Involvement of descending serotonergic and noradrenergic pathways in CB1 receptor-mediated antinociception

Doğrul, Ahmet; Seyrek, Melik; Yalçın, Bülent; Ulugöl, Ahmet

doi:10.1016/j.pnpbp.2012.01.007

Cited by 46 publications

(18 citation statements)

References 134 publications

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“…In this review, I provide an overview of the current understanding about the processes accounting for the biosynthesis, transport and metabolism of endocannabinoids, and pharmacological approaches and potential therapeutic applications in this area, regarding the use of drugs elevating endocannabinoid levels in pain conditions. (Balkan Med J 2014;31:115-20 nor activation of potassium channels mediates this inhibitory effect ( Figure 1) (1,2,(12)(13)(14). Phytocannabinoids, synthetic cannabinoids and endocannabinoids are thought to produce their anti-nociceptive action primarily through CB 1 receptors, located at the supraspinal, spinal and peripheral levels (15, 16).…”

Section: Cannabinoid Receptors and The Site Of Action Of Cannabinoidsmentioning

confidence: 99%

The Endocannabinoid System as a Potential Therapeutic Target for Pain Modulation

Ulugöl¹

2014

Balkan Med J

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Cannabinoids are a group of chemical compounds that produce their effects via activating cannabinoid receptors; they include the phytocannabinoids (herbal cannabinoids/natural cannabinoids found in the cannabis plant), synthetic cannabinoids, and endogenous cannabinoids (endocannabinoids) (1, 2). Cannabis, also known as marijuana, has been used as both a recreational and medicinal drug for centuries. Pain management is the most important among the medicinal purposes, and has been drawing intense attention following the discovery of cannabinoid receptors and their endogenous ligands, endocannabinoids (3-5). ∆ 9 -tetrahydrocannabinol (THC) and cannabidiol, the critical components of the cannabis plant, and the synthetic cannabinoids and their analogues have been shown to exert strong analgesic action both in preclinical and clinical studies (6)(7)(8)(9). In this review, after a brief introduction to cannabinoid receptors, phytocannabinoids and synthetic cannabinoids, I provide an overview of what is currently known about the synthesis, release, degradation and biological actions of endocannabinoids, regarding their role in pain modulation, and describe the recent evidence of the promising results of augmentation of endogenous cannabinoid tonus for the treatment of pain. CANNABINOID RECEPTORS AND THE SITE OF ACTION OF CANNABINOIDSTo date, two subtypes of cannabinoid receptors, termed cannabinoid-1 (CB 1 ) and cannabinoid-2 (CB 2 ) receptors, have been cloned (10, 11). CB 1 receptors are most abundantly expressed in the central nervous system (CNS), most densely in motor and limbic regions, and in areas that are involved in pain transmission and modulation, such as periaqueductal grey (PAG), rostral ventromedial medulla (RVM), spinal cord dorsal horn, and in the periphery. CB 1 receptors are generally located pre-synaptically on axons and terminals of neurons and mediate the inhibition of neurotransmitter release by the inhibition of adenylate cyclase, blockade of voltage-dependent calcium channels, and/or by the activation of potassium channels and mitogen-activated protein kinase. CB 2 receptors, on the other hand, are found mainly, but not exclusively, outside the CNS, predominantly in peripheral tissues with immune functions, and most densely in the spleen. Similar to CB 1 receptors, CB 2 receptors are also G-protein coupled, inhibits adenylate cyclase and produce cellular inhibition, but neither blockade of calcium channels Although cannabis has been used for pain management for millennia, very few approved cannabinoids are indicated for the treatment of pain and other medical symptoms. Cannabinoid therapy re-gained attention only after the discovery of endocannabinoids and fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), the enzymes playing a role in endocannabinoid metabolism. Nowadays, research has focused on the inhibition of these degradative enzymes and the elevation of endocannabinoid tonus locally; special emphasis is given on multi-target analgesia compounds, where one of the targe...

