Cav3.2 calcium channels : the key protagonist of the supraspinal effect of paracetamol Article - 2014

Nicolas Kerckhove, Christophe Mallet, Amaury François, Mathieu Boudes, Jean Chemin, Thomas Voets, Emmanuel Bourinet, Abdelkrim Alloui, Alain Eschalier

Nicolas Kerckhove, Christophe Mallet, Amaury François, Mathieu Boudes, Jean Chemin, Thomas Voets, Emmanuel Bourinet, Abdelkrim Alloui, Alain Eschalier, « Cav3.2 calcium channels : the key protagonist of the supraspinal effect of paracetamol  », PAIN, 2014, pp. 764–772. ISSN 0304-3959

Résumé

To 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 (Cav3.2). In this study we show that the antinociceptive effect of paracetamol in mice is lost when supraspinal Cav3.2 channels are inhibited. Therefore, we hypothesized a relationship between supraspinal Cav3.2 and TRPV1, via AM404, which mediates the analgesic effect of paracetamol. AM404 is able to activate TRPV1 and weakly inhibits Cav3.2. Interestingly, activation of TRPV1 induces a strong inhibition of Cav3.2 current. Supporting this, intracerebroventricular administration of AM404 or capsaicin produces antinociception that is lost in Cav3.2−/− 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 Cav3.2 channel ; and 3) suggests supraspinal Cav3.2 inhibition as a potential pharmacological strategy to alleviate pain.

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