An evaluation of the effects of activation of neuropeptide Y receptors on nociceptors.

摘要

Neuropeptide Y (NPY) is widely expressed in the central and peripheral nervous system and is involved in the modulation of numerous physiologic processes including satiety, vascular tone, and learning and memory. However, much less is known about NPY modulation of pain. NPY and its cognate receptors, the Y receptors, display altered expression after peripheral injury, particularly injury to peripheral nerves. The second messenger pathways which Y receptors couple to may lead to either excitatory or inhibitory cellular effects. Consequently drugs acting at NPY receptors may produce different effects depending upon the magnitude and type of injury present. An evaluation of the effects of activation of individual NPY receptors on nociceptor activity therefore has considerable scientific and therapeutic implications.;Although to date six NPY receptors have been cloned, only the Y1 and Y2 receptor have been identified on sensory neurons. Both are G-protein coupled receptors and activation of the receptors can lead to either facilatory or inhibitory effects, depending on which second-messenger pathways are activated. The overall hypothesis of this thesis is that NPY receptors present on sensory neurons will modulate the activation of nociceptors under normal (i.e. uninjured) conditions, and specifically that the Y1 receptor will inhibit nociceptors.;To test this hypothesis, we examined the effect of activation of Y1 receptors. Pretreatment with the Y1 agonist, [Leu31,Pro34]NPY maximally inhibited capsaicin-evoked CGRP release from isolated dorsal horn neurons by 60%. This effect was concentration dependent and reversible by administration of the Y1 receptor antagonist BIBP3226. Separate experiments demonstrated that the majority of NPY inhibition of capsaicin-evoked CGRP release (70%) was due to Y1 receptor activation as demonstrated by pretreatment with the Y1 antagonist BIBP3226. Parallel immunohistochemical studies indicated that the Y1 receptor is co-expressed with the capsaicin receptor TRPV1 in dorsal root ganglia. Together, these studies demonstrate that activation of the Y1 receptor inhibits capsaicin-sensitive nociceptors in the dorsal horn.;Peripheral administration of [Leu31,Pro34]NPY also significantly attenuated capsaicin-evoked secondary mechanical allodynia in a dose-dependent, antagonist reversible, manner. Parallel in vitro studies demonstrated that application of Y1 agonists to isolated superfused rat skin biopsies significantly inhibited capsaicin-evoked CGRP release. Together, these studies provide support for the hypothesis that activation of peripheral Y1 receptors inhibit capsaicin-sensitive nociceptors. (Abstract shortened by UMI.).