• Nicolas Kerckhove, Christophe Mallet, Amaury François, Mathieu Boudes, Jean Chemin, Thomas Voets, Emmanuel Bourinet, Abdelkrim Alloui, and Alain Eschalier.
• Clermont Université, Université d'Auvergne, Pharmacologie Fondamentale et Clinique de la Douleur, 63000 Clermont-Ferrand, France; INSERM, U 1107, Neuro-Dol, 63000 Clermont-Ferrand, France.
• Pain. 2014 Apr 1;155(4):764-72.

AbstractTo exert its analgesic action, paracetamol requires complex metabolism to produce a brain-specific lipoamino acid compound, AM404, which targets central transient receptor potential vanilloid receptors (TRPV1). Lipoamino acids are also known to induce analgesia through T-type calcium-channel inhibition (Ca(v)3.2). In this study we show that the antinociceptive effect of paracetamol in mice is lost when supraspinal Ca(v)3.2 channels are inhibited. Therefore, we hypothesized a relationship between supraspinal Ca(v)3.2 and TRPV1, via AM404, which mediates the analgesic effect of paracetamol. AM404 is able to activate TRPV1 and weakly inhibits Ca(v)3.2. Interestingly, activation of TRPV1 induces a strong inhibition of Ca(v)3.2 current. Supporting this, intracerebroventricular administration of AM404 or capsaicin produces antinociception that is lost in Ca(v)3.2(-/-) mice. Our study, for the first time, (1) provides a molecular mechanism for the supraspinal antinociceptive effect of paracetamol; (2) identifies the relationship between TRPV1 and the Ca(v)3.2 channel; and (3) suggests supraspinal Ca(v)3.2 inhibition as a potential pharmacological strategy to alleviate pain.Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

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