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PHARMACOLOGICAL MECHANISMS INVOLVED IN THE ANTINOCICEPTIVE EFFECTS OF DEXMEDETOMIDINE IN MICE
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Universidade do Estado do Rio de Janeiro. Departamento de Farmacologia e Psicobiologia. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Instituto de Ciências Biomédicas. Programa de Desenvolvimento de Fármacos. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Instituto de Ciências Biomédicas. Programa de Desenvolvimento de Fármacos. Rio de Janeiro, RJ, Brasil
Universidade do Estado do Rio de Janeiro. Departamento de Farmacologia e Psicobiologia. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Investigação Cardiovascular. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Instituto de Ciências Biomédicas. Programa de Desenvolvimento de Fármacos. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Instituto de Ciências Biomédicas. Programa de Desenvolvimento de Fármacos. Rio de Janeiro, RJ, Brasil
Universidade do Estado do Rio de Janeiro. Departamento de Farmacologia e Psicobiologia. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Investigação Cardiovascular. Rio de Janeiro, RJ, Brasil.
Abstract
Dexmedetomidine (DEX) is a α2-adrenoceptor (α2-AR) agonist used as an anesthetic adjuvant and as sedative in critical care settings. Typically, α2-AR agonists release nitric oxide (NO) and subsequently activate NO-GMPc pathway and have been implicated with antinociception. In this study, we investigate the pharmacological mechanisms involved in the antinociceptive effects of DEX, using an acetic acid-induced writhing assay in mice. Saline or DEX (1, 2, 5, or 10 μg/kg) was intravenously injected 5 min before ip administration of acetic acid and the resulting abdominal constrictions were then counted for 10 min. To investigate the possible mechanisms related to antinociceptive effect of DEX (10 μg/kg), the animals were also pretreated with one of the following drugs: 7-nitroindazole (7-NI; 30 mg/kg ip); 1H-[1,2,4] oxadiazole [4,3-a] quinoxaline-1-one (ODQ; 2.5 mg/kg, ip); yohimbine (YOH; 1 mg/kg, ip); atropine (ATRO; 2 mg/kg, ip); glibenclamide (GLIB; 1 mg/kg, i.p.) and naloxone (NAL; 0.2 mg/kg, ip). A rotarod and open-field performance test were performed with DEX at 10 μg/kg dose. DEX demonstrated its potent antinociceptive effect in a dose-dependent manner. The pretreatment with 7-NI, ODQ, GLIB, ATRO, and YOH significantly reduced the antinociceptive affects of DEX. However, NAL showed no effecting DEX-induced antinociception. The rotarod and open-field tests confirmed there is no detectable sedation or even significant motor impairment with DEX at 10 μg/kg dose. Our results suggest that the α2-AR and NO-GMPc pathways play important roles in the systemic antinociceptive effect of DEX in a murine model of inflammatory pain. Furthermore, the antinociceptive effect exerted by DEX appears to be dependent on KATP channels, independent of opioid receptor activity.
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