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Section: Cannabinoid Receptors and The Site Of Action Of Cannabinoidsmentioning

confidence: 99%

The Endocannabinoid System as a Potential Therapeutic Target for Pain Modulation

Ulugöl¹

2014

Balkan Med J

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“…Evidence continues to accumulate suggesting that cannabinoids can impact normal inhibitory pathways and pathophysiological processes influencing nociception in humans 59,65. When cannabinoids do have an analgesic effect, it is more likely to occur in hyperalgesic and inflammatory states 66.…”

Section: Cannabinoids and The Management Of Painmentioning

confidence: 99%

The Endocannabinoid System, Cannabinoids, and Pain

Fine¹,

Rosenfeld²

2013

Rambam Maimonides Med J

134

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The endocannabinoid system is involved in a host of homeostatic and physiologic functions, including modulation of pain and inflammation. The specific roles of currently identified endocannabinoids that act as ligands at endogenous cannabinoid receptors within the central nervous system (primarily but not exclusively CB1 receptors) and in the periphery (primarily but not exclusively CB2 receptors) are only partially elucidated, but they do exert an influence on nociception. Exogenous plant-based cannabinoids (phytocannabinoids) and chemically related compounds, like the terpenes, commonly found in many foods, have been found to exert significant analgesic effects in various chronic pain conditions. Currently, the use of Δ9-tetrahydrocannabinol is limited by its psychoactive effects and predominant delivery route (smoking), as well as regulatory or legal constraints. However, other phytocannabinoids in combination, especially cannabidiol and β-caryophyllene, delivered by the oral route appear to be promising candidates for the treatment of chronic pain due to their high safety and low adverse effects profiles. This review will provide the reader with the foundational basic and clinical science linking the endocannabinoid system and the phytocannabinoids with their potentially therapeutic role in the management of chronic pain.

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“…The literature demonstrates a considerable increase of anandamide and 2-AG in areas known to be involved in nociceptive transmission during noxious stimulation of different origins [12]. These authors also correlated increases in endocannabinoid levels with an increase in activation of the inhibitory descending pain pathway.…”

Section: Discussionmentioning

confidence: 89%

Hemopressin, an inverse agonist of cannabinoid receptors, inhibits neuropathic pain in rats

Toniolo¹,

Maique²,

Ferreira³

et al. 2014

Peptides

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Direct-acting cannabinoid receptor ligands are well known to reduce hyperalgesic responses after nerve injury, although their psychoactive side effects have damped enthusiasm for their therapeutic development. Hemopressin (Hp) is a nonapeptide that selectively binds CB1 cannabinoid receptors (CB1 receptors) and exerts antinociceptive action in inflammatory pain models. We investigated the effect of Hp on neuropathic pain in rats subjected to chronic constriction injury (CCI) of the sciatic nerve, and explored the mechanisms involved. Oral administration of Hp inhibits mechanical hyperalgesia of CCI-rats up to 6h. Hp treatment also decreases Egr-1 immunoreactivity (Egr-1Ir) in the superficial layer of the dorsal horn of the spinal cord of CCI rats. The antinociceptive effect of Hp seems to be independent of inhibitory descending pain pathway since methysergide (5HT1A receptor antagonist) and yohimbine (α-2 adrenergic receptor antagonist) were unable to prevent Hp antinociceptive effect. Hp decreased calcium flux on DRG neurons from CCI rats, similarly to that observed for AM251, a CB1 receptor antagonist. We also investigated the effect of Hp on potassium channels of CCI rats using UCL 1684 (a blocker of Ca2+-activated K+ channels) which reversed Hp-induced antinociception. Furthermore, concomitant administration of URB-584 (FAAH inhibitor) but not JZL-184 (MAGL inhibitor) potentiates antinociceptive effect of Hp in CCI rats indicating an involvement of anadamide on HP-induced antinociception. Together, these data demonstrate that Hp displays antinociception in pain from neuropathic etiology through local effects. The release of anandamide and the opening of peripheral K+ channels are involved in the antinociceptive effect.

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Involvement of descending serotonergic and noradrenergic pathways in CB1 receptor-mediated antinociception

Cited by 46 publications

References 134 publications

The Endocannabinoid System as a Potential Therapeutic Target for Pain Modulation

The Endocannabinoid System as a Potential Therapeutic Target for Pain Modulation

The Endocannabinoid System, Cannabinoids, and Pain

Hemopressin, an inverse agonist of cannabinoid receptors, inhibits neuropathic pain in rats

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