PubMed 24447516

Referenced in Channelpedia wiki pages of: none

Automatically associated channels: Cav3.2 , TRP , TRPV , TRPV1

Title: Cav3.2 calcium channels: the key protagonist of the supraspinal effect of paracetamol.

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

Journal, date & volume: Pain, 2014 Jan 18 , ,

PubMed link:

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.