Neuropeptide Y modulates effects of bradykinin and prostaglandin E 2 on trigeminal nociceptors via activation of the Y 1 and Y 2 receptors

Abstract

Background and Purpose: Although previous studies have demonstrated that neuropeptide Y (NPY) modulates nociceptors, the relative contributions of the Y 1 and Y 2 receptors are unknown. Therefore, we evaluated the effect of Y 1 and Y 2 receptor activation on nociceptors stimulated by bradykinin (BK) and prostaglandin E 2 (PGE 2). Experimental approach: Combined immunohistochemistry (IHC) with in situ hybridization (ISH) demonstrated that Y 1- and Y 2-receptors are collocated with bradykinin 2 (B 2)-receptors in rat trigeminal ganglia (TG). The relative functions of the Y 1 and Y 2 receptors in modulating BK/PGE 2-evoked CGRP release and increased intracellular calcium levels in cultured TG neurons were evaluated. Key results: The Y 1 and Y 2 receptors are co-expressed with B 2 in TG neurons, suggesting the potential for direct NPY modulation of BK responses. Pretreatment with the Y 1 agonist [Leu31,Pro34]-NPY, inhibited BK/PGE 2-evoked CGRP release. Conversely, pretreatment with PYY(3-36), a Y 2 agonist, increased BK/PGE 2 evoked CGRP release. Treatment with NPY evoked an overall inhibitory effect, although of lesser magnitude. Similarly, [Leu31,Pro34]-NPY inhibited BK/PGE 2-evoked increases in intracellular calcium levels whereas PYY(3-36) increased responses. NPY inhibition of BK/PGE 2-evoked release of CGRP was reversed by the Y 1 receptor antagonist, BIBO3304, and higher concentrations of BIBO3304 significantly facilitated CGRP release. The Y 2 receptor antagonist, BIIE0246, enhanced the inhibitory NPY effects. Conclusions and implications: These results demonstrate that NPY modulation of peptidergic neurons is due to net activation of inhibitory Y 1 and excitatory Y 2 receptor systems. The relative expression or activity of these opposing receptor systems may mediate dynamic responses to injury and pain. © 2007 Nature Publishing Group. All rights reserved.