Abstract
Agmatine, an endogenous cationic amine resulting from the decarboxylation of l-arginine, produces antihyperalgesic and antiallodynic effects in animal models of chronic neuropathic and inflammatory pain. We examined the effect of agmatine on tactile and thermal allodynia and on mechanical hyperalgesia in streptozocin-induced diabetic rats. To determine its mechanism of action and the potential interest of some of its combinations, the antihyperalgesic effect of agmatine was challenged with α2-adrenergic imidazoline and opioid-receptor antagonists, and its interaction with the opioid-receptor agonist morphine, the competitive N-methyl-d-aspartate receptor antagonist D-CPP [R(–)-3-(2-carboxypiperazine-4-yl)-propyl-1-phosphonic acid], and the nitric-oxide synthase inhibitor l-NAME (l-NG-nitro-l-arginine methyl ester) were examined. When intrathecally (i.t.) injected (4.4 to 438 nmol/rat), agmatine was ineffective in normal rats but suppressed tactile allodynia (von Frey hair test), thermal allodynia (tail immersion test), and mechanical hyperalgesia (paw-pressure test) in diabetic rats. This spinal antihyperalgesic effect was suppressed by idazoxan (40 μmol/rat i.t.) but not by yohimbine (40 μmol/rat i.t.) or naloxone (0.69 μmol/rat i.v.). In diabetic rats, an isobolographic analysis showed that combinations of i.t. agmatine with i.v. l-NAME or with i.t. morphine resulted in an additive antihyperalgesic effect, whereas the agmatine/D-CPP i.t. combination was superadditive. In summary, the present findings reveal that spinal agmatine produces antiallodynic and antihyperalgesic effects in diabetic neuropathic pain involving, at least for its antihyperalgesic effect, the imidazoline receptors. Moreover, agmatine combined with D-CPP produces an antinociceptive synergy in experimental neuropathy, opening opportunities in the development of new strategies for pain therapy.
Footnotes
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This work was supported by grants from Institut UPSA de la Douleur (Paris, France) and Grant 1040873 from Fondecyt (Santiago, Chile).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.123018.
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ABBREVIATIONS: AG, agmatine, 4-(aminobutyl) guanidine; CL, confidence limit; D-CPP, R(–)-3-(2-carboxypiperazine-4-yl)-propyl-1-phosphonic acid; D, diabetic; DMSO, dimethyl sulfoxide; l-NAME, l-NG-nitro-l-arginine methyl ester; ME, maximal effect; N, normal; NMDA, N-methyl-d-aspartate; NOS, nitric-oxide synthase; STZ, streptozocin; α2-AD, α2-adrenergic; MK801, 5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate).
- Received March 20, 2007.
- Accepted June 4, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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