title: Neuropeptide Y modulates effects of bradykinin and prostaglandin E2 on trigeminal nociceptors via activation of the Y1 and Y2 receptors.
abstract: OBJECTIVE
  Although previous studies have demonstrated that neuropeptide Y (NPY) modulates nociceptors, the relative contributions of the Y1 and Y2 receptors are unknown. Therefore, we evaluated the effect of Y1 and Y2 receptor activation on nociceptors stimulated by bradykinin (BK) and prostaglandin E2 (PGE2).
  
  
  METHODS
  Combined immunohistochemistry (IHC) with in situ hybridization (ISH) demonstrated that Y1- and Y2-receptors are collocated with bradykinin (2) (B2)-receptors in rat trigeminal ganglia (TG). The relative functions of the Y1 and Y2 receptors in modulating BK/PGE2-evoked CGRP release and increased intracellular calcium levels in cultured TG neurons were evaluated.
  
  
  RESULTS
  The Y1 and Y2 receptors are co-expressed with B2 in TG neurons, suggesting the potential for direct NPY modulation of BK responses. Pretreatment with the Y1 agonist [Leu31,Pro34]-NPY, inhibited BK/PGE2-evoked CGRP release. Conversely, pretreatment with PYY(3-36), a Y2 agonist, increased BK/PGE2 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/PGE2-evoked release of CGRP was reversed by the Y1 receptor antagonist, BIBO3304, and higher concentrations of BIBO3304 significantly facilitated CGRP release. The Y2 receptor antagonist, BIIE0246, enhanced the inhibitory NPY effects.
  
  
  CONCLUSIONS
  These results demonstrate that NPY modulation of peptidergic neurons is due to net activation of inhibitory Y1 and excitatory Y2 receptor systems. The relative expression or activity of these opposing receptor systems may mediate dynamic responses to injury and pain.
authors.affiliation: Department of Pharmacology, The University of Texas Health Science Center at San Antonio, TX 78229-3900, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Gibbs
authors.forename: A
authors.initials: A
authors.lastname: Diogenes
authors.forename: K M
authors.initials: KM
authors.lastname: Hargreaves
mesh_terms: D000818:Animals; D001920:Bradykinin / Q000494:pharmacology*; D015232:Dinoprostone / Q000494:pharmacology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D009478:Neuropeptide Y / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects*; D018013:Receptors, Neuropeptide / Q000187:drug effects*; D017476:Receptors, Neuropeptide Y / Q000187:drug effects*; D014276:Trigeminal Nerve / Q000187:drug effects*
chemical_list: D009478:Neuropeptide Y; C066211:Npy1r protein, rat; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D017476:Receptors, Neuropeptide Y; C095889:neuropeptide Y2 receptor; D015232:Dinoprostone; D001920:Bradykinin