BTP2, a store-operated calcium channel inhibitor, attenuates morphine antinociceptive tolerance in rats

Introduction Morphine antinociceptive tolerance remains a critical problem in the clinical management of pain. Spinal cord glial cell activation and neuroinflammation appear to play a crucial role in the development and maintenance of this tolerance. BTP2, a potent store-operated calcium channel inhibitor, has anti-inflammatory properties in the central nervous system. This study aimed to investigate the effect of BTP2 on the development of morphine antinociceptive tolerance and glial cell-derived pro-inflammatory cytokines production by chronic morphine treatment. Methods A rat model of morphine antinociceptive tolerance was made by intrathecal injection of morphine (15 μg/d). Two separate studies were conducted: Firstly, to investigate whether BTP2 could attenuate the development of tolerance, BTP2 (2 and 10 nmol) was given intrathecally 30 min before each intrathecal delivery of morphine for consecutive 7 days. Secondly, to investigate whether BTP2 could reverse the established tolerance, BTP2 administration was initiated on day 8 after 7 days of morphine treatment and continued for 4 days. Results The results showed that BTP2 not only attenuated the development of morphine tolerance but also partially reversed the established tolerance. Immunohistochemistry revealed that chronic morphine-induced activation of astrocytes in the spinal cord, while BTP2 was shown to suppress the activation of astrocytes. Moreover, the administration of BTP2 alleviated the activation of astrocytic ERK and the production of proinflammatory cytokines (e.g., TNF-α and Il-1β) in the spinal cord. Discussion These findings suggest that BTP2 can be a potential therapeutic drug for morphine antinociceptive tolerance, and the store-operated calcium channel may play an important role in morphine antinociceptive tolerance.