Does dietary caffeine interfere with

(8) Does dietary caffeine interfere with antinociception by other modalities that alter pain (TENS, exercise, joint mobilization, water immersion therapy)? Caffeine and/or A1R antagonists inhibit antinociception by each of these modalities in preclinical studies, such that there is potential for interference in human studies. Caffeine intake levels should be monitored in clinical trials of these modalities. See Section Adenosine as a mediator of procedures used to manage pain. (9) Are there gender differences in the effects of novel adenosine therapeutic targets in neuropathic pain? There are recognized differences in gender sensitivity to pain, and recent preclinical studies implicate differences in glial involvement in pain in the two genders. Given that each of A1-, A2A- and A3Rs can have important effects on spinal glia to produce antinociception (Boxes 1–3), and there are sex differences in glial involvement in pain, effects in both genders should be considered. See Section The issue of caffeine.
Disclaimer
Acknowledgments All work from the author’s laboratory quoted in this reboxetine review was supported by grants from the Canadian Institutes of Health Research.
Introduction Adenosine is a nucleoside that has been implicated in a wide variety of biological functions, including the regulation of lipid (e.g., cholesterol, triglycerides and fatty acids) availability in the cell (Reiss and Cronstein, 2012) and in the systemic circulation (Koupenova et al., 2012a). The effects of adenosine are mediated by the action of this nucleoside on four different adenosine receptors (ARs). Interestingly, the adenosine levels in the extracellular space are also modulated by the synthesis and transport of the nucleoside into the cell (Karmouty-Quintana et al., 2013). Based in the role of adenosine in the regulation of lipid availability, this molecule, as well as specific agonists and antagonists that can increase or inhibit AR function, respectively, have been proposed as therapeutic agents for classical diseases related to disturbed lipid levels, such as diabetes and atherosclerosis, and diseases that involve the nervous system, such as Niemann-Pick type C1 and Alzheimer disease. This article reviews the evidence showing the mechanism of adenosine/AR modulation of lipid levels. We also propose a possible regulatory mechanism of ARs on the increased levels of circulating lipids. Finally, we propose a possible role for adenosine/ARs in the development of maternal dyslipidaemia during pregnancy.
Adenosine synthesis and signalling Adenosine is a purine nucleoside with a wide variety of basic functions in the vascular, nervous, respiratory, endocrine and reproductive systems that are mediated by the activation of ARs localized to the extracellular surface of the cell membrane (Ralevic and Dunn, 2015). Adenosine participates in the regulation of the immune response (Di Virgilio and Vuerich, 2015), angiogenesis (Auchampach, 2007), thrombosis (Fuentes et al., 2014), lipolysis (Peng et al., 2009, Schwabe et al., 1974), plasma lipid levels (Koupenova et al., 2012b), vasodilatation; additionally, it has been shown to affect the cardiovascular system (Eisenstein et al., 2015), the placenta (Sobrevia et al., 2015) and cholesterol efflux and inflammation, the latter two of which are involved in the development of atherosclerosis (Reiss and Cronstein, 2012).
The role of adenosine in regulating lipid availability
The role of plasma lipid levels in the regulation of adenosin receptors function
Dyslipidaemia in pregnancy: a possible role for adenosine/adenosine receptors
Concluding remarks Adenosine as well as agonists and antagonists of the different AR subtypes play a role in the regulation of lipid availability in the cell and in the systemic circulation as well in humans and animal models. Therefore, adenosine/ARs regulate (1) lipolysis leading to a reduction of circulating fatty acid levels (Fig. 2A); (2) atherosclerosis by inhibiting the formation of foam cells via stimulation of cholesterol efflux and reducing the inflammatory process (Fig. 2, Fig. 3); (3) intracellular cholesterol trafficking; and (4) the plasma levels of total cholesterol and triglycerides (Fig. 3). Additionally, increased levels of lipids impair the effects of adenosine/ARs in the control of vascular tone possibly by altering the membrane microdomain composition where ARs are localized.