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. 2014 Jul;15(7):771-7.
doi: 10.1016/j.jpain.2014.04.005. Epub 2014 May 2.

ATP release mechanisms of endothelial cell-mediated stimulus-dependent hyperalgesia

Elizabeth K Joseph  1 , Paul G Green  1 , Jon D Levine  2
Affiliations

ATP release mechanisms of endothelial cell-mediated stimulus-dependent hyperalgesia

Elizabeth K Joseph et al. J Pain. 2014 Jul.

Abstract

Endothelin-1 (ET-1) acts on endothelial cells to enhance mechanical stimulation-induced release of adenosine triphosphate (ATP), which in turn can act on sensory neurons innervating blood vessels to contribute to vascular pain, a phenomenon we have referred to as stimulus-dependent hyperalgesia (SDH). In the present study, we evaluated the role of the major classes of ATP release mechanisms to SDH: vesicular exocytosis, plasma membrane-associated ATP synthase, ATP-binding cassette transporters, and ion channels. Inhibitors of vesicular exocytosis (ie, monensin, brefeldin A, and bafilomycin), plasma membrane-associated ATPase (ie, oligomycin and pigment epithelium-derived factor peptide 34-mer), and connexin ion channels (carbenoxolone and flufenamic acid) but not ATP-binding cassette transporter (ie, dipyridamole, nicardipine, or CFTRinh-172) attenuated SDH. This study reports a role of ATP in SDH and suggests novel targets for the treatment of vascular pain syndromes.

Perspective: ET-1 acts on endothelial cells to produce mechanical stimulation-induced hyperalgesia. Inhibitors of 3 different ATP release mechanisms attenuated this SDH. This study provides support for a role of ATP in SDH and suggests novel targets for the treatment of vascular pain syndromes.

Keywords: Endothelin-1; adenosine triphosphate release; endothelium; vascular pain.

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Conflict of interest statement

Disclosures: This work was supported by NIH grant AR063312. The authors report no conflicts of interest.

Figures

Figure 1
Figure 1. Effect of bafilomycin (vacuolar H-ATPase inhibitor), monensin (inhibitor of vesicle formation) and brefeldin A (inhibitor of vesicle transport) on ET-1 induced mechanical hyperalgesia and stimulus-dependent hyperalgesia (SDH)
15 min before ET-1, rats received vehicle (5 μl), bafilomycin, monensin or brefeldin A (each 1 μg in 5 μl/paw). Paw withdrawal thresholds were measured 15, 20, 25 & 30 min after ET-1 administration. Bafilomycin, monensin and brefeldin A each significantly inhibited ET-1–induced SDH compared to vehicle treated controls, and monensin also significantly inhibited ET-1 hyperalgesia (*P
Figure 2
Figure 2. Effect of dipyridamole, nicardipine and CFTRinh-172 (ABC transport inhibitors) on ET-1 induced mechanical hyperalgesia and SDH
15 min before ET-1, rats received vehicle (5 μl), dipyridamole, nicardipine or CFTRinh-172 (all 1 μg in 5 μl/paw). Paw withdrawal thresholds were measured 15, 20, 25 & 30 min after ET-1 administration. Neither dipyridamole, nicardipine nor CFTRinh-172 affected ET-1 SDH (P=N.S., two-way repeated measures ANOVA, N = 6), however CFTRinh-172 significantly attenuated ET-1 hyperalgesia (2-way ANOVA with Dunnet’s post hoc test, *P<0.05). Note that the ET-1 alone data is the same group as in Figure 1.
Figure 3
Figure 3. Effect of flufenamic acid (voltage gated sodium channel blocker) and carbenoxolone (interneuronal gap junction blocker) on ET-1 induced mechanical hyperalgesia and SDH
15 min before ET-1, rats received vehicle (5 μl), flufenamic acid or carbenoxolone (both 1 μg in 5 μl/paw). Paw withdrawal thresholds were measured 15, 20, 25 & 30 min after ET-1 administration. Both flufenamic acid and carbenoxolone significantly inhibited SDH; flufenamic acid, but not carbenoxolone, significantly attenuated ET-1 induced hyperalgesia (*P
Figure 4
Figure 4. Effect of oligomycin A (ATP synthase inhibitor) or PEDF-34-mer (extracellular ATP synthase inhibitor) on ET-1 induced mechanical hyperalgesia and SDH
15 min before ET-1, rats received vehicle (5 μl), oligomycin or PEDF-34-mer (both 1 μg in 5 μl/paw). Paw withdrawal thresholds were measured 15, 20, 25 & 30 min after ET-1 administration. Both oligomycin and PEDF-34-mer significantly inhibited SDH as well as ET-1 hyperalgesia compared to vehicle treated controls (*P
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References

    1. Akopova I, Tatur S, Grygorczyk M, Luchowski R, Gryczynski I, Gryczynski Z, Borejdo J, Grygorczyk R. Imaging exocytosis of ATP-containing vesicles with TIRF microscopy in lung epithelial A549 cells. Purinergic Signal. 2012;8:59–70. - PMC - PubMed
    1. Aley KO, Levine JD. Multiple receptors involved in peripheral alpha 2, mu, and A1 antinociception, tolerance, and withdrawal. J Neurosci. 1997;17:735–744. - PMC - PubMed
    1. Aley KO, Levine JD. Role of protein kinase A in the maintenance of inflammatory pain. J Neurosci. 1999;19:2181–2186. - PMC - PubMed
    1. Bodin P, Burnstock G. Evidence that release of adenosine triphosphate from endothelial cells during increased shear stress is vesicular. J Cardiovasc Pharmacol. 2001;38:900–908. - PubMed
    1. Burnstock G. Release of vasoactive substances from endothelial cells by shear stress and purinergic mechanosensory transduction. J Anat. 1999;194:335–342. - PMC - PubMed

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