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 (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 v3.2 channel">Cav3.2 channel; and 3) suggests supraspinal Cav3.2 inhibition as a potential pharmacological strategy to alleviate pain.
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Nicolas Kerckhove, Christophe Mallet, Amaury Francois, Mathieu Boudes, Jean Chemin, et al.. Ca v 3.2 calcium channels: The key protagonist in the supraspinal effect of paracetamol. PAIN, Elsevier, 2014, 155 (4), pp.764-772. ⟨10.1016/j.pain.2014.01.015⟩. ⟨hal-02370511⟩



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