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

J. L. Gibbs, A. Diogenes, K. M. Hargreaves

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)72-79
Number of pages8
JournalBritish Journal of Pharmacology
Issue number1
StatePublished - Jan 27 2007


  • Bradykinin
  • CGRP
  • Inflammation
  • NPY
  • Neurogenic inflammation
  • Neuropeptide Y
  • Pain
  • Sensory neuron
  • Y receptor
  • Y receptor

ASJC Scopus subject areas

  • Pharmacology


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