Tachykinin NK₁ receptor antagonist co-administration attenuates opioid withdrawal-mediated spinal microglia and astrocyte activation.
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spinal microglia and astrocyte marker and pro-inflammatory mediator immunoreactivity as well as hyperalgesia in withdrawn rats.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.
Department of Pharmacology, The University of Arizona, Tucson, AZ 85724, USA.
Suneeta
S
Tumati
Tally M
TM
Largent-Milnes
Attila I
AI
Keresztes
Takashi
T
Yamamoto
Todd W
TW
Vanderah
William R
WR
Roeske
Victor J
VJ
Hruby
Eva V
EV
Varga
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000009:adverse effects*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D009020:Morphine / Q000008:administration & dosage / Q000009:adverse effects; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064729:Neurokinin-1 Receptor Antagonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology*; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014364:Tryptophan / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D000701:Analgesics, Opioid; D015415:Biomarkers; D039481:CD11b Antigen; D009419:Nerve Tissue Proteins; D064729:Neurokinin-1 Receptor Antagonists; D014409:Tumor Necrosis Factor-alpha; C086089:3,5-bis(trifluoromethyl)benzyl N-acetyltryptophan; D009020:Morphine; D014364:Tryptophan