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Ca 2+ -loaded calmodulin normally inhibits multiple Ca 2+ -channels upon dangerous elevation of intracellular Ca 2+  and protects cells from Ca 2+ -cytotoxicity, so blocking of calmodulin should theoretically lead to uncontrolled elevation of intracellular Ca 2+ . Paradoxically, classical anti-psychotic, anti-calmodulin drugs were noted here to inhibit Ca 2+ -uptake  via  the vanilloid inducible Ca 2+ -channel/inflamatory pain receptor 1 (TRPV1), which suggests that calmodulin inhibitors may block pore formation and Ca 2+  entry. Functional assays on TRPV1 expressing cells support direct, dose-dependent inhibition of vanilloid-induced  45 Ca 2+ -uptake at µM concentrations: calmidazolium (broad range)≥trifluoperazine (narrow range)>chlorpromazine/amitriptyline>fluphenazine>>W-7 and W-13 (only partially). Most likely a short acidic domain at the pore loop of the channel orifice functions as binding site either for Ca 2+  or anti-calmodulin drugs. Camstatin, a selective peptide blocker of calmodulin, inhibits vanilloid-induced Ca 2+ -uptake in intact TRPV1 +  cells, and suggests an extracellular site of inhibition. TRPV1 + , inflammatory pain-conferring nociceptive neurons from sensory ganglia, were blocked by various anti-psychotic and anti-calmodulin drugs. Among them, calmidazolium, the most effective calmodulin agonist, blocked Ca 2+ -entry by a non-competitive kinetics, affecting the TRPV1 at a different site than the vanilloid binding pocket. Data suggest that various calmodulin antagonists dock to an extracellular site, not found in other Ca 2+ -channels. Calmodulin antagonist-evoked inhibition of TRPV1 and NMDA receptors/Ca 2+ -channels was validated by microiontophoresis of calmidazolium to laminectomised rat monitored with extracellular single unit recordings  in vivo . These unexpected findings may explain empirically noted efficacy of clinical pain adjuvant therapy that justify efforts to develop hits into painkillers, selective to sensory Ca 2+ -channels but not affecting motoneurons.

Anti-calmodulins and Tricyclic Adjuvants in Pain Therapy Block the TRPV1 Channel