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Activation of postsynaptic NPY Y1 and presynaptic Y2 receptors reduce spinal nociceptive transmission

Corder GF, Donahue R, Winter MK, Chen W, Mccarson KE, Marvizon J, Taylor B (2011) Activation of postsynaptic NPY Y1 and presynaptic Y2 receptors reduce spinal nociceptive transmission. Neuroscience 2011 Abstracts 179.17. Society for Neuroscience, Washington, DC.

Summary: Exogenous (Intondi et al, Neuroscience, 2008) and endogenous (Solway et al, PNAS 108:7224-9, 2011) neuropeptide Y (NPY) acts at Y1 and Y2 receptors in the dorsal horn (DH) to inhibit hypersensitivity to mechanical and thermal stimuli. The adjacent poster (Donahue, et al, SFN 2011) describes our use of a targeted NPY-saporin neurotoxin approach to selectively remove spinal cord (SC) neurons expressing the Y1 receptor — the data implicate a contribution of Y1-expressing, pain transmission neurons to behavioral signs of persistent pain. To determine whether persistent noxious input is associated with a compensatory increase in NPY-mediated inhibitory signaling (presumably at Y1-expressing DH neurons), we performed GTPγS binding assays in SC slices taken from animals following the intraplantar (i.pl) injection of complete Freund’s adjuvant (CFA). CFA significantly reduced the EC50 of Y1 agonist (Leu31,Pro34-NPY)-induced [35S]GTPγS binding in ipsilateral DH to 0.24 ± 0.17 μM, as compared to sham (1.38 ± 0.51 μM). This support the hypothesis that injury increases in the efficiency of coupling between Y1-receptors and G-proteins. To determine whether compensatory NPY inhibition occurs at presynaptic sites, we studied the activity of presynaptic Y2 receptor in NPY-saporin-treated rats. Intrathecal injection of the Y2 receptor antagonist BIIE0246 reduced von Frey thresholds (saporin group from 1.3±0.4 to 0.6 ±0.1g; 750 ng NPY-saporin group from 5.4±1.0 to 1.2±0.2g, p<0.05), suggesting that presynaptic Y2 receptors contribute to a tonic endogenous inhibition of inflammatory pain. In support of this hypothesis, BIIE0246-induced hyperalgesia (21 days after CFA) significantly increased the Emax of Y2 agonist (PYY3-36)-induced [35S]GTPγS binding. We next determined whether NPY acts at presynaptic terminals of primary afferent neurons to reduce the release of substance P (SP). First, in both the i.pl carrageenan and CFA models of inflammatory pain, intrathecal administration of NPY reduced in vivo neurokin-1 (NK1) receptor internalization (an indirect measure of functional SP release). Second, application of either (Leu31,Pro34)-NPY) or PYY3-36 to spinal cord slices concentration-dependently reduced NK1 internalization in the ipsilateral dorsal horn evoked by electrical stimulation of the dorsal root (1000 pulses of 20 V, 0.4 ms at 100 Hz); these effects were reversed by the Y1 antagonist BIBO3304. We conclude that injury up-regulates post-synaptic Y1 and pre-synaptic Y2 spinal inhibitory mechanisms to reduce behavioral signs of persistent pain.

Related Products: NPY-SAP (Cat. #IT-28)