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

• Published in: European journal of pharmacology Vol. 684; no. 1-3; pp. 64 - 70
• Main Authors: Tumati, Suneeta, Largent-Milnes, Tally M., Keresztes, Attila I., Yamamoto, Takashi, Vanderah, Todd W., Roeske, William R., Hruby, Victor J., Varga, Eva V.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 05.06.2012
• Subjects: agonists; Analgesics, Opioid - administration & dosage; Analgesics, Opioid - adverse effects; Animals; antagonists; astrocytes; Astrocytes - drug effects; Astrocytes - metabolism; Biomarkers - metabolism; CD11b Antigen - metabolism; Hyperalgesia - chemically induced; Hyperalgesia - drug therapy; Hyperalgesia - metabolism; Hyperalgesia - pathology; Male; Microglia - drug effects; Microglia - metabolism; morphine; Morphine - administration & dosage; Morphine - adverse effects; Nerve Tissue Proteins - metabolism; Neurokinin-1 Receptor Antagonists; neurons; Opioid-induced hyperalgesia; pain; patients; Rats; Rats, Sprague-Dawley; receptors; Spinal Cord - drug effects; Spinal Cord - pathology; Spinal glia; substance P; Substance Withdrawal Syndrome - drug therapy; Substance Withdrawal Syndrome - metabolism; Substance Withdrawal Syndrome - pathology; Tachykinin NK1 receptor; Tachykinin NK1 receptor antagonist; Tryptophan - administration & dosage; Tryptophan - analogs & derivatives; Tryptophan - pharmacology; Tryptophan - therapeutic use; Tumor Necrosis Factor-alpha - metabolism; Up-Regulation - drug effects; Opioid-induced hyperalgesia; Tachykinin NK1 receptor; Tachykinin NK1 receptor antagonist; Spinal glia
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2012.03.025

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 (6days, twice daily) of a selective Tachykinin NK1 receptor antagonist (N-acetyl-l-tryptophan 3,5-bis(trifluoromethyl)benzylester (L-732,138; 20μg/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. [Display omitted]