Antinociceptive activity of the novel RAGE inhibitor, papaverine, in a mouse model of chronic inflammatory pain

Abstract

It has been recognized that a chronic pain state involves sensory neuronal excitability enhanced by pro-inflammatory cytokines or other inflammatory mediators secreted from immune cells (Grace et al., 2014). Many researchers have attempted to interfere with this mechanism as a novel therapeutic approach. High-mobility group box 1 (HMGB1), released from damaged necrotic cells or activated immune cells, is an essential nuclear protein for gene transcriptional modulation or DNA structural support (Agalave & Svensson, 2015). The variation in receptors for HMGB1 makes it difficult to target its signaling. Extracellular HMGB1 mediates the inflammatory response through the activation of pattern recognition receptors, including the receptor for advanced glycation end products (RAGE) and toll-like receptors (TLRs) (van Beijnum et al., 2008). Furthermore, HMGB1 mediates the release of inflammatory cytokines, such as interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and interferons from microglia (Agalave & Svensson, 2015). These signaling pathways are involved in pathological conditions, such as sepsis, rheumatoid arthritis, cancer, ischemia, and

Papaverine attenuates the progression of alpha naphthylisothiocyanate induce cholestasis in rats

“…The High Mobility Group Box 1 (HMGB1) molecule is crucial in initiating inflammation following an injury; in the case of cholestasis, the release of HMGB1 occurs, creating inflammation and developing liver disease; this process is facilitated by the activation of TLR4, which subsequently triggers the synthesis of NFκB, TNFα, and interleukin 6 (IL6); consequently, there has been a growing interest in the development of medicinal approaches aimed at regulating the activity of HMGB1( Nabih & El-kharashi, 2019 ). The report shows that the opiate alkaloid papaverine, acting as a new receptor for Advanced Glycation Endproducts RAGE inhibitor, directly inhibited HMGB1/RAGE interaction in vitro, ex vivo, and in vivo in the setting of potentially fatal sepsis ( Yoshizawa et al, 2021 ).…”

Possible Protective Effect of Low Dose of Papaverine on ANIT Induce Cholestasis in Rat

“…High-mobility group box 1 (HMGB1) is a nuclear protein required for the regulation of gene transcription; HMGB1 is released from necrotic cells or activated immune cells and extracellular HMGB1 regulates the release of pro-inflammatory cytokines such as interleukin IL-1β, IL-6, and tumor necrosis factor TNF-α by activating the receptor for advanced glycation end products (RAGE) and tolllike receptors (TLRs) (44) .…”

Therapeutic potential of targeting the receptor for advanced glycation end products (RAGE) by small molecule inhibitors

“…The amino acids of V‐domain of RAGE involved in these interactions are still unknown. Recent studies stated that papaverine also can suppress the chronic inflammatory pain in mice model, while it did not show the anti‐nociceptive effects in the state of oxidative stress at the site of inflammation (Yoshizawa et al, 2021). Therefore, papaverine and its derivatives could act as lead molecules in the development of novel potent RAGE antagonist that can be used to treat various RAGE‐associated diseases.…”