electrophysiological studies on lampreys indicate that this retrograde signalling mechanism occurs throughout the vertebrates, whereas system-level studies point to conserved roles for endocannabinoid signalling in neural mechanisms of learning and control of locomotor activity and feeding. CB 1 /CB 2 -type receptors originated in a common ancestor of extant chordates, and in the sea squirt Ciona intestinalis a CB 1 / CB 2 -type receptor is targeted to axons, indicative of an ancient role for cannabinoid receptors as axonal regulators of neuronal signalling. Although CB 1 /CB 2 -type receptors are unique to chordates, enzymes involved in biosynthesis/inactivation of endocannabinoids occur throughout the animal kingdom. Accordingly, non-CB 1 /CB 2 -mediated mechanisms of endocannabinoid signalling have been postulated. For example, there is evidence that 2-AG mediates retrograde signalling at synapses in the nervous system of the leech Hirudo medicinalis by activating presynaptic transient receptor potential vanilloid-type ion channels. Thus, postsynaptic synthesis of 2-AG or anandamide may be a phylogenetically widespread phenomenon, and a variety of proteins may have evolved as presynaptic (or postsynaptic) receptors for endocannabinoids.

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Section: Review Evolution and Comparative Neurobiology M R Elphickmentioning

confidence: 99%

The evolution and comparative neurobiology of endocannabinoid signalling

Elphick

2012

Phil. Trans. R. Soc. B

151

137

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“…URB597 dosedependently enhances PAG levels of anandamide and/or 2-AG, which may activate TRPV1 and CB 1 receptors, respec-tively. The TRPV1-mediated antinociception and CB 1 -mediated nociception caused by URB597 correlates with an enhanced or reduced activity of RVM "OFF" neurons, suggesting that they occur through the stimulation or inhibition of output PAG neurons [52]. Finally, at the highest doses tested, URB597 and WIN 55,212-2 also cause CB 1 -mediated analgesia, which correlates with a dis-inhibition of RVM "OFF" neurons.…”

Section: Pag Cannabinoid Receptors In Pain Proc-essingmentioning

confidence: 85%

“…We have shown that URB597 either suppresses or increases thermal nociception via indirect activation of either TRPV1 or CB 1 receptors, respectively, depending on the dose and time schedule of administration [52]. Accordingly, TRPV1 and CB 1 receptors are coexpressed in several PAG neurons [52,16]. The TRPV1 and cannabinoid receptor agonists, capsaicin and WIN 55,212-2, suppress and induce nociception, respectively.…”

Section: Pag Cannabinoid Receptors In Pain Proc-essingmentioning

confidence: 99%

“…This cation channel receptor is activated not only by vanilloids (such as capsaicin, which is responsible for piquancy in hot chili peppers, or resiniferatoxin, which is isolated from cactus-like plants), but also by noxious heat and low pH, representing a molecular integrator of noxious stimuli. We have shown that URB597 either suppresses or increases thermal nociception via indirect activation of either TRPV1 or CB 1 receptors, respectively, depending on the dose and time schedule of administration [52]. Accordingly, TRPV1 and CB 1 receptors are coexpressed in several PAG neurons [52,16].…”

Section: Pag Cannabinoid Receptors In Pain Proc-essingmentioning

confidence: 99%

“…We recently studied the effect of intra-PAG injections of the selective FAAH inhibitor, URB597, on (i) nocifensive responses to heat in the plantar test; (ii) PAG levels of anandamide and 2-AG; and (iii) the spontaneous activity of "OFF" and "ON" neurons in the RVM [52].…”

Section: Pag Cannabinoid Receptors In Pain Proc-essingmentioning

confidence: 99%

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Metabotropic Glutamate and Cannabinoid Receptor Crosstalk in Periaqueductal Grey Pain Processing

