title: Immunoneutralization of agmatine sensitizes mice to micro-opioid receptor tolerance.
abstract: Systemically or centrally administered agmatine (decarboxylated arginine) prevents, moderates, or reverses opioid-induced tolerance and self-administration, inflammatory and neuropathic pain, and sequelae associated with ischemia and spinal cord injury in rodents. These behavioral models invoke the N-methyl-D-aspartate (NMDA) receptor/nitric-oxide synthase cascade. Agmatine (AG) antagonizes the NMDA receptor and inhibits nitric-oxide synthase in vitro and in vivo, which may explain its effect in models of neural plasticity. Agmatine has been detected biochemically and immunohistochemically in the central nervous system. Consequently, it is conceivable that agmatine operates in an anti-glutamatergic manner in vivo; the role of endogenous agmatine in the central nervous system remains minimally defined. The current study used an immunoneutralization strategy to evaluate the effect of sequestration of endogenous agmatine in acute opioid analgesic tolerance in mice. First, intrathecal pretreatment with an anti-AG IgG (but not normal IgG) reversed an established pharmacological effect of intrathecal agmatine: antagonism of NMDA-evoked behavior. This result justified the use of anti-AG IgG to sequester endogenous agmatine in vivo. Second, intrathecal pretreatment with the anti-AG IgG sensitized mice to induction of acute spinal tolerance of two micro-opioid receptor-selective agonists, [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin and endomorphin-2. A lower dose of either agonist that, under normal conditions, produces moderate or no tolerance was tolerance-inducing after intrathecal pretreatment of anti-AG IgG (but not normal IgG). The effect of the anti-AG IgG lasted for at least 24 h in both NMDA-evoked behavior and the acute opioid tolerance. These results suggest that endogenous spinal agmatine may moderate glutamate-dependent neuroplasticity.
authors.affiliation: Departments of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota 55455, USA. carfair@umn.edu
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Wade
authors.forename: Lori L
authors.initials: LL
authors.lastname: Eskridge
authors.forename: H Oanh X
authors.initials: HO
authors.lastname: Nguyen
authors.forename: Kelley F
authors.initials: KF
authors.lastname: Kitto
authors.forename: Laura S
authors.initials: LS
authors.lastname: Stone
authors.forename: George
authors.initials: G
authors.lastname: Wilcox
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Fairbanks
mesh_terms: D000376:Agmatine / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology*; D001120:Arginine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists; D006168:Guinea Pigs; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000494:pharmacology; D007150:Immunohistochemistry; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D016202:N-Methylaspartate; D009842:Oligopeptides / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000187:drug effects*; D013116:Spinal Cord / Q000187:drug effects
chemical_list: D000701:Analgesics, Opioid; D019138:Antibodies, Blocking; D018690:Excitatory Amino Acid Agonists; D007074:Immunoglobulin G; D009842:Oligopeptides; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C105294:endomorphin 2; D016202:N-Methylaspartate; D000376:Agmatine; D001120:Arginine
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