Arizona Health Sciences

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

TitleTachykinin NK₁ receptor antagonist co-administration attenuates opioid withdrawal-mediated spinal microglia and astrocyte activation.
Publication TypeJournal Article
Year of Publication2012
AuthorsTumati S, Largent-Milnes TM, Keresztes AI, Yamamoto T, Vanderah TW, Roeske WR, Hruby VJ, Varga EV
JournalEur J Pharmacol
Volume684
Issue1-3
Pagination64-70
Date Published2012 Jun 5
ISSN1879-0712
KeywordsAnalgesics, Opioid, Animals, Antigens, CD11b, Astrocytes, Biological Markers, Hyperalgesia, Male, Microglia, Morphine, Nerve Tissue Proteins, Neurokinin-1 Receptor Antagonists, Rats, Rats, Sprague-Dawley, Spinal Cord, Substance Withdrawal Syndrome, Tryptophan, Tumor Necrosis Factor-alpha, Up-Regulation
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 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 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spinal microglia and astrocyte marker and pro-inflammatory mediator immunoreactivity as well as hyperalgesia in withdrawn rats.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 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.

Alternate JournalEur. J. Pharmacol.
PubMed ID22724132
PubMed Central IDPMC3565540
Grant ListDA027786 / DA / NIDA NIH HHS / United States
DA13449 / DA / NIDA NIH HHS / United States
P01 DA006284 / DA / NIDA NIH HHS / United States
P01 DA006284-04 / DA / NIDA NIH HHS / United States
R01 DA013449 / DA / NIDA NIH HHS / United States
R01 DA013449-13 / DA / NIDA NIH HHS / United States
R21 DA027786-02 / DA / NIDA NIH HHS / United States
Faculty Member Reference: 
Victor Hruby, Ph.D.
Tally Largent-Milnes, Ph.D.
Todd Vanderah, PhD
Eva Varga, Ph.D.