Antinociceptive and pro-inflammatory roles for NPY Y 1 receptors

Abstract

Neuropetide Y (NPY) is a 36-amino-acid neuropeptide that is widely distributed in the CNS and PNS, where it is stored along with noradrenaline in sympathetic postganglionic fibres, and is also expressed in other autonomic (possibly parasympathetic) and sensory neurones. The physiological effects of NPY are mediated by at least six receptors (Y1–6), showing variable expression among mammalian species. An inhibitory modulation by NPY on the release of substance P (SP) from capsaicin-sensitive primary afferent neurones, from both central and peripheral nerve endings, was confirmed in many experimental conditions. Therefore, until recently, there was a general consensus that NPY had a putative anti-inflammatory effect at the peripheral level and an antinociceptive effect in the CNS. Y1, Y2 and possibly other NPY receptors are expressed by dorsal root ganglion neurones. The recent availability of Y1 receptor knockout (Y1−/−) mice was expected to elucidate whether this receptor is involved in the inhibitory effect of NPY on neurogenic inflammation and nociception.Naveilhan and colleagues 1xReduced antinociception and plasma protein extravasation in mice lacking a neuropeptide Y receptor. Naveilhan, P. et al. Nature. 2001; 409: 513–517Crossref | PubMed | Scopus (129)See all References1 showed that Y1−/− mice displayed a hyperalgesic phenotype in tests of thermal (hot plate and tail flick), chemical (first phase of formalin test, acetic-acid- and magnesium-sulfate-induced writhings), mechanical (Von Frey hairs) and neuropathic (partial nerve injury) nociception, and the antinociceptive effect observed following the intrathecal administration of NPY in wild-type animals was not evident in Y1−/− mice. Concomitantly, however, the capsaicin-induced, SP-mediated pro-inflammatory effects were blunted in Y1−/− mice. In fact, the administration of capsaicin in a paw did not induce plasma extravasation and oedema in Y1−/− mice, and the effects of mustard oil were also attenuated. By contrast, neither the inflammatory responses induced by carrageenan nor those induced by SP were modified in Y1−/− animals. Furthermore, the pro-inflammatory effects of capsaicin in wild-type mice were mimicked by a Y1 receptor agonist and were prevented by the selective Y1 receptor antagonist BIBP3226. In Y1−/− mice, tissue concentrations of SP were comparable with those found in normal mice, but capsaicin failed to induce SP release and subsequent neuropeptide depletion.These results led the authors to conclude that Y1 receptors exert a tonic physiological role in reducing nociceptive inputs at the spinal cord level, whereas at the peripheral level, the stimulation of these receptors is both necessary and sufficient for triggering neurogenic inflammation. An alternative hypothesis could reconcile previous and present findings on the role of NPY and NPY receptors in neurogenic inflammation: an opposing role of Y1 and Y2 receptors (or other Y receptors) in the excitability of capsaicin-sensitive nerve terminals could exist if both receptors are tonically stimulated by endogenous NPY. In wild-type animals, the exogenous administration of NPY has an inhibitory effect on capsaicin-induced inflammatory responses, possibly because of a preferential stimulation of Y2 receptors. In Y1−/− animals, endogenous NPY could be sufficient for the inhibition of the excitability of capsaicin-sensitive nerve terminals through the stimulation of Y2 receptors. This hypothesis could be tested either through the construction of Y2−/− mice, or with the use of already available selective Y2 receptor antagonists.