Our published results also show that the Y

Our published results also show that the Y2 and the Y5, but not the Y1, receptors mediate NPY-induced excitation-secretion coupling in EECs (Abdel-Samad et al., 2012). Thus, it is highly important to consider controlling ET-1 circulating level via blockade of Y2 and/or Y5 receptor activation (Abdel-Samad et al., 2012). In addition, since the ET-1 released by NPY is contributing further to its own release via activation of the ETA and ETB receptors, then it is highly possible to control, at least in part, the actions of NPY-induced increase of ET-1 secretion via blockade of ETA or ETB receptors. Furthermore, such a blockade of ET-1 secretion induced by NPY would control only the secretory capacity of REECs since NPY-induced ET-1 secretion in LEECs is insensitive to ETA or ETB blockade. In addition, since secretion of REECs takes place at the entry of the pulmonary circulation, thus, blockade of ETA or ETB receptor activation at that level would preferentially affect the level of tuning of ET-1 by LEECs. It has become increasingly apparent from data in the literature that receptor activation can result in much more complex patterns of signaling within MCC950 sodium sale than previously thought. There is considerable evidence, for example, that signaling through GPCRs that couple preferentially to a certain signaling pathway can be modulated by inputs from GPCRs that couple to other pathways. Such crosstalk between receptors can result in loss of function at times, and gain or enhancement of function at others (Werry et al., 2003). The crosstalk between NPY receptors, which are mainly Gi/o coupled receptors, and other GPCRs such as α1-adrenoceptors, which are Gq/11coupled, and β-adrenoceptors has been reported in vascular smooth muscle cells (Racchi et al., 1999, Pons et al., 2003) and may also be true of other cell types. Such synergistic crosstalk results in the augmentation of physiological responses such as smooth muscle contraction (in the case of interaction between the NPY receptors and α1-adrenoceptors) and mitogenesis (in the case of interaction between the NPY receptors and β-adrenoceptors) (Selbie and Hill, 1998, Pons et al., 2003). Based on our previous (Abdel-Samad et al., 2012) and present results, a similar synergistic crosstalk could be taking place between the NPY receptors, Y2 and Y5, which are, as mentioned before, mainly Gi/o coupled receptors, and the ET-1 receptors, ETA and ETB, which couple, among others, to Gq/11 proteins. This should be definitely further explored in the future because it could have important implications on the physiological and pathophysiological consequences of receptor activation, and thus, could provide novel targets for therapeutic interventions (Werry et al., 2003).
Sources of funding This work was supported by grants from the Canadian Institutes of Health Research (CIHR) (No. MOP-111096) and from the Heart and Stroke Foundation of Canada awarded to Dr. Danielle Jacques.
Disclosures
Acknowledgments
Introduction Neuropathic pain (NP), which affects approximately 7% of the European population (Bouhassira et al., 2008), can be difficult to manage because of the complexity and multiplicity of its nature (Attal, 2012). In clinical practice, the treatment of NP is frequently inadequate because effective pharmacological therapy is not always available or its application is limited by its adverse side-effects (Attal, 2012, Varrassi et al., 2010). Therefore, investigations of the underlying mechanisms of NP and new potential therapeutic target for its treatment are important future directions to improve the quality of life of the patients as well as its economic burden on society (Doth et al., 2010). Endothelin-1 (ET-1), a 21-amino acid multifunctional peptide, has been suggested to modulate pathological pain processing by the differential regulation of its receptors — endothelin type A receptor (ETA-R) or endothelin type B receptor (ETB-R) (Hans et al., 2008, Hans et al., 2009, Khodorova et al., 2009a). The role of ET-1 and its receptors in nociception and pathological pain has been described extensively in animal studies following the direct administration of exogenous ET-1 peptide with or without pharmacological interventions on ET receptor activities (Jarvis et al., 2000, Joseph et al., 2011, Khodorova et al., 2003, Khodorova et al., 2009b, Klass et al., 2005, Nikolov et al., 1992, Piovezan et al., 2000, Yamamoto et al., 1994). The involvement of ET systems has also been illustrated in a rat model of NP in association with a diabetic condition using a selective ETA-R antagonist (Jarvis et al., 2000). In addition, neuron-specific knockout of ET-1 has been shown to exacerbate the degree of mechanical allodynia in spinal nerve ligation-induced NP (SNL-NP) (Hasue et al., 2005). These studies have implied that neuronal ET-1 and ETA-R may contribute to the development of NP. Although substantial efforts have been made to elucidate the signal transduction pathway that underlies the modulation of ET-1-mediated nociception, the effects of endogenous central ET-1 in pathological pain have not been clearly explained to date. Two cell type-specific mouse models that over-express ET-1, namely GET-1 and TET-1 mice, have been developed to elucidate the effect of astrocyte- or endothelial cell-derived endogenous ET-1 in the etiology of pathological pain (Leung et al., 2004, Lo et al., 2005). In these two transgenic mouse models, astrocytic, but not endothelial, ET-1 over-expression exerted a potent anti-hyperalgesic effect on formalin-induced inflammatory pain (Hung et al., 2012). Therefore, in this study, continuous over-expression of ET-1 in the central nervous system (CNS) of GET-1 mice was used to study the long-term effects of central ET-1 at various time-points on the development and maintenance of SNL-NP. In addition, the transgene did not affect the physiological normality or the baseline threshold following thermal and tactile stimuli in these mice (Hung et al., 2012), suggesting that astrocytic ET-1 over-expression may be involved in the direct modulation of pathological pain processing without affecting the normal physiological nociceptive response. Thus, GET-1 mice were chosen to study the effect of central endogenous ET-1 on the development and maintenance of SNL-NP.