Open AccessCav3.2 calcium channels: The key protagonist in the supraspinal effect of paracetamol
Author(s) -
Nicolas Kerckhove,
Christophe Mallet,
Amaury François,
Mathieu Boudes,
Jean Chemin,
Thomas Voets,
Emmanuel Bourinet,
Abdelkrim Alloui,
Alain Eschalier
Publication year - 2014
Publication title -
pain
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.524
H-Index - 258
eISSN - 1872-6623
pISSN - 0304-3959
DOI - 10.1016/j.pain.2014.01.015
Subject(s) - key (lock) , neuroscience , medicine , psychology , computer science , computer security
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.