Neuropeptide Y modulates effects of bradykinin and prostaglandin E2 on trigeminal nociceptors via activation of the Y1 and Y2 receptors

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 132 in TG neurons, suggesting the potential for direct NPY modulation of BK responses. Pretreatment with the Y-1 agonist [Leu31, Pro34]-NPY, inhibited BK/PGE2-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/PGE2-evoked increases in intracellular calcium levels whereas PYY(3-36) increased responses. NPY inhibition of BK/PCE2-evoked release of CGRP was reversed by the Y-1 receptor antagonist, 1311303304, 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.