Nimesulide inhibits protein kinase C epsilon and substance P in sensory neurons – comparison with paracetamol

Vittorio Vellani¹, Silvia Franchi², Massimiliano Prandini¹, Sarah Moretti², Giorgia Pavesi¹, Chiara Giacomoni³, Paola Sacerdote^2
1Dipartimento di Scienze Biomediche, Università di Modena e Reggio Emilia, Modena, Italy; ²Dipartimento di Farmacologia Chemioterapia e Tossicologia Medica, Università degli Studi di Milano, Italy; ³Dipartimento di Economia e Tecnologia, Università degli Studi della Repubblica di San Marino, Montegiardino, Repubblica di San Marino

Abstract: In this paper we describe new actions of nimesulide and paracetamol in cultured peripheral neurons isolated from rat dorsal root ganglia (DRG). Both drugs were able to decrease in a dose-dependent fashion the number of cultured DRG neurons showing translocation of protein kinase C epsilon (PKCε) caused by exposure to 1 µM bradykinin or 100 nM thrombin. In addition, the level of substance P (SP) released by DRG neurons and the level of preprotachykinin mRNA expression were measured in basal conditions and after 70 minutes or 36 hours of stimulation with nerve growth factor (NGF) or with an inflammatory soup containing bradykinin, thrombin, endothelin-1, and KCl. Nimesulide (10 µM) significantly decreased the mRNA levels of the SP precursor preprotachykinin in basal and in stimulated conditions, and decreased the amount of SP released in the medium during stimulation of neurons with NGF or with the inflammatory soup. The effects of paracetamol (10 µM) on such response was lower. Nimesulide completely inhibited the release of prostaglandin E₂ (PGE₂) from DRG neurons, either basal or induced by NGF and by inflammatory soup, while paracetamol decreased PGE₂ release only partially. Our data demonstrate, for the first time, a direct effect of two drugs largely used as analgesics on DRG neurons. The present results suggest that PKCε might be a target for the effect of nimesulide and paracetamol, while inhibition of SP synthesis and release is clearly more relevant for nimesulide than for paracetamol mechanism of action.

Keywords: nociceptors, analgesia, hyperalgesia, dorsal root ganglia, PKCε