Ca(v)3.2 calcium channels: the key protagonist in the supraspinal effect of paracetamol.
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.
Clermont Université, Université d'Auvergne, Pharmacologie Fondamentale et Clinique de la Douleur, 63000 Clermont-Ferrand, France INSERM, U 1107, Neuro-Dol, 63000 Clermont-Ferrand, France CHU Clermont-Ferrand, Service de Pharmacologie, 63003 Clermont-Ferrand, France Laboratories of Excellence, Ion Channel Science and Therapeutics, Institut de Génomique Fonctionnelle, 141 rue de la Cardonille, 34094 Montpellier, France CNRS UMR5203, Montpellier, France INSERM, U661, Montpellier, France IFR3 Universités Montpellier I & II, Montpellier, France Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
Nicolas
N
Kerckhove
Christophe
C
Mallet
Amaury
A
François
Mathieu
M
Boudes
Jean
J
Chemin
Thomas
T
Voets
Emmanuel
E
Bourinet
Abdelkrim
A
Alloui
Alain
A
Eschalier
D015761:4-Aminopyridine / Q000494:pharmacology; D000082:Acetaminophen / Q000494:pharmacology*; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001168:Arthritis / Q000139:chemically induced / Q000188:drug therapy; D020747:Calcium Channels, T-Type / Q000172:deficiency* / Q000235:genetics; D002478:Cells, Cultured; D004333:Drug Administration Routes; D004347:Drug Interactions; D005727:Ganglia, Spinal / Q000166:cytology; D006801:Humans; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects; D010147:Pain Measurement / Q000187:drug effects; D026902:Potassium Channel Blockers / Q000494:pharmacology; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects*; D050916:TRPV Cation Channels / Q000172:deficiency / Q000235:genetics; D019789:Tetraethylammonium / Q000494:pharmacology
D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; C504883:Cacna1h protein, mouse; D020747:Calcium Channels, T-Type; D026902:Potassium Channel Blockers; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D000082:Acetaminophen; D019789:Tetraethylammonium; D009020:Morphine; D015761:4-Aminopyridine
Analgesia; Ca(v)3.2 channel; Paracetamol; TRPV1