Abstract
Celastrol, a major active ingredient of Chinese herb Tripterygium wilfordii Hook. f. (thunder god vine), has exhibited a broad spectrum of pharmacological activities, including anti-inflammation, anti-cancer and immunosuppression. In the present study, we used animal models of inflammatory pain and neuropathic pain, generated by carrageenan injection and spared nerve injury (SNI), respectively, to evaluate the effect of celastrol and to address the mechanisms underlying pain processing. Intraperitoneal (i.p.) injection of celastrol produced a dose-dependent inhibition of carrageenan-induced edema and allodynia. Real-time PCR analysis showed that celastrol (0.3 mg/kg, i.p.) significantly reduced mRNA expressions of inflammatory cytokines, TNF-α, IL-6, IL-1β, in carrageenan-injected mice. In SNI mice, pain behavior studies showed that celastrol (1 mg/kg, i.p.) effectively prevented the hypersensitivity of mechanical nociceptive response on the third day post-surgery and the seventh day post-surgery. Furthermore, the anti-hyperalgesic effects of celastrol in carrageenan-injected mice and SNI mice were reversed by SR144528 (1 mg/kg, i.p.), a specific cannabinoid receptor-2 (CB2) receptor antagonist, but not by SR141716 (1 mg/kg, i.p.), a specific cannabinoid receptor-1 (CB1) receptor antagonist. Taken together, our results demonstrate the analgesia effects of celastrol through CB2 signaling and propose the potential of exploiting celastrol as a novel candidate for pain relief.
Highlights
Herb extracts of Tripterygium Wilfordii Hook. f. (T. wilfordii) have been widely used in China for years as anti-inflammation agents in many chronic inflammatory diseases and autoimmune diseases [1,2]
Inflammatory pain was induced by left paw intraplantar injection (i.pl.) of carrageenan, and inflammatory pain was evaluated by the induction of local edema and the rapid mechanical allodynia test [26] 6 h after carrageenan injection
When we pretreated mice with 0.3 mg/kg of celastrol (i.p.) 30 min before carrageenan administration, we found that celastrol significantly reduced the paw edema (p < 0.01, n = 5–6) and the mechanical hyperalgesia (p < 0.01, n = 5–6) (Figure 1A,B) induced by carrageenan injection
Summary
Herb extracts of Tripterygium Wilfordii Hook. f. (T. wilfordii) have been widely used in China for years as anti-inflammation agents in many chronic inflammatory diseases and autoimmune diseases [1,2]. Endocannabinoids have been discovered as one of the most common endogenous systems engaged in the modulation of inflammation and pain perception [10,11,12] They comprise two major components, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), along with two cannabinoid receptors, cannabinoid receptor-1 (CB1) and cannabinoid receptor-2 (CB2), and the enzymes involved in their biosynthesis and hydrolysis [10]. Previous studies showed that targeting a cannabinoid-hydrolyzing enzyme, monoacylglycerol lipase (MGL), attenuated inflammatory pain and neuropathic pain through elevating 2-AG levels, which potently activated the CB2 receptor [19,20,21]. We assessed the effect of natural compound celastrol and elucidated the mechanisms underlying celastrol’s action in preventing inflammatory and neuropathic pain. As few drugs are currently available for the treatment of chronic pain, our study provides the evidence that celastrol might be a promising molecule for the management of inflammatory and neuropathic pain
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