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Role of PDGFR-β signal pathway in morphine tolerance

2015; Nanjing General of Nanjing Military Region; Linguagem: Inglês

1008-8199

Hongju Liu,

Cancer Treatment and Pharmacology

Objective Beta platelet-derived growth factor receptor( PDGFR-β)-mediated signaling plays a key role in morphine tolerance,but its molecular mechanisms are not yet completely understood. The present study aims to investigate whether the extracellular signal-regulated kinase( ERK) and cyclic AMP response element binding protein( REB) signaling pathways are involved in the development of PDGFR-β activation-induced morphine tolerance in rats. Methods Thirty-six adult male SD rats were randomly divided into six groups of equal number: normal saline( 20 μL),morphine( 15 μg),morphine + imatinib( morphine 15 μg + imatinib 10 μg),morphine + PDGF-BB( morphine 15 μg + PDGF-BB 10 ng),imatinib( 10 μg),and PDGF-BB( 10 ng),all treated intrathecally at 20 μL once daily for 7 consecutive days. Paw withdrawal latency( PWL) was measured 1 d before and 30 min after medication at 1,3,5,and 7 days,respectively,followed by calculation of the maximal possible effect of analgesia( MPE). On the8 th day,PWL was again obtained from all the rats at 30 min after intrathecal injection of morphine( 15 μg). Then,all the animals were sacrificed and the L4- 5 segment of the spinal cord was isolated for determination of the expressions of ERK, phosphorylated ERK( p-ERK),CREB,and phosphorylated CREB( p-CREB) by Western blot. Results At 5 and 7 days after medication,MPE was significant decreased in the morphine group( [52. 90 ± 8. 20] and[15. 12 ± 3. 80]%) and the morphine + PDGF-BB group( [43. 51 ± 5. 42]and[14. 81 ± 3. 60]%) as compared with( 100. 00 ±0. 00) % in both groups at 1 day( P 0. 05),but had no significant changes in the morphine + imatinib group at 1,3,5,and 7days. After intrathecal injection of morphine on the 8th day,MPE was( 16. 22 ± 2. 51) % in the morphine group,( 15. 22 ± 3. 50) %in the morphine + PDGF-BB group,and( 35. 21 ± 4. 51) % in the PDGF-BB group,all remarkably lower than( 100. 00 ± 0. 00) %in the control group( P 0. 05). There were no significant differences in the expression levels of ERK and CREB among the six groups. The expressions of spinal p-ERK and p-CREB were markedly increased in the morphine,morphine + PDGF-BB,and PDGFBB groups as compared with the control group( P 0. 05),but significantly decreased in the morphine + imatinib group in comparison with the morphine group,( P 0. 05). Conclusion The PDGFR-β signaling pathway plays an important role in the development of tolerance to morphine-induced analgesia and its underlying mechanisms may be associated with the activation of the ERK and CREB pathways.