Spinal Endocannabinoids and CB
            <sub>1</sub>
            Receptors Mediate C-Fiber–Induced Heterosynaptic Pain Sensitization

Pernía-Andrade, Alejandro Javier; Kato, Ako; Witschi, Robert; Nyilas, Rita; Katona, István; Freund, Tamás F.; Watanabe, Masahiko; Filitz, Jörg; Koppert, Wolfgang; Schüttler, J.; Ji, Guangchen; Neugebauer, Volker; Marsicano, Giovanni; Lutz, Beat; Vanegas, Horacio; Zeilhofer, Hanns Ulrich

doi:10.1126/science.1171870

Cited by 167 publications

(171 citation statements)

References 26 publications

(23 reference statements)

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“…Recent evidence suggests, however, that one should move away from the 'old' concept that selective activation of CB1 or TRPV1 attenuate or worsen nociception, respectively. It is now clear that the former receptor can also participate in supra-spinal pro-nociceptive [97] or spinal painsensitization [98] mechanisms, which can be activated following elevation of endocannabinoid levels. Conversely, activation of TRPV1 can enhance the activity of supra-spinal pathways of pain control [97,99] or be easily followed by desensitization and hence produce analgesia as efficaciously as its inactivation [100].…”

Section: Anandamide Dual Actions At Cb1 and Trpv1 As A 'Plastic' Way mentioning

confidence: 99%

Why do cannabinoid receptors have more than one endogenous ligand?

Marzo

Petrocellis

2012

Phil. Trans. R. Soc. B

251

176

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The endocannabinoid system was revealed following the understanding of the mechanism of action of marijuana's major psychotropic principle, D 9-tetrahydrocannabinol, and includes two G-proteincoupled receptors (GPCRs; the cannabinoid CB1 and CB2 receptors), their endogenous ligands (the endocannabinoids, the best studied of which are anandamide and 2-arachidonoylglycerol (2-AG)), and the proteins that regulate the levels and activity of these receptors and ligands. However, other minor lipid metabolites different from, but chemically similar to, anandamide and 2-AG have also been suggested to act as endocannabinoids. Thus, unlike most other GPCRs, cannabinoid receptors appear to have more than one endogenous agonist, and it has been often wondered what could be the physiological meaning of this peculiarity. In 1999, it was proposed that anandamide might also activate other targets, and in particular the transient receptor potential of vanilloid type-1 (TRPV1) channels. Over the last decade, this interaction has been shown to occur both in peripheral tissues and brain, during both physiological and pathological conditions. TRPV1 channels can be activated also by another less abundant endocannabinoid, N-arachidonoyldopamine, but not by 2-AG, and have been proposed by some authors to act as ionotropic endocannabinoid receptors. This article will discuss the latest discoveries on this subject, and discuss, among others, how anandamide and 2-AG differential actions at TRPV1 and cannabinoid receptors contribute to making this signalling system a versatile tool available to organisms to fine-tune homeostasis.

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Section: Anandamide Dual Actions At Cb1 and Trpv1 As A 'Plastic' Way mentioning

confidence: 99%

Why do cannabinoid receptors have more than one endogenous ligand?

Marzo

Petrocellis

2012

Phil. Trans. R. Soc. B

251

176

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“…(Opposite.) (a) Under basal conditions, endocannabinoids modulate spinal nociceptive transmission through activation of pre- [10,24] and post-synaptic [25] CB1 receptors expressed on primary afferent fibres. Increased intracellular calcium ([ Ca 2þ ] i ) in postsynaptic neurons can stimulate AEA and 2-AG production and consequently activation of CB1 receptors.…”

Section: A Novel Role Of Cb2 Receptors In Chronic Pain Statesmentioning

confidence: 99%

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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“…4). Mice lacking CB1 receptors, either globally or specifically from inhibitory dorsal horn neurons, are largely protected from capsaicin-induced mechanical pain sensitization [25]. Spinally injected CB1 receptor antagonists or group I metabotropic glutamate receptor antagonists can reverse secondary hyperalgesia in animal models.…”

Section: Disinhibition Following Nociceptor Stimulationmentioning

confidence: 99%

Spinal neuroplasticity in chronic pain

Zeilhofer

2011

E-Neuroforum

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Neuroplastic changes play an important role in the generation and maintenance of chronic pain syndromes. Such changes occur at all levels of the neuraxis, from the peripheral terminals of primary sensory neurons to the cerebral cortex. Changes observed in the spinal dorsal horn in particular provide a mechanistic basis for many of the characteristics of chronic pain syndromes. While facilitated synaptic transmission between nociceptive fibers and spinal projection neurons contributes to enhanced perception of noxious stimuli (hyperalgesia), diminished function of GABA-ergic and glycinergic interneurons not only induces hyperalgesia, but also triggers nociceptive reactions on exposure to innocuous stimuli and spontaneous pain behavior in the absence of any sensory stimulation. Spinal disinhibition thus recapitulates typical symptoms of chronic pathological pain syndromes. Studies performed by various groups over the last 10 years demonstrate that such spinal disinhibition occurs naturally in response to peripheral inflammation and nerve damage. The present article summarizes current status of this research.

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Spinal Endocannabinoids and CB ₁ Receptors Mediate C-Fiber–Induced Heterosynaptic Pain Sensitization

Cited by 167 publications

References 26 publications

Why do cannabinoid receptors have more than one endogenous ligand?

Why do cannabinoid receptors have more than one endogenous ligand?

Dynamic changes to the endocannabinoid system in models of chronic pain

Spinal neuroplasticity in chronic pain

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Spinal Endocannabinoids and CB 1 Receptors Mediate C-Fiber–Induced Heterosynaptic Pain Sensitization

Cited by 167 publications

References 26 publications

Why do cannabinoid receptors have more than one endogenous ligand?

Why do cannabinoid receptors have more than one endogenous ligand?

Dynamic changes to the endocannabinoid system in models of chronic pain

Spinal neuroplasticity in chronic pain

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Product

Resources

About

Spinal Endocannabinoids and CB ₁ Receptors Mediate C-Fiber–Induced Heterosynaptic Pain Sensitization