Gaba

Life Sciences 80 (2007) 1268 – 1273 www.elsevier.com/locate/lifescie

Involvement of chloride channel coupled GABAC receptors in the peripheral antinociceptive effect induced by GABAC receptor agonist cis-4-aminocrotonic acid
Gláucia Maria Lopes Reis, Igor Dimitri Gama Duarte ⁎
Department of Pharmacology, Institute of Biological Sciences, UFMG, Av. Antônio Carlos, 6627, 31270-100, BeloHorizonte, Brazil Received 5 September 2006; accepted 12 December 2006

Abstract We investigated the effect of chloride and potassium channel blockers on the antinociception induced by GABAC receptor agonist CACA (cis-4aminocrotonic acid) using the paw pressure test, in which pain sensitivity was increased by an intraplantar injection (2 μg) of prostaglandin E2 (PGE2). CACA administered locally intothe right hindpaw (25, 50 and 100 μg/paw) elicited a dose-dependent antinociceptive effect which was demonstrated to be local, since only higher doses produced an effect when injected in the contralateral paw. The GABAC receptor antagonist (1,2,5,6 tetrahydropyridin-4-yl) methylphosphinic acid (TPMPA; 5, 10 and 20 μg/paw) antagonized, in a dose-dependent manner, the peripheral antinociceptioninduced by CACA (100 μg), suggesting a specific effect. This effect was reversed by the chloride channel coupled receptor blocker picrotoxin (0.8 μg/paw). Glibenclamide (160 μg) and tolbutamide (320 μg), blockers of ATP-sensitive potassium channels, charybdotoxin (2 μg), a large-conductance potassium channel blocker, dequalinium (50 μg), a small-conductance potassium channel blocker, and cesium (500μg), a nonspecific potassium channel blocker did not modify the peripheral antinociception induced by CACA. This study provides evidence that activation of GABAC receptors in the periphery induces antinociception, that this effect results from the activation of chloride channel coupled GABAC receptors and that potassium channels appear not to be involved. © 2007 Elsevier Inc. All rights reserved.Keywords: cis-4-aminocrotonic acid; CACA; K+ channel; Cl− channel; Peripheral antinociception; Picrotoxin; TPMPA

Introduction In the vertebrate central nervous system, γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter. GABA receptors can be classified as GABAA and GABAC receptors, which are ionotropic receptors, or as GABAB receptors, which are metabotropic receptors coupled tothe GTP-binding protein (Bormann, 2000; Bowery and Enna, 2000). GABAA receptors have several subunits (6α, 4β, 3γ, 1δ, 1ε, 1π, and 3ρ), which form a pentameric chloride channel (Barnard et al., 1998). GABAC receptors are pentameric Cl− channels composed of the ρ subunits (ρ 1–3). The GABAA and GABAB receptors show
⁎ Corresponding author. Departamento de Farmacologia, ICB-UFMG, Av. Antônio Carlos,6627, Campus da Pampulha, Belo Horizonte, MG, Brasil, CEP: 31.270-100, Brazil. E-mail address: dimitri@icb.ufmg.br (I.D.G. Duarte). 0024-3205/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.lfs.2006.12.015

sensitivities to bicuculline and baclofen, respectively. GABAC receptors do not respond to either drug. GABA analogue cis-4aminocrotonic acid (CACA) selectivelyactivates GABAC receptors while TPMPA has been identified as a potent and highly selective antagonist for GABAC receptors (Bowery et al., 1981; Bormann, 2000; Bowery and Enna, 2000). The function of GABA in the modulation of nociception is crucial and complex. Several reports have demonstrated the participation of GABAergic system in modulation of pain at the supraspinal (Millan, 2002) and spinallevel (Malcangio and Bowery, 1996; Hammond, 2001). In addition, studies have demonstrated a peripheral GABAergic antinociceptive action (Carlton and Zhou, 1998; Motta et al., 2004). Most of these studies examined the effects of activation of GABAA and GABAB receptors in nociception. In contrast, less is known about the involvement of the GABAC receptor in pain. The function of the GABAC...