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Brain Research Bulletin Sensitization of Voltage Activated Calcium Channel Currents for Capsaicin in Nociceptive Neurons by Tumo

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Brain Research Bulletin Sensitization of Voltage Activated Calcium Channel Currents for Capsaicin in Nociceptive Neurons by Tumo 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 abstract Article history: It is known that application of tumor-necrosis-factor-␣ (TNF-␣) sensitizes neuronal calcium channels Received 9 July 2009 for heat stimuli in rat models of neuropathic pain. This study examines whether TNF-␣ modulates the Received in revised form capsaicin-induced effects after transient receptor potential vanilloid (TRPV)-1 receptor activation on 16 September 2009 voltage activated calcium channel currents (I ). Accepted 27 September 2009 Ca(V) TRPV-1 receptors are activated by heat and play an important role in the pathogenesis of thermal hyper- Available online 7 October 2009 algesia in neuropathic pain syndromes, while voltage activated channels are essential for transmission of neuronal signals. Keywords: Voltage activated calcium channels Eliciting ICa(V) in DRG neurons of rats by a depolarization from the resting potential to 0 mV, TNF- ␣ ± ␮ ± Tumor-necrosis-factor-␣ (100 ng/ml) reduces ICa(V) by 16.9 2.2%, while capsaicin (0.1 M) decreases currents by 27 4.3%. Capsaicin Pre-application of TNF-␣ (100 ng/ml) for 24 h results in a sensitization of ICa(V) to capsaicin (0.1 ␮M) Neuropathic pain with a reduction of 42.8 ± 4.4% mediated by TRPV-1. While L-type (36.6 ± 5.2%) and P/Q-type cur- TRPV-1 rents (35.6 ± 4.1%) are also sensitized by TRPV-1 activation, N-type channel currents are most sensitive Electrophysiology (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 of these pain diseases [26,30]. Nevertheless, the mechanisms how TNF-␣ initiates pain sensations are not yet fully under- 1.1. Role of cytokines in neuropathic pain syndromes stood. Recently, hypotheses were developed to understand the gen- Neuropathic pain syndromes caused by peripheral nerve injury, esis of induced hypersensitivity [1,5,11,13]. The activation of TNF metabolic diseases or chronic constrictions are often associated receptor 1 (TNFR-1) increases pathologic ectopic discharges after with mechanical and thermal hyperalgesia. These phenomena cor- stimulation of DRG neurons [27]. This enlarges the receptive field respond to modulations of intracellular signaling cascades and and lowers the threshold for mechanical and thermal stimuli within in protein expression. Neuroinflammatory cytokines, which are this area [18,3]. While the reception of mechanical stimuli under upregulated when tissue is damaged, are involved in the patho- physiological and pathological conditions are mediated by mechan- genesis of neuropathic pain syndromes (for review see [20]). For ically sensitive receptors, thermal stimuli are received by a group of example, dorsal root ganglion (DRG) neurons increase the expres- specific receptors (transient receptor potential vanilloid receptors, sion of tumor-necrosis-factor-␣ (TNF-␣) after nerve injury [25] and, TRPV-R) which are expressed in peripheral nerve fibers, DRG neu- in axotomized DRG neurons, the concentration of TNF-mRNA is rons and central structures [22,19,28]. TRPV-R are associated with increased [23]. ion pores which are activated by heat or chemical (e.g. capsaicin) In vivo application of TNF-␣ to rats induces allodynia stimuli. Their activation triggers intracellular signaling cascades with neuropathic hypersensitivity, while an inhibition of the and the opening of other membrane channels that can modulate signal cascade activated by TNF-␣ (e.g. using antibodies, sig- the membrane potential. These receptor/channel complexes are nal inhibitors or soluble receptors) prevents the development also located in the intracellular membranes of the endoplasmic reticulum (ER) where they release Ca2+ from its stores. They are over-expressed after neuronal nerve lesions [2] and may be par- ∗ tially responsible for the development of thermal hyperalgesia. Corresponding author at: Universitätsklinikum Essen, Klinik für Neurologie, Hufelandstr. 55, 45122 Essen, Germany. TRPV-1 receptors are modulated by intracellular phosphorylation E-mail address: [email protected] (T. Hagenacker). 