| Abstract No.: | A-B1044 |
| Country: | Canada |
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| Title: | ACTIVATED CELL-TYPE SPECIFIC ERK AND P38 MITOGEN-ACTIVATED PROTEIN KINASES MEDIATE MORPHINE ANALGESIC TOLERANCE |
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| Authors/Affiliations: | 1 Zhiyong Wang*; 1 Weiya Ma; 1 Jean-Guy Chabot; 1 Quirion Remi;
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 produces decreased antinociceptive efficacy, related to the development of tolerance. Although much knowledge has been known about the mechanisms underlying morphine analgesic tolerance, it still remains unclear how protein kinases and subsequent possible targets are involved in tolerance. In this study we demonstrated that a 7-day intrathecal delivery of morphine (15µg/day) induced extracelluar signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) activation by western blot analysis. Pre-treatment with the specific MEK (upstream kinase of ERK) inhibitor PD98059 (1 and 10µg) or p38 inhibitor SB203580 (2 and 10µg) 30 min before daily delivery of morphine attenuated the development of tolerance to morphine analgesia. We also detected other kinases including c-Jun N-terminal kinase (JNK), Akt and glycogen synthase kinase-3beta (GSK-3 ¦Â). No activation of these kinases were found following chronic morphine treatment. These data indicate that both ERK and p38 are involved in morphine analgesic tolerance. Furthermore, co-localization study of p-ERK or p-p38 showed that ERK was specifically activated in astrocyte and p-p38 was mainly expressed in microglia. It has been well documented that inflammatory mediators including proinflammatory interleukin 1 beta (IL-1¦Â), IL-6, tumor necrosis factor alpha (TNF¦Á) as well as prostaglandins (PGE2) are implicated in morphine tolerance. We then investigated the possible link between protein kinases and these inflammatory mediators. Western blot analysis displayed 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 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 activated ERK in astrocyte and p38 in microglia mediate tolerance to morphine analgesia by modulating inflammatory mediators IL-1¦Â level and mPGES-1 activity as well as IL-6 and TNF¦Á level, respectively. Targeting ERK and p38 MAP kinases may be the direction of drug development against morphine tolerance. (Supported by the Canadian Institutes of Health Research) |
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