Role of ASIC3 in the primary and secondary hyperalgesia produced by joint inflammation in mice

Abstract

The acid sensing ion channel 3 (ASIC3) is critical for the development of secondary hyperalgesia as measured by mechanical stimulation of the paw following muscle insult. We designed experiments to test whether ASIC3 was necessary for the development of both primary and secondary mechanical hyperalgesia that develops after joint inflammation. We used ASIC3 -/-mice and examined the primary (response to tweezers) and secondary hyperalgesia (von Frey filaments) that develops after joint inflammation comparing to ASIC3 +/+ mice. We also examined the localization of ASIC3 to the knee joint afferents innervating the joint capsule using immunohistochemical techniques before and after joint inflammation. We show that secondary mechanical hyperalgesia does not develop in ASIC3 -/-mice. However, the primary mechanical hyperalgesia of the inflamed knee joint still develops in ASIC3 -/-mice and is similar to ASIC3 +/+ mice. In knee joint synovium from ASIC3 +/+ mice without joint inflammation, ASIC3 was not localized to joint afferents that were stained with an antibodies to protein gene product (PGP) 9.5 or calcitonin gene-related peptide (CGRP). ASIC3 was found, however, in synoviocytes of the knee joint of uninflamed mice. In ASIC3 +/+ mice with joint inflammation, ASIC3 co-localized with PGP 9.5 or CGRP in joint afferents innervating the synovium. We conclude that the decreased pH that occurs after inflammation would activate ASIC3 on primary afferent fibers innervating joint, increasing the input to the spinal cord resulting in central sensitization manifested behaviorally as secondary hyperalgesia of the paw.

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

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Acid-Sensing Ion Channels in Postoperative Pain

“…The more robust effect seen here after knockdown of ASIC3 on weight bearing compared with primary thermal hyperalgesia may thus reflect an important role of ASIC3 in deep tissue, including muscle (Sutherland et al, 2001;Sluka et al, 2003;Ikeuchi et al, 2008), after surgery. However, postural pain that appears 24 h postsurgery in animals subjected to skin incision alone is also blocked by APETx2 (supplemental Fig.…”

Novel Insights into Acid-Sensing Ion Channels: Implications for Degenerative Diseases

“…Proton (H + ) accumulation in tissues was recently shown to directly cause algesia and hyperalgesia. ASIC3, a main acid receptor, plays a key role in acid-induced injury and pain [74]. Babinski et al [75] reported that ASIC3 is activated in the collageninduced arthritis pain model, which was also verified in AA [76].…”