Potassium- and capsaicin-induced release of agmatine from spinal nerve terminals.
Agmatine (decarboxylated arginine) was originally identified in the CNS as an imidazoline receptor ligand. Further studies demonstrated that agmatine antagonizes NMDA receptors and inhibits nitric oxide synthase. Intrathecally administered agmatine inhibits opioid tolerance and hyperalgesia evoked by inflammation, nerve injury, and intrathecally administered NMDA. These actions suggest an anti-glutamatergic role for agmatine in the spinal cord. We have previously reported that radiolabeled agmatine is transported into spinal synaptosomes in an energy- and temperature-dependent manner. In the present study, we demonstrate that agmatine is releasable from purified spinal nerve terminals upon depolarization. When exposed to either elevated potassium or capsaicin, tritiated agmatine (but not its precursor L-arginine or its metabolite putrescine) is released in a calcium-dependent manner. Control experiments confirmed that the observed release was specific to depolarization and not due to permeabilization of or degradation of synaptosomes. That capsaicin-evoked stimulation results in agmatine release implicates the participation of primary afferent nerve terminals. Radiolabeled agmatine also accumulates in purified spinal synaptosomal vesicles in a temperature-dependent manner, suggesting that the source of releasable agmatine may be vesicular in origin. These results support the proposal that agmatine may serve as a spinal neuromodulator involved in pain processing.
Goracke-Postle
Cory J
CJ
Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota, USADepartment of Pharmacology, University of Minnesota, Minneapolis, Minnesota, USADepartment of Neuroscience, University of Minnesota, Minneapolis, Minnesota, USADepartment of Anesthesiology, University of Minnesota, Minneapolis, Minnesota, USACenter for Pain Research, University of Minnesota, Minneapolis, Minnesota, USA.
Overland
Aaron C
AC
Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota, USADepartment of Pharmacology, University of Minnesota, Minneapolis, Minnesota, USADepartment of Neuroscience, University of Minnesota, Minneapolis, Minnesota, USADepartment of Anesthesiology, University of Minnesota, Minneapolis, Minnesota, USACenter for Pain Research, University of Minnesota, Minneapolis, Minnesota, USA.
Riedl
Maureen S
MS
Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota, USADepartment of Pharmacology, University of Minnesota, Minneapolis, Minnesota, USADepartment of Neuroscience, University of Minnesota, Minneapolis, Minnesota, USADepartment of Anesthesiology, University of Minnesota, Minneapolis, Minnesota, USACenter for Pain Research, University of Minnesota, Minneapolis, Minnesota, USA.
Stone
Laura S
LS
Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota, USADepartment of Pharmacology, University of Minnesota, Minneapolis, Minnesota, USADepartment of Neuroscience, University of Minnesota, Minneapolis, Minnesota, USADepartment of Anesthesiology, University of Minnesota, Minneapolis, Minnesota, USACenter for Pain Research, University of Minnesota, Minneapolis, Minnesota, USA.
Fairbanks
Carolyn A
CA
Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota, USADepartment of Pharmacology, University of Minnesota, Minneapolis, Minnesota, USADepartment of Neuroscience, University of Minnesota, Minneapolis, Minnesota, USADepartment of Anesthesiology, University of Minnesota, Minneapolis, Minnesota, USACenter for Pain Research, University of Minnesota, Minneapolis, Minnesota, USA.
D000344:Afferent Pathways / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D000376:Agmatine / Q000378:metabolism*; D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D008297:Male; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D010146:Pain / Q000378:metabolism / Q000503:physiopathology; D011189:Potassium Chloride / Q000378:metabolism / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D013126:Spinal Nerve Roots / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D013572:Synaptic Vesicles / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure
D011189:Potassium Chloride; D000376:Agmatine; D002211:Capsaicin