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.2009.09.012 158 T. Hagenacker et al. / Brain Research Bulletin 81 (2010) 157–163 activated protein kinase (MAPK) linked kinases, which are also after seeding. Cultured DRG neurons have been chosen as a model for peripheral activated by TNFR-1. nerve endings which mainly express the receptors described. Acute dissociation of The activation of TNFR-1 and -2 is linked to phosphorylation the neuronal endings leads to lack of the amount of nociceptive receptors, which are not mainly located at the soma. 24 h after incubation, the amount of receptors processes via the activation of intracellular kinases of the MAPK- on the soma membrane is significantly increased and therefore a better model for family [24]. The conductance of TRPV-1 receptor-associated ion the techniques that were used in this study. pores is mainly regulated by the state of phosphorylation of dif- ferent amino acids in the protein (e.g. threonin) [21]. Because 2.2. Recording techniques and isolation of different calcium channel currents unspecific kinases are also involved in this phosphorylation, the ␮ activation of TNFR could influence TRPV-1 receptor functions. Currents were isolated from small DRG neurons (diameter < 30 M) since only these neurons express TRPV-1 receptors [9,6]. ICa(V) of DRG neurons were recorded Since it is known that TNFR is involved in the genesis of ther- using the whole cell patch clamp technique with a HEKA EPC10 (Germany) amplifier mal hyperalgesia in neuropathic pain syndromes, which is directly and EPC screen software (HEKA, Patchmaster). mediated by TRPV-1, modulation of these channel currents could Microelectrodes were pulled from borosilicate glass with a Sutter electrode demonstrate a functional correlation in this process. Therefore, we puller (Model P-87). Electrodes were fire polished with a micro forge (MF-830, investigated whether TNF-␣ changes the modulation of voltage Narashige, Japan) to a final resistance of 4–5 M and filled with the internal solution (CsCl, 140 mM; HEPES, 10 mM; EGTA, 10 mM; MgCl2, 4 mM; Na-ATP 2 mM; osmolar- gated channel currents induced by the activation of TRPV-1 via ity 316 mOsm; pH adjusted to 7.2). The F12 medium was substituted with external capsaicin. solution to isolate currents through VACCs (tetraethylammonium (TEA), 130 mM; glucose, 10 mM; HEPES, 10 mM; MgCl2, 1 mM; BaCl2 or CaCl2,10mM).OnceaG- seal and stable access to the neurons was established, the membrane potential was 1.2. Voltage activated ion channels clamped at −80 mV. ICa(V) were routinely elicited by depolarizing command pulses to 0 mV for 150 ms, every 10 s. Voltage activated ion channel currents are essential for the All substances were applied with a continuous flow system ensuring a complete generation and propagation of action potentials. While voltage exchange of the bath solution in several minutes. TNF-␣ (Sigma–Aldrich, Germany) activated sodium channels are crucial for the induction of action was freshly dissolved in the bath solution to a final concentration of 100 ng/ml. This concentration was used, because in former studies it was found to be effective on potentials, voltage activated potassium channels are important ICa(V) [4]. Capsaicin was freshly dissolved in ethanol (100%). Final concentration of for the repolarization of excited neuronal membranes. Voltage ethanol was below 0.1%. Isolated ethanol application did not influence ion currents activated calcium channel currents (I ) modulate the neuronal (data not shown). Ca(V) excitation resulting in an increase of the intracellular calcium con- 5 -Iodoresiniferatoxin (10 ␮M) was freshly dissolved in distilled water and applied 30 min before starting electrophysiological experiments to block the TRPV-1 centration ([Ca2+] ). [Ca2+] is tightly regulated and is elevated by i i receptor. 2+ Ca entry from the extracellular space or by calcium release from For the isolation of VACC subtypes adequate channel blockers were applied 2+ ␮ the intracellular stores. Reduction in [Ca ]i is caused by ATPases 30 min before starting recordings. To isolate N-type ICa(V), nimodipin (10 M) and ␻ ␻ which pump calcium into the ER stores or out of the cell [8]. -Agatoxin TK (100 nM) were used. For isolation of L-type ICa(V) -Conotoxin GVIA ␻ Especially subtypes of voltage activated calcium channels (100 nM) and -Agatoxin TK (100 nM) was were used and for P/Q-Type channel isolation ␻-Conotoxin GVIA (100 nM) and nimodipin (10 ␮M) were applied. (VACCs) are promising targets for the treatment of pain: N-type Series resistance was monitored and stable for the time of recording. calcium channels are localized to synaptic nerve terminal of the Pre-incubation of the cells with TNF-␣ started 24 h before the beginning of the dorsal horn. Their activation results in an intracellular elevation of experiments. calcium, triggering the release of neurotransmitters. A critical role of N-type channels in pain modulation is supported by data from N- 2.3. Data analysis type deficient-mice and by the analgetic effects of selective N-type All currents were low-pass filtered online at 5 kHz and leak corrected using channel antagonists like Conotoxin (e.g.
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