Ca(v)3.2 calcium channels: the key protagonist in the supraspinal effect of paracetamol

Abstract : 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 (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.
Type de document :
Article dans une revue
Pain, 2014, 155 (4), pp.764--72. 〈10.1016/j.pain.2014.01.015〉
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Soumis le : lundi 3 décembre 2018 - 15:13:13
Dernière modification le : mardi 4 décembre 2018 - 01:18:58




Nicolas Kerckhove, C. Mallet, A. Francois, Mathieu Boudes, J. Chemin, et al.. Ca(v)3.2 calcium channels: the key protagonist in the supraspinal effect of paracetamol. Pain, 2014, 155 (4), pp.764--72. 〈10.1016/j.pain.2014.01.015〉. 〈hal-01942942〉



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