Tachykinin NK₁ receptor antagonist co-administration attenuates opioid withdrawal-mediated spinal microglia and astrocyte activation

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• 作者：Suneeta Tumati^a ; Tally M. Largent-Milnes^a ; Attila I. Keresztes^a ; Takashi Yamamoto^b ; Todd W. Vanderah^a ; ^d ; William R. Roeske^a ; ^c ; ^e ; Victor J. Hruby^b ; Eva V. Varga^a ; ^e ; ^{evarga@email.arizona.edu}
• 关键词：Opioid-induced hyperalgesia ; Spinal glia ; Tachykinin NK1 receptor ; Tachykinin NK1 receptor antagonist
• 刊名：European Journal of Pharmacology
• 出版年：2012
• 出版时间：5 June, 2012
• 年：2012
• 卷：684
• 期：1-3
• 页码：64-70
• 全文大小：925 K

文摘

Prolonged morphine treatment increases pain sensitivity in many patients. Enhanced spinal Substance P release is one of the adaptive changes associated with sustained opioid exposure. In addition to pain transmitting second order neurons, spinal microglia and astrocytes also express functionally active Tachykinin NK₁ (Substance P) receptors. In the present work we investigated the role of glial Tachykinin NK₁ receptors in morphine withdrawal-mediated spinal microglia and astrocyte activation. Our data indicate that intrathecal co-administration (6 days, twice daily) of a selective Tachykinin NK₁ receptor antagonist (N-acetyl-l-tryptophan 3,5-bis(trifluoromethyl)benzylester (L-732,138; 20 ¦Ìg/injection)) attenuates spinal microglia and astrocyte marker and pro-inflammatory mediator immunoreactivity as well as hyperalgesia in withdrawn rats. Furthermore, covalent linkage of the opioid agonist with a Tachykinin NK₁ antagonist pharmacophore yielded a bivalent compound that did not augment spinal microglia or astrocyte marker or pro-inflammatory mediator immunoreactivity and did not cause paradoxical pain sensitization upon drug withdrawal. Thus, bivalent opioid/Tachykinin NK₁ receptor antagonists may provide a novel paradigm for long-term pain management.