Effect of Cannabinoid Receptor Agonists on Streptozotocin-Induced Hyperalgesia in Diabetic Neuropathy

Bujalska, Magdalena

doi:10.1159/000156485

Cited by 19 publications

(25 citation statements)

References 59 publications

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“…The beneficial effect of AM1241 in a preclinical model of DN makes CB2 agonism an attractive new strategy for the treatment of DN. CB2 activation may also positively affect other diabetes-related complications as CB2 agonists may, under certain conditions, delay progression of atherosclerotic lesions (14) and ameliorate diabetes-induced neuropathic pain (46,47) in rodents. The observation that CB2 receptors are also expressed by podocytes of human origin and undergo downregulation in patients with advanced DN suggests that our results may also have clinical relevance in humans.…”

Section: Discussionmentioning

confidence: 99%

Protective Role of Cannabinoid Receptor Type 2 in a Mouse Model of Diabetic Nephropathy

Piscitelli²,

et al. 2011

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OBJECTIVEThe cannabinoid receptor type 2 (CB2) has protective effects in chronic degenerative diseases. Our aim was to assess the potential relevance of the CB2 receptor in both human and experimental diabetic nephropathy (DN).RESEARCH DESIGN AND METHODSCB2 expression was studied in kidney biopsies from patients with advanced DN, in early experimental diabetes, and in cultured podocytes. Levels of endocannabinoids and related enzymes were measured in the renal cortex from diabetic mice. To assess the functional role of CB2, streptozotocin-induced diabetic mice were treated for 14 weeks with AM1241, a selective CB2 agonist. In these animals, we studied albuminuria, renal function, expression of podocyte proteins (nephrin and zonula occludens-1), and markers of both fibrosis (fibronectin and transforming growth factor-β1) and inflammation (monocyte chemoattractant protein-1 [MCP-1], CC chemokine receptor 2 [CCR2], and monocyte markers). CB2 signaling was assessed in cultured podocytes.RESULTSPodocytes express the CB2 receptor both in vitro and in vivo. CB2 was downregulated in kidney biopsies from patients with advanced DN, and renal levels of the CB2 ligand 2-arachidonoylglycerol were reduced in diabetic mice, suggesting impaired CB2 regulation. In experimental diabetes, AM1241 ameliorated albuminuria, podocyte protein downregulation, and glomerular monocyte infiltration, without affecting early markers of fibrosis. In addition, AM1241 reduced CCR2 expression in both renal cortex and cultured podocytes, suggesting that CB2 activation may interfere with the deleterious effects of MCP-1 signaling.CONCLUSIONSThe CB2 receptor is expressed by podocytes, and in experimental diabetes, CB2 activation ameliorates both albuminuria and podocyte protein loss, suggesting a protective effect of signaling through CB2 in DN.

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Section: Discussionmentioning

confidence: 99%

Protective Role of Cannabinoid Receptor Type 2 in a Mouse Model of Diabetic Nephropathy

Piscitelli²,

et al. 2011

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“…Blocking CB1 function has been presented as an effective means of alleviating both hyperglycaemia and dyslipidemia at several levels . Recent studies have also suggested a possible role for CB1 and CB2 in various diabetic complications, such as diabetic cardiovascular dysfunction, nephropathy and neuropathy, particularly highlighting the mechanisms beyond the metabolic consequences of the activation of the endocannabinoid system .…”

Section: Discussionmentioning

confidence: 99%

Cannabinoid receptors 1 and 2 are associated with bladder dysfunction in an experimental diabetic rat model

