Brain Research Bulletin 81 (2010) 157–163 Contents lists available at ScienceDirect Brain Research Bulletin journal homepage: www.elsevier.com/locate/brainresbull Research report Sensitization of voltage activated calcium channel currents for capsaicin in nociceptive neurons by tumor-necrosis-factor- T. Hagenacker a,b,∗ , J.C. Czeschik b , M. Schäfers a , D. Büsselberg b,c a Universitätsklinikum Essen, Klinik für Neurologie, Hufelandstr. 55, 45122 Essen, Germany b Universitätsklinikum Essen, Institut für Physiologie, Hufelandstr. 55, 45122 Essen, Germany c Texas Tech University, Health Science Center, Paul L. Foster School of Medicine, 5001 El Paso Drive, El Paso, TX 79905, USA article info Article history: Received 9 July 2009 Received in revised form 16 September 2009 Accepted 27 September 2009 Available online 7 October 2009 Keywords: Voltage activated calcium channels Tumor-necrosis-factor- Capsaicin Neuropathic pain TRPV-1 Electrophysiology abstract It is known that application of tumor-necrosis-factor- (TNF-) sensitizes neuronal calcium channels for heat stimuli in rat models of neuropathic pain. This study examines whether TNF- modulates the capsaicin-induced effects after transient receptor potential vanilloid (TRPV)-1 receptor activation on voltage activated calcium channel currents (I Ca(V) ). TRPV-1 receptors are activated by heat and play an important role in the pathogenesis of thermal hyper- algesia in neuropathic pain syndromes, while voltage activated channels are essential for transmission of neuronal signals. Eliciting I Ca(V) in DRG neurons of rats by a depolarization from the resting potential to 0 mV, TNF-  (100 ng/ml) reduces I Ca(V) by 16.9 ± 2.2%, while capsaicin (0.1 M) decreases currents by 27 ± 4.3%. Pre-application of TNF- (100 ng/ml) for 24 h results in a sensitization of I Ca(V) to capsaicin (0.1 M) with a reduction of 42.8 ± 4.4% mediated by TRPV-1. While L-type (36.6 ± 5.2%) and P/Q-type cur- rents (35.6 ± 4.1%) are also sensitized by TRPV-1 activation, N-type channel currents are most sensitive (74.5 ± 7.3%). The capsaicin-induced shift towards the hyperpolarizing voltage range does not occur when TNF- is applied. Summarizing, TNF- sensitizes nociceptive neurons for capsaicin. © 2009 Elsevier Inc. All rights reserved. 1. Introduction 1.1. Role of cytokines in neuropathic pain syndromes Neuropathic pain syndromes caused by peripheral nerve injury, metabolic diseases or chronic constrictions are often associated with mechanical and thermal hyperalgesia. These phenomena cor- respond to modulations of intracellular signaling cascades and in protein expression. Neuroinflammatory cytokines, which are upregulated when tissue is damaged, are involved in the patho- genesis of neuropathic pain syndromes (for review see [20]). For example, dorsal root ganglion (DRG) neurons increase the expres- sion of tumor-necrosis-factor- (TNF-) after nerve injury [25] and, in axotomized DRG neurons, the concentration of TNF-mRNA is increased [23]. In vivo application of TNF- to rats induces allodynia with neuropathic hypersensitivity, while an inhibition of the signal cascade activated by TNF- (e.g. using antibodies, sig- nal inhibitors or soluble receptors) prevents the development ∗ Corresponding author at: Universitätsklinikum Essen, Klinik für Neurologie, Hufelandstr. 55, 45122 Essen, Germany. E-mail address: Tim.Hagenacker@uk-essen.de (T. Hagenacker). of these pain diseases [26,30]. Nevertheless, the mechanisms how TNF- initiates pain sensations are not yet fully under- stood. Recently, hypotheses were developed to understand the gen- esis of induced hypersensitivity [1,5,11,13]. The activation of TNF receptor 1 (TNFR-1) increases pathologic ectopic discharges after stimulation of DRG neurons [27]. This enlarges the receptive field and lowers the threshold for mechanical and thermal stimuli within this area [18,3]. While the reception of mechanical stimuli under physiological and pathological conditions are mediated by mechan- ically sensitive receptors, thermal stimuli are received by a group of specific receptors (transient receptor potential vanilloid receptors, TRPV-R) which are expressed in peripheral nerve fibers, DRG neu- rons and central structures [22,19,28]. TRPV-R are associated with ion pores which are activated by heat or chemical (e.g. capsaicin) stimuli. Their activation triggers intracellular signaling cascades and the opening of other membrane channels that can modulate the membrane potential. These receptor/channel complexes are also located in the intracellular membranes of the endoplasmic reticulum (ER) where they release Ca 2+ from its stores. They are over-expressed after neuronal nerve lesions [2] and may be par- tially responsible for the development of thermal hyperalgesia. TRPV-1 receptors are modulated by intracellular phosphorylation of protein kinases like protein kinase A and C or the p38-mitogen- 0361-9230/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.brainresbull.2009.09.012