| Abstract No.: | B-B2044 |
| Country: | Canada |
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| Title: | ACTIVATED CELL-TYPE SPECIFIC ERK AND P38 MITOGEN-ACTIVATED PROTEIN KINASES MEDIATE TOLERANCE TO MORPHINE INDUCED ANALGESIA |
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| Authors/Affiliations: | 1 Zhiyong Wang*; 1 Weiya Ma; 1 Jean-Guy Chabot; 1 Remi Quirion;
1 Douglas Mental Health University, Montreal, QC, Canada
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| Content: | Opiates including morphine are frequently used in management of chronic pain. However, chronic or prolonged exposure to morphine often produces decreased antinociceptive efficacy, related to the development of tolerance. Although much knowledge is known about the mechanisms underlying tolerance to morphine induced analgesia, it still remains unclear how protein kinases and subsequent possible targets are involved in this effect. In this study, we demonstrate that a 7-day intrathecal delivery of morphine (15µg/day) induced extracelluar signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) activation. Pre-treatment with the specific MEK (upstream kinase of ERK) inhibitor PD98059 (2 and 10µg) or p38 inhibitor SB203580 (2 and 10µg) 30 min before daily delivery of morphine attenuated the development of tolerance to morphine induced analgesia. We also investigated other kinases including c-Jun N-terminal kinase (JNK), Akt and glycogen synthase kinase-3beta (GSK-3 ¦Â). Chronic morphine treatment did not modulate these kinases. These data indicate both ERK and p38 are involved in tolerance to morphine induced analgesia. Furthermore, co-localization study of p-ERK or p-p38 showed that ERK was specifically activated in astrocytes while p-p38 is mainly expressed in microglia. It has been well documented that inflammatory mediators including proinflammatory cytokine interleukin 1 beta (IL-1¦Â), IL-6, tumor necrosis factor alpha (TNF¦Á) and prostaglandins (PGE2) are implicated in morphine tolerance. We investigated next the possible link between protein kinases and these inflammatory mediators. Western blot analysis has shown that up-regulation of IL-1¦Â level induced by chronic morphine treatment was reversed by PD98059 treatment, but not SB203580. However, treatment with SB203580 inhibited the up-regulation of IL-6 and TNF¦Á levels in our model. In addition, the level of microsomal prostaglandin E synthase 1 (mPGES-1), an enzyme catalyzing the formation of PGE2 from cyclooxygenase-derived PGH2, was up-regulated by chronic morphine treatment, an effect reversed by treatment with PD98059. Taken together, these data suggest that activated ERK in astrocytes and p38 in microglia are involved in tolerance to morphine induced analgesia by modulating inflammatory mediators such as IL-1¦Â and mPGES-1. Targeting ERK and p38 MAP kinases may be a novel approach to regulate the development of tolerance to morphine induced analgesia. (Supported by a grant from CIHR to RQ)
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