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

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spinal microglia and astrocyte marker and pro-inflammatory mediator immunoreactivity as well as hyperalgesia in withdrawn rats.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.

• Authors: Suneeta Tumati, Tally M Largent-Milnes, Attila I Keresztes, Takashi Yamamoto, Todd W Vanderah, William R Roeske, Victor J Hruby, Eva V Varga
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 684 Issue 1-3 Pg. 64-70 (Jun 05 2012) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 22724132 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Analgesics, Opioid
• Biomarkers
• CD11b Antigen
• Nerve Tissue Proteins
• Neurokinin-1 Receptor Antagonists
• Tumor Necrosis Factor-alpha
• 3,5-bis(trifluoromethyl)benzyl N-acetyltryptophan
• Morphine
• Tryptophan

Topics

• Analgesics, Opioid (administration & dosage, adverse effects)
• Animals
• Astrocytes (drug effects, metabolism)
• Biomarkers (metabolism)
• CD11b Antigen (metabolism)
• Hyperalgesia (chemically induced, drug therapy, metabolism, pathology)
• Male
• Microglia (drug effects, metabolism)
• Morphine (administration & dosage, adverse effects)
• Nerve Tissue Proteins (metabolism)
• Neurokinin-1 Receptor Antagonists
• Rats
• Rats, Sprague-Dawley
• Spinal Cord (drug effects, pathology)
• Substance Withdrawal Syndrome (drug therapy, metabolism, pathology)
• Tryptophan (administration & dosage, analogs & derivatives, pharmacology, therapeutic use)
• Tumor Necrosis Factor-alpha (metabolism)
• Up-Regulation (drug effects)