Tachykinin NK 1 receptor antagonist co-administration attenuates opioid withdrawal-mediated spinal microglia and astrocyte activation

Suneeta Tumati, Tally M. Largent-Milnes, Attila I. Keresztes, Takashi Yamamoto, Todd W. Vanderah, William R. Roeske, Victor J. Hruby, Eva V. Varga

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

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 NK 1 (Substance P) receptors. In the present work we investigated the role of glial Tachykinin NK 1 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 NK 1 receptor antagonist (N-acetyl-l-tryptophan 3,5-bis(trifluoromethyl)benzylester (L-732,138; 20 μg/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spinal microglia and astrocyte marker and pro-inflammatory mediator immunoreactivity as well as hyperalgesia in withdrawn rats.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 NK 1 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 NK 1 receptor antagonists may provide a novel paradigm for long-term pain management.

Original languageEnglish (US)
Pages (from-to)64-70
Number of pages7
JournalEuropean Journal of Pharmacology
Volume684
Issue number1-3
DOIs
StatePublished - Jun 5 2012

Keywords

  • Opioid-induced hyperalgesia
  • Spinal glia
  • Tachykinin NK receptor
  • Tachykinin NK1 receptor antagonist

ASJC Scopus subject areas

  • Pharmacology

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