Palazzos

Novellis²,

Marabese³

et al. 2006

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Metabotropic glutamate (mGlu) and cannabinoid receptors are G-protein coupled receptors which have shown synaptic co-operation through small lipid messengers in the central nervous system (CNS). A functional interaction between these two receptor families could have a relevant potential in the treatment of CNS disorders, including chronic pain. Indeed, both mGlu and cannabinoid receptors play a crucial role in the neurobiology of pain and their simultaneous manipulation could lead to novel strategies in pain management. In particular, as both mGlu and cannabinoid receptors have been found in the periaqueductal gray (PAG), a crucial station in the pain modulatory system, these receptors could be a substrate for producing analgesia at this level. In this review we aim to briefly illustrate the role of mGlu and cannabinoid receptors in controlling nociceptive processes, some points of convergence, and their functional interaction in pain processing. Further insights into this functional linkage between the mGlu and cannabinoid receptors could pave the way to a new strategy for pain relief, such as a drug cocktail acting on cannabinoid/metabotropic glutamate receptors.Key Words: Periaqueductal grey, metabotropic glutamate receptors; cannabinoid receptors, pain. METABOTROPIC GLUTAMATE RECEPTORS AND PAINMetabotropic glutamate (mGlu) receptors play an important role in the modulation of nociceptive processing and central sensitisation associated with persistent and chronic pain at several levels in the CNS [29,42,67,68].Several studies have shown that mGlu receptors modulate nociception from peripheral terminals [5,10,67,98,104]. This may stimulate the search for peripherally active mGlu receptor ligands, which are devoid of central adverse effects [30]. A role for mGlu receptors in spinal nociceptive processing has been reported, with particular emphasis on group I mGlu receptors [13,20,69,70,100,101,102,103]. Stimulation of group I mGlu receptors at spinal level generally produces pro-nociceptive effects [31,100], although functional differences between mGlu 1 and mGlu 5 receptors in modulating pain are recently emerging at the same rate as new selective mGlu receptor ligands are developed [69,90,101]. Spinal group I mGlu receptors also play an important role in nociceptive hypersensitivity associated with inflammation [8,69,101]. Intrathecal application of group II and group III agonists inhibit nociceptive responses [20,70,91], which may reflect the inhibition of glutamate release from nerve endings. Upregulation of mGlu 3 mRNA in the spinal cord following hind paw inflammation has also been reported [6]. A role for supraspinal mGlu receptors in the modulation of pain is also emerging, mGlu receptors modulate nociceptive responses at the level of ventrobasal thalamus [83][84][85], dorsal raphe [72] and amygdala [32,33,48]. This review will *Address correspondence to these authors at Department of Experimental Medicine, Section of Pharmacology "L. Donatelli"-Faculty of Medicine and Surgery, Second Universi...

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Endocannabinoid System

Marzo

2011

Encyclopedia of Life Sciences

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The endocannabinoid system (ECS) is defined as the signalling system composed of: (1) the two G‐protein‐coupled receptors known as cannabinoid receptors of type‐1 and ‐2 (CB 1 and CB 2 ); (2) the two most studied endogenous agonists of such receptors, the endocannabinoids anandamide ( N ‐arachidonoyl‐ethanolamine) and 2‐AG (2‐arachidonoyl‐glycerol); (3) enzymes and other proteins regulating the tissue levels of endocannabinoids; and (4) enzymes and other proteins that, together with endocannabinoids, regulate the activity of cannabinoid receptors. A key role of the ECS is emerging in the control not only of central and peripheral nervous system functions, but also of most aspects of mammalian physiology, including energy intake, processing and storage, the immune response, reproduction and cell fate. The ECS is also subject to dysregulation, and this seems to contribute to the symptoms and progress of several diseases. Hence, the possibility of developing new therapies starting from our increasing knowledge of the ECS is discussed. Key Concepts: Endocannabinoids are local mediators with autocrine or paracrine function. Endocannabinoids are usually produced de novo and ‘on demand’ following elevation of intracellular Ca 2+ concentrations. Endocannabinoids often act in the central nervous system as ‘retrograde neuromodulators’, that is, they are released from post‐synaptic neurons and act at cannabinoid CB 1 receptors on pre‐synaptic axon terminals. Endocannabinoids possess immune‐modulatory functions and usually inhibit cytokine release from immune cells and regulate the migration of the latter. Endocannabinoids are key regulators of food intake, gastrointestinal function, energy storage in the adipose tissue and energy processing by the liver and the skeletal muscle. Endocannabinoids are deeply involved in pain processing at peripheral, spinal and supra ‐spinal sites. Endocannabinoids regulate both male and female reproduction. Endocannabinoid can differentially affect cell fate in healthy and cancer cells by regulating differentiation, proliferation and apoptosis. Endocannabinoids, and anandamide in particular, also directly interact with non‐CB 1 , non‐CB 2 receptors, the most studied of which is the transient receptor potential vanilloid type‐1 (TRPV1) channel. Dysregulation of the ECS underlies several neurological, immune and metabolic disorders, and therapeutic strategies manipulating the ECS are being developed.

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Elevation of Endocannabinoid Levels in the Ventrolateral Periaqueductal Grey through Inhibition of Fatty Acid Amide Hydrolase Affects Descending Nociceptive Pathways via Both Cannabinoid Receptor Type 1 and Transient Receptor Potential Vanilloid Type-1 Receptors

Cited by 264 publications

References 36 publications

The evolution and comparative neurobiology of endocannabinoid signalling

The evolution and comparative neurobiology of endocannabinoid signalling

Metabotropic Glutamate and Cannabinoid Receptor Crosstalk in Periaqueductal Grey Pain Processing

Endocannabinoid System

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