Sun

Zhang

et al. 2013

BJU International

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Objective• To investigate diabetes-associated changes in urinary bladder expression of cannabinoid receptors 1 and 2 (CB1 and CB2) and the functional role of CB agonists and antagonists in mediating phasic contractions of isolated bladder strips using a streptozotocin-induced diabetic rat model. Materials and Methods• The bladder and dorsal root ganglion (DRG) were removed from diabetic rats and age-matched controls 8-10 weeks after diabetes induction.• Expression of CB1 and CB2 mRNA was studied using quantitative real-time PCR and protein levels were determined by Western blot analysis.• The effect of increasing concentrations (0.1-100 mM) of the mixed CB1/CB2 agonist R(+)-WIN 55,212-2 (WIN), selective CB1 antagonist (AM251) and selective CB2 antagonist (AM630) on carbachol-evoked contraction of bladder strips from control and diabetic rats was investigated.• WIN-induced alterations of bladder strip contraction were then studied after pre-incubation with AM251 and AM630. Results• Diabetes induced decreased CB1 protein and mRNA expression in both the bladder and DRG (P < 0.05), while decreased CB2 expression was observed in the bladder (P < 0.05).• WIN decreased the amplitude, but not frequency, of carbachol-induced phasic contractions of bladder strips in a concentration-dependent manner and this effect was diminished in the diabetic state. • AM630 and AM251 had no effect on isolated detrusor muscle function. Moreover, pre-incubation with AM251 partially counteracted the effect of WIN on detrusor muscle contraction. Conclusion• The results indicate that CB1 and CB2 are responsible for the pathogenesis of bladder dysfunction in diabetes mellitus and represent a viable target for pharmacological treatment of bladder cystopathy.

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“…Several studies have demonstrated that THC (Williams et al, 2008) and WIN55,212-2 (Bujalska, 2008;Doğrul et al, 2004;Ikeda et al, 2013;Jahanabadi et al, 2016;Mohammadi-Farani et al, 2010;Ulugol et al, 2004;Vera et al, 2012;Vincenzi et al, 2013) produce antinociception in rodent STZinduced peripheral neuropathy. In particular, either single or repeated administration of WIN55,212-2 or AM1241, dosedependently attenuated STZ-induced hyperalgesia (Bujalska, 2008). Furthermore, repeated administration for 1 month of medium or high doses of intranasal WIN55,212-2 improved thermal hyperalgesia and mechanical allodynia in STZtreated mice (Toth et al, 2010).…”

Section: Streptozotocin-induced Diabetesmentioning

confidence: 99%

The Endogenous Cannabinoid System: A Budding Source of Targets for Treating Inflammatory and Neuropathic Pain

Donvito

Nass

Wilkerson

et al. 2017

Neuropsychopharmacol.

234

168

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A great need exists for the development of new medications to treat pain resulting from various disease states and types of injury. Given that the endogenous cannabinoid (that is, endocannabinoid) system modulates neuronal and immune cell function, both of which play key roles in pain, therapeutics targeting this system hold promise as novel analgesics. Potential therapeutic targets include the cannabinoid receptors, type 1 and 2, as well as biosynthetic and catabolic enzymes of the endocannabinoids N-arachidonoylethanolamine and 2-arachidonoylglycerol. Notably, cannabinoid receptor agonists as well as inhibitors of endocannabinoid-regulating enzymes fatty acid amide hydrolase and monoacylglycerol lipase produce reliable antinociceptive effects, and offer opioid-sparing antinociceptive effects in myriad preclinical inflammatory and neuropathic pain models. Emerging clinical studies show that 'medicinal' cannabis or cannabinoid-based medications relieve pain in human diseases such as cancer, multiple sclerosis, and fibromyalgia. However, clinical data have yet to demonstrate the analgesic efficacy of inhibitors of endocannabinoid-regulating enzymes. Likewise, the question of whether pharmacotherapies aimed at the endocannabinoid system promote opioid-sparing effects in the treatment of pain reflects an important area of research. Here we examine the preclinical and clinical evidence of various endocannabinoid system targets as potential therapeutic strategies for inflammatory and neuropathic pain conditions.

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Effect of Cannabinoid Receptor Agonists on Streptozotocin-Induced Hyperalgesia in Diabetic Neuropathy

Cited by 19 publications

References 59 publications

Protective Role of Cannabinoid Receptor Type 2 in a Mouse Model of Diabetic Nephropathy

Protective Role of Cannabinoid Receptor Type 2 in a Mouse Model of Diabetic Nephropathy

Cannabinoid receptors 1 and 2 are associated with bladder dysfunction in an experimental diabetic rat model

The Endogenous Cannabinoid System: A Budding Source of Targets for Treating Inflammatory and Neuropathic Pain

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