Reversal of acid‐induced and inflammatory pain by the selective ASIC3 inhibitor, APETx2

Abstract

BACKGROUND AND PURPOSE Inflammatory pain is triggered by activation of pathways leading to the release of mediators such as bradykinin, prostaglandins, interleukins, ATP, growth factors and protons that sensitize peripheral nociceptors. The activation of acid‐sensitive ion channels (ASICs) may have particular relevance in the development and maintenance of inflammatory pain. ASIC3 is of particular interest due to its restricted tissue distribution in the nociceptive primary afferent fibres and its high sensitivity to protons. EXPERIMENTAL APPROACH To examine the contribution of ASIC3 to the development and maintenance of muscle pain and inflammatory pain, we studied the in vivo efficacy of a selective ASIC3 inhibitor, APETx2, in rats. KEY RESULTS Administration of APETx2 into the gastrocnemius muscle prior to the administration of low pH saline prevented the development of mechanical hypersensitivity, whereas APETx2 administration following low‐pH saline was ineffective in reversing hypersensitivity. The prevention of mechanical hypersensitivity produced by acid administration was observed whether APETx2 was applied via i.m. or i.t. routes. In the complete Freund's adjuvant (CFA) inflammatory pain model, local administration of APETx2 resulted in a potent and complete reversal of established mechanical hypersensitivity, whereas i.t. application of APETx2 was ineffective. CONCLUSIONS AND IMPLICATIONS ASIC3 contributed to the development of mechanical hypersensitivity in the acid‐induced muscle pain model, whereas ASIC3 contributed to the maintenance of mechanical hypersensitivity in the CFA inflammatory pain model. The contribution of ASIC3 to established hypersensitivity associated with inflammation suggests that this channel may be an effective analgesic target for inflammatory pain states.

Acid-sensing ion channel (ASIC) structure and function: Insights from spider, snake and sea anemone venoms

“…In agreement with this, several independent labs have reported that APETx2 is analgesic in rat models of inflammatory and osteoarthritic pain (Deval et al, 2008;Ikeuchi et al, 2009;Karczewski et al, 2010). Peripheral application of APETx2 also reduces mechanical hypersensitivity in non-inflammatory muscular pain models and angina (Ikeuchi et al, 2008;Yagi et al, 2006).…”

Sea Anemone Peptide with Uncommon β-Hairpin Structure Inhibits Acid-sensing Ion Channel 3 (ASIC3) and Reveals Analgesic Activity

“…Ugr 9-1 produced an inhibition effect in vitro with IC 50 less than that of small organic molecules but higher than that of APETx2. In vivo studies have shown that the administration of Ugr 9-1 reverses acid-induced and CFA-induced inflammatory pain as much as APETx2, which attenuates acid-induced and inflammatory pain at doses of 0.01 to 0.5 mg/kg in rats (7,46). Doubtless, an advantage of Ugr 9-1 over APETx2 for pain relief is its short length, which reduces the resources that must be consumed for production by chemical or biotechnological synthesis.…”

X-Ray Structure of Acid-Sensing Ion Channel 1–Snake Toxin Complex Reveals Open State of a Na+-Selective Channel

“…Recently, snake (Bohlen et al, 2011; Diochot et al, 2012), spider (Escoubas et al, 2000) and sea anemone toxins (Diochot et al, 2004; Karczewski et al, 2010) have been identified that elicit or suppress pain by selectively activating or blocking ASICs (Bohlen and Julius, 2012; Chen et al, 2005; Karczewski et al, 2010). In addition to validating a role for ASICs in nociception and pain sensation, peptide toxins provide powerful tools to arrest ASICs in specific conformational states for pharmacological, biophysical, and structural studies (Baconguis and Gouaux, 2012; Baconguis et al, 2013; Bohlen et al, 2011; Chen et al, 2006).…”