<Reviews> Dr. G. Sieben: Der Substanzwert der Unternehmung

The processing of pain undergoes several changes in aging that affect sensory nociceptive fibers and the endogenous neuronal inhibitory systems. So far, it is not completely clear whether age-induced modifications are associated with an increase or decrease in pain perception. In this study, we assessed the impact of age on inflammatory nociception in mice and the role of the hormonal inhibitory systems in this context. We investigated the nociceptive behavior of 12-month-old versus 6–8-week-old mice in two behavioral models of inflammatory nociception. Levels of TRP channels, and cortisol as well as cortisol targets, were measured by qPCR, ELISA, and Western blot in the differently aged mice. We observed an age-related reduction in nociceptive behavior during inflammation as well as a higher level of cortisol in the spinal cord of aged mice compared to young mice, while TRP channels were not reduced. Among potential cortisol targets, the NF-κB inhibitor protein alpha (IκBα) was increased, which might contribute to inhibition of NF-κB and a decreased expression and activity of the inducible nitric oxide synthase (iNOS). In conclusion, our results reveal a reduced nociceptive response in aged mice, which might be at least partially mediated by an augmented inflammation-induced increase in the hormonal inhibitory system involving cortisol

Cleavage of SNAP‐25 ameliorates cancer pain in a mouse model of melanoma

Background: Cancer pain is associated with increased pain sensitivity to noxious (hyperalgesia) and normally innocuous (allodynia) stimuli due to activation of nociceptors by tumour‐derived mediators or tumour infiltration of nerves. The pain sensitization is accompanied by modifications in gene expression, but specifically regulated genes are largely unknown. The 25 kDa synaptosomal‐associated protein (SNAP‐25) is involved in chemical neurotransmission at the synaptic cleft. Its inhibition by Botulinum neurotoxin A (BoNT/A) has been associated with antinociceptive effects in migraine, inflammatory and neuropathic pain. However, its potential to reduce tumour‐associated pain remains to be clarified. Methods: We applied a melanoma model of tumour pain in C57BL/6 mice and investigated SNAP‐25 expression and regulation by qRT‐PCR, Western Blot and immunofluorescence as well as tumour‐associated mechanical allodynia with and without BoNT/A treatment. Results: We found increased SNAP‐25 expression in the dorsal root ganglia and the sciatic nerve. Intraplantar injection of BoNT/A induced the cleavage of SNAP‐25 in these tissues and was associated with decreased mechanical allodynia after therapeutic treatment at early and late stages of tumour pain while the tumour size was not affected. Conclusions: Our data indicate that SNAP‐25 plays a role in tumour pain but has no influence on the initiation and progression of skin cancer. Its cleavage inhibits the development of allodynia in the mouse melanoma model and might be useful as new therapeutic approach for the treatment of cancer pain. What does this study add? SNAP‐25 is differentially regulated during melanoma‐induced tumour pain. Its cleavage by BoNT/A might be a suitable therapeutic option for tumour pain patients since tumour‐associated pain can be strongly and significantly reduced after preventive and therapeutic BoNT/A treatment, respectively