title: Pharmacological mechanisms involved in the antinociceptive effects of dexmedetomidine in mice.
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.
authors.affiliation: Department of Pharmacology and Psychobiology, State University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Rafael A S
authors.initials: RA
authors.lastname: Rangel
authors.forename: Bruno G
authors.initials: BG
authors.lastname: Marinho
authors.forename: Patrícia D
authors.initials: PD
authors.lastname: Fernandes
authors.forename: Roberto S
authors.initials: RS
authors.lastname: de Moura
authors.forename: Marcos A
authors.initials: MA
authors.lastname: Lessa
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D020927:Dexmedetomidine / Q000494:pharmacology*; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism; D010147:Pain Measurement / Q000379:methods; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism
chemical_list: D000700:Analgesics; D018341:Receptors, Adrenergic, alpha-2; D009569:Nitric Oxide; D020927:Dexmedetomidine