title: Nitric oxide synthase modulates the antihyperalgesic effect of the NMDA receptor antagonist MK-801 on Carrageenan-induced inflammatory pain in rats.
abstract: The N-methyl-D-aspartate (NMDA) receptor, an ionotropic glutamate receptor, may play a significant role in the development and maintenance of an inflammatory pain. Activation of NMDA receptors may cause nitric oxide (NO) release through activation of NO synthase (NOS). MK-801, a noncompetitive NMDA receptor antagonist is commonly used as a neuropharmacological tool. The interaction between MK-801 and NOS in the inflammatory pain has not been evaluated before. We investigated whether MK-801 affects inflammatory pain and whether NOS modulates the effect of MK-801. Carrageenan-induced hyperalgesia was evaluated by measuring the withdrawal response to mechanical stimuli, using an electronic version of the von Frey anesthesiometer in Wistar rats. MK-801 given subcutaneously (0.5-20 μg/kg) or intraplantarly (0.1 and 0.15 μg/paw) significantly reduced mechanical hyperalgesia. Intraplantarly given MK-801 exerted a local antihyperalgesic effect, because when applied to the contralateral side it did not reduce mechanical sensitivity in the ipsilateral side. N-nitro-L-arginine methyl ester hydrochloride (5 and 10 mg/kg), a non-selective NOS inhibitor, significantly reduced the effects of MK-801. N-ω-Propyl-L-arginine hydrochloride (0.5-2 mg/kg), a selective inhibitor of neuronal NOS, increased the antihyperalgesic effect of MK-801, whereas S-methylisothiourea (5-15 μg/kg), a selective inhibitor of inducible NOS, lowered the antihyperalgesic effect of MK-801. Importantly, each NOS inhibitor given alone did not affect carrageenan-induced hyperalgesia. In conclusion, MK-801 is effective against inflammatory pain and its antihyperalgesic effect is modulated in a different ways by NOS, being enhanced by a neuronal NOS inhibitor but reduced by an inducible NOS inhibitor.
authors.affiliation: Department of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade.
authors.forename: Dragana P
authors.initials: DP
authors.lastname: Srebro
authors.forename: Sonja M
authors.initials: SM
authors.lastname: Vucković
authors.forename: Katarina R
authors.initials: KR
authors.lastname: Savic Vujovic
authors.forename: Milica S
authors.initials: MS
authors.lastname: Prostran
mesh_terms: D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D002351:Carrageenan; D016291:Dizocilpine Maleate / Q000494:pharmacology / Q000627:therapeutic use*; D006930:Hyperalgesia / Q000150:complications / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D007249:Inflammation / Q000150:complications / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology; D007550:Isothiuronium / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D010146:Pain / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D017288:Pain Threshold / Q000187:drug effects; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C109599:N(omega)-propylarginine; D016194:Receptors, N-Methyl-D-Aspartate; D007550:Isothiuronium; D016291:Dizocilpine Maleate; D002351:Carrageenan; D001120:Arginine; D019001:Nitric Oxide Synthase; C027744:S-methylisothiopseudouronium; D019331:NG-Nitroarginine Methyl Ester