The effect of WIN 55,212-2, a cannabinoid agonist, on tactile allodynia in diabetic rats

Ulugöl, Ahmet; Karadağ, Çetin Hakan; İpçi, Yeşim; Tamer, Melek; Dökmeci, İsmet

doi:10.1016/j.neulet.2004.08.061

Cited by 68 publications

(50 citation statements)

References 27 publications

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“…Taken together with previous reports 9, [19][20][21][22]30,[42][43][44] , this study presents a strong basis for the design of novel synthetic cannabinoids that do not cross the blood-brain barrier as a new class of peripherally acting analgesics without the psychotropic liability of centrally acting CB 1 agonists.…”

Section: Discussionsupporting

confidence: 70%

Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors

et al. 2007

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Although endocannabinoids constitute one of the first lines of defense against pain, the anatomical locus and the precise receptor mechanisms underlying cannabinergic modulation of pain are uncertain. Clinical exploitation of the system is severely hindered by the cognitive deficits, memory impairment, motor disturbances and psychotropic effects resulting from the central actions of cannabinoids. We deleted the type 1 cannabinoid receptor (CB 1 ) specifically in nociceptive neurons localized in the peripheral nervous system of mice, preserving its expression in the CNS, and analyzed these genetically modified mice in preclinical models of inflammatory and neuropathic pain. The nociceptor-specific loss of CB 1 substantially reduced the analgesia produced by local and systemic, but not intrathecal, delivery of cannabinoids. We conclude that the contribution of CB 1 -type receptors expressed on the peripheral terminals of nociceptors to cannabinoid-induced analgesia is paramount,

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Section: Discussionsupporting

confidence: 70%

Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors

et al. 2007

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“…The latter is consistent with less severe or absent tactile allodynia in STZ-diabetic inducible nitric oxide synthasedeficient and PARP-deficient mice, compared with the corresponding wild-type mice with STZ-diabetes of similar severity and duration. 14,44 Other agents effective against tactile allodynia in STZ-diabetic rat model include nitecapone, a catechol-O-methyltransferase inhibitor with potent antioxidant properties, 91 agmatine, an endogenous cationic amine resulting from the decarboxylation of L-arginine, 92 allopurinol, 28 interleukin-6, 31 melatonin, 93 benfotiamine, 94 and the cannabinoid agonist WIN 55,212-2, 95 as well as a cocktail of B 1 , B 6 , and B 12 vitamins. 96 Tactile allodynia in STZ-diabetic mice was found preventable by sulfasalazine, probably via blockage of NF-B activation, 87 as well as the cyclooxygenase-2 inhibitor meloxicam 97 and the 12/15-lipoxygenase inhibitors baicalein and cinnamyl-3,4-dihydroxy-␣-cyanocinnamate.…”

Section: Diabetes-associated Tactile Allodyniamentioning

confidence: 99%

Diabetic Painful and Insensate Neuropathy: Pathogenesis and Potential Treatments

2009

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Summary:Advanced peripheral diabetic neuropathy (PDN) is associated with elevated vibration and thermal perception thresholds that progress to sensory loss and degeneration of all fiber types in peripheral nerve. A considerable proportion of diabetic patients also describe abnormal sensations such as paresthesias, allodynia, hyperalgesia, and spontaneous pain. One or several manifestations of abnormal sensation and pain are described in all the diabetic rat and mouse models studied so far (i.e., streptozotocin-diabetic rats and mice, type 1 insulinopenic BB/Wor and type 2 hyperinsulinemic diabetic BBZDR/Wor rats, Zucker diabetic fatty rats, and nonobese diabetic, Akita, leptin-and leptin-receptor-deficient, and highfat diet-fed mice). Such manifestations are 1) thermal hyperalgesia, an equivalent of a clinical phenomenon described in early PDN; 2) thermal hypoalgesia, typically present in advanced PDN; 3) mechanical hyperalgesia, an equivalent of pain on pressure in early PDN; 4) mechanical hypoalgesia, an equivalent to the loss of sensitivity to mechanical noxious stimuli in advanced PDN; 5) tactile allodynia, a painful perception of a light touch; and 5) formalin-induced hyperalgesia. Rats with short-term diabetes develop painful neuropathy, whereas those with longer-term diabetes and diabetic mice typically display manifestations of both painful and insensate neuropathy, or insensate neuropathy only. Animal studies using pharmacological and genetic approaches revealed important roles of increased aldose reductase, protein kinase C, and poly(ADPribose) polymerase activities, advanced glycation end-products and their receptors, oxidative-nitrosative stress, growth factor imbalances, and C-peptide deficiency in both painful and insensate neuropathy. This review describes recent achievements in studying the pathogenesis of diabetic neuropathic pain and sensory disorders in diabetic animal models and developing potential pathogenetic treatments. Key Words: Animal models, diabetic insensate neuropathy, diabetic painful neuropathy, formalin-induced hyperalgesia, mechanical hyper-and hypoalgesia, pathogenetic treatments of diabetic neuropathic pain and sensory loss, symptomatic treatments of diabetic pain, tactile allodynia, thermal hyper-and hypoalgesia.

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“…-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.…”

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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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The effect of WIN 55,212-2, a cannabinoid agonist, on tactile allodynia in diabetic rats

Cited by 68 publications

References 27 publications

Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors

Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors

Diabetic Painful and Insensate Neuropathy: Pathogenesis and Potential Treatments

The Endocannabinoid System as a Potential Therapeutic Target for Pain Modulation

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