Peripheral and central antinociceptive action of Na+–K+–2Cl− cotransporter blockers on formalin-induced nociception in rats

Granados-Soto, Vinicio; Arguelles, Carlos F.; Álvarez-Leefmans, Francisco J.

doi:10.1016/j.pain.2004.12.023

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Volume 114, Issue 1 , Pages 231-238, March 2005

Peripheral and central antinociceptive action of Na⁺–K⁺–2Cl⁻ cotransporter blockers on formalin-induced nociception in rats

Vinicio Granados-Soto
- Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados, Calzada Tenorios 235, Col. Granjas Coapa, México, DF 14330, México
Carlos F. Arguelles
- Laboratorio de Farmacología, Centro Nacional de Rehabilitación, Secretaría de Salud, México, DF, México
Francisco J. Álvarez-Leefmans
- Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados, Calzada Tenorios 235, Col. Granjas Coapa, México, DF 14330, México
- Departamento de Neurobiología, Instituto Nacional de Psiquiatría ‘Ramón de la Fuente,’ México, DF, México
- Corresponding author. Address: Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados, Calzada Tenorios 235, Col. Granjas Coapa, México, DF 14330, México. Tel.: +52 55 5655 3031; fax: +52 55 5655 9980.

Received 6 May 2004; received in revised form 3 November 2004; accepted 15 December 2004.

AIB-400619

Abstract

The possible local peripheral and spinal (intrathecal) antinociceptive effect of Na⁺–K⁺–2Cl⁻ cotransporter (NKCC) inhibitors was investigated in the rat formalin test. Nociceptive flinching behavior induced by formalin (1%) injection in the hind paw was assessed following administration of cotransporter inhibitors. Local peripheral pretreatment in the ipsilateral paw with bumetanide (ED₃₀, 27.1±12.7μg/paw), piretanide (ED₃₀, 109.2±21.6μg/paw) or furosemide (ED₃₀, 34.3±5.0μg/paw), but not vehicle (DMSO 100%), produced dose-dependent antinociception in phase 2 of the test. Local bumetanide had the greatest effect (∼70% antinociception). Bumetanide also inhibited formalin-induced flinching behavior during phase 1 (ED₃₀, 105.6±99.1μg/paw). Spinal intrathecal pretreatment with bumetanide (ED₃₀, 194.6±97.9μg), piretanide (ED₃₀, 254.4±104.9μg) or furosemide (ED₃₀, 32.0±6.9μg), but not vehicle (DMSO 100%), also produced antinociception in phase 2. In this case, only intrathecal furosemide reduced flinching behavior during phase 1 (ED₃₀, 99.4±51.4μg) and had the maximal antinociceptive effect in phase 2 (∼65% antinociception). The opioid receptor-antagonist naloxone (2mg/kg, s.c.) did not reverse antinociception induced by either peripheral or spinal administration of NKCC blockers. Our data suggest that the Na⁺–K⁺–2Cl⁻ cotransporter localized in sensory neurons at intraspinal and peripheral sites is involved in formalin-induced nociception.