Immunoneutralization of Agmatine Sensitizes Mice to μ-Opioid Receptor Tolerance
Autor: | Carrie L. Wade, Kelley F. Kitto, George L. Wilcox, Lori L. Eskridge, H. Oanh X. Nguyen, Laura S. Stone, Carolyn A. Fairbanks |
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Rok vydání: | 2009 |
Předmět: |
Male
Agonist N-Methylaspartate Agmatine Arginine medicine.drug_class Guinea Pigs Central nervous system Receptors Opioid mu Endogeny Pharmacology Rats Sprague-Dawley Mice chemistry.chemical_compound Neuropharmacology Opioid receptor Excitatory Amino Acid Agonists medicine Animals Antibodies Blocking Injections Spinal Pain Measurement Behavior Animal Dose-Response Relationship Drug Drug Tolerance Enkephalin Ala(2)-MePhe(4)-Gly(5) Immunohistochemistry Rats Analgesics Opioid medicine.anatomical_structure Spinal Cord chemistry Immunoglobulin G Neuropathic pain Molecular Medicine NMDA receptor Oligopeptides |
Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 331:539-546 |
ISSN: | 1521-0103 0022-3565 |
Popis: | 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. |
Databáze: | OpenAIRE |
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