【期刊导读】EJP（上海六院）：mGlu(5) R敲除减轻慢性吗啡治疗相关的镇痛耐受及其所致的脊髓PKC表达上调

来自上海六院麻醉科江伟教授研究团队的文章

Eur J Pharmacol. 2012 Mar 12. [Epub ahead of print]

Antisense oligonucleotide knockdown of mGlu(5) receptor attenuates the antinociceptive tolerance and up-regulated expression of spinal protein kinase C associated with chronic morphine treatment.

Xu T, Chen M, Zhou Q, Xue Y, Wang L, De Arce VJ, Zhang X, Jiang W.

Source

Department of Anesthesiology, Shanghai Sixth People's Hospital, Shanghai Jiaotong University, Shanghai 200233, China.

Abstract

Spinal metabotropic glutamate receptor 5 (mGlu(5) receptor) is known to influence the development of intrathecal morphine antinociceptive tolerance. However, the signaling mechanisms remain unknown. We carried out intrathecal administration of an antisense oligodeoxynucleotide (ODN), which results in reduced expression of spinal mGlu(5) receptor, to determine its effects on morphine tolerance and spinal protein kinase C (PKC) expression. Rats were treated intrathecally with saline, morphine, mGlu5 receptor antisense ODN or mGlu5 receptor mismatched ODN. Behavioral tests were used to test the thermal and mechanical pain thresholds. Eight days later, rats were sacrificed and spinal cords were harvested to assess the expression of spinal PKC (α, γ and ε) by Western blotting and real-time polymerase chain reaction (PCR). Compared to control, intrathecal mGlu(5) receptor antisense ODN resulted in a ~53.9% reduction of spinal mGlu(5) receptor after 8days treatment. The mGlu5 receptor antisense ODN prevented the development of morphine tolerance. Expression of spinal PKC (α, γ and ε) was up-regulated at the mRNA and protein levels during the development of tolerance. Meanwhile, antisense ODN but not mismatched ODN reduced the spinal dorsal horn levels of PKC (α, γ and ε) which had been up-regulated after morphine exposure. We conclude that mGlu(5) receptor participates in the development of morphine tolerance. Expression of spinal PKC (α, γ and ε) at the mRNA and protein levels increased during morphine tolerance. Antisense ODN of mGlu(5) receptor prevented the tolerance and inhibited the altered expression of spinal PKC (α, γ and ε) during the development of tolerance.

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PMID:22429573