RT Journal Article
SR Electronic
T1 Propacetamol-induced injection pain is associated with activation of TRPV1
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.116.233452
DO 10.1124/jpet.116.233452
A1 Florian Schillers
A1 Esther Eberhardt
A1 Andreas Leffler
A1 Mirjam Eberhardt
YR 2016
UL http://jpet.aspetjournals.org/content/early/2016/07/25/jpet.116.233452.abstract
AB Propacetamol (PPCM) is a prodrug of paracetamol (PCM) which was generated to increase water solubility of PCM for intravenous delivery. PPCM is rapidly hydrolyzed by plasma esterases to PCM and diethylglycine, and it shares some structural and metabolic properties with lidocaine. While PPCM is considered to be comparable to PCM regarding its analgesic properties, injection pain is a common side effect only described for PPCM. Injection pain is a frequent and unpleasant side effect of numerous drugs in clinical use, and previous reports have indicated that the ligand gated ion channels TRPA1 and TRPV1 on sensory neurons can mediate this effect. The aim of this paper was to investigate molecular mechanisms by which PPCM, in contrast to PCM, causes injection pain. Therefor human TRPV1 and TRPA1 receptors were expressed in HEK 293 cells and investigated by means of whole cell patch clamp and ratiometric calcium imaging. PPCM, but not PCM activated TRPV1, sensitized heat-induced currents and caused an increase in intracellular calcium. In TRPA1 expressing cells however, PPCM and PCM both evoked calcium responses but failed to induce inward currents. Intracutaneous injection of PPCM, but not of PCM, in human volunteers induced an intense and short-lasting pain and an increase in superficial blood flow indicating activation of nociceptive C-fibers and subsequent neuropeptide release. In conclusion, activation of human TRPV1 by propacetamol seems to be a relevant mechanism for induction of pain upon intracutaneous injection and thus also for pain reported as an adverse side effect upon intravenous administration.