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Expert's view EFFECTS OF NIMESULIDE ON PKC- EPSILON TRANSLOCATION AND ON SUBSTANCE P SYNTHESIS AND RELEASE IN CULTURED NOCICEPTORS
 
EFFECTS OF NIMESULIDE ON PKC- EPSILON TRANSLOCATION AND ON SUBSTANCE P SYNTHESIS AND RELEASE IN CULTURED NOCICEPTORS

Vittorio Vellani
Tenured Research Fellow and Aggregate Professor of Physiology, Department of Biomedical Sciences at the University of Modena and Reggio Emilia in Modena (Italy).

 

1) Could you please tell us something about the nature and the characteristics of nociceptors?

Nociceptors are the sensory neurons specialized in converting a noxious stimulus in a nervous signal. They are very interesting cells and display some peculiar characteristics, unique in the nervous system: they can specifically respond to more than one stimulus (i.e. chemical, thermal and mechanical stimuli), and they can sensitize to the stimulus (increase the response to noxious stimuli of the same intensity and lower the response threshold). Sensitisation is caused by factors released by injured/inflamed tissues acting on receptors expressed on nociceptors. These neurons can be easily isolated and grown in culture, where they maintain a nociceptive phenotype as well as all of the above extremely interesting properties. Cultured nociceptors, isolated from dorsal root or trigeminal ganglia, are therefore a suitable model for in vitro studies on mechanisms of nociception and hyperalgesia/allodyinia caused by inflammatory mediators.

 

2) How can they be studied?

In vivo they can be studied with behavioural experiments in several animal models of acute or inflammatory/neuropathic pain. In vitro a variety of preparations are used, including isolated nerve-skin patches, spinal cord slices or, as I mentioned, cultures of isolated nociceptors, which is the preparation I mostly use in my lab. This preparation allows functional studies on single cells, or on populations of cells with techniques like calcium imaging, PCR, electrophysiology, quantitative dosages of nociceptor-released neuropeptides, and other mediators such as prostaglandins and endocannabinoids. It is also possible to evaluate the activation of PKCε, an isoform of protein kinaseC that is particularly relevant for inflammatory pain. When activated, PKCε translocates from the cytoplasm to the cell membrane where it phosphorilates ion channels (i.e. TRPV1, the capsaicin receptor) that are extremely important for acute and inflammatory pain . We can directly visualize and quantify translocation by using immunocytochemistry.

 

3) Could you please tell us something about the results of your study regarding the effects of different analgesic drugs on nociceptors' activity?

In our experiments we tested the effect of nimesulide, diclofenac, celecoxib, ibuprofen and paracetamol on:
the release of substance P from nociceptors,
the level of expression of the mRNA of the substance P precursor (pre-protachykinin),
the release of prostaglandin E2 (PGE2),
the translocation of PKCε.
Release and expression studies were performed both in basal conditions and following stimulation with a mixture of pro-inflammatory mediators (bradykinin, thrombin, endothelin-1, NGF, KCl etc.). Translocation of PKCε was induced with application of either bradykinin or thrombin. Among the tested drugs, nimesulide had the best performance on all the evaluated parameters, while the other drugs had either similar, lower, or no effect. A particularly strong and fast effect of nimesulide was observed on substance P release induced by the inflammatory mixture; the same strong and fast effect was observed on pre-protachykinin mRNA expression both in basal and in stimulated conditions. Also the effect on translocation of PKCε was the strongest among the tested drugs. I find particularly worth of attention this latter effect especially considering the increasing interest in PKCε as a target for analgesic drugs.

 

4) It was demonstrated that nimesulide can reduce the levels of SP (Substance P) in vivo, both in animals and in humans, do you think that the experimental data coming from your study can be related to this evidence?

Our results confirm and support the previous data on the effects of nimesulide on the release of substance P. We provided the evidence of a fast and direct action of nimesulide not only on the release of this neuropeptide from nociceptors, but also on its synthesis. These experimental evidences, combined with in vivo studies both in animals and humans, strongly support the analgesic effect of nimesulide which acts also through other mechanisms other than the "traditional" COX-2 inhibition.

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HELSINN Last Update: 22.02.2013
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