Neuropeptide Y inhibits capsaicin-sensitive nociceptors via a Y1-receptor-mediated mechanism

Abstract

Neuropeptide Y (NPY) is expressed in certain primary afferent fibers, is up-regulated in response to tissue injury and is capable of inhibiting nociceptive behavior at the spinal level. However, the spinal mechanism(s) for NPY-evoked antinociception is unknown. In this study, we evaluated the hypothesis that agonists at the NPY Y1 receptor subtype (Y1-R) inhibit exocytosis from the capsaicin-sensitive class of nociceptors. Using in vitro superfusion of rat dorsal spinal cord slices, pre-treatment with the Y1-R agonist [Leu 31 Pro 34 ]NPY significantly inhibited capsaicin-evoked release of immunoreactive calcitonin gene-related peptide with an EC 50 value of 10.6 nM. This inhibitory effect was concentration dependent, significantly attenuated by pre-treatment with the Y1 receptor antagonist BIBP3226 and reproduced by synthetic NPY. Examination of adult rat dorsal root ganglia using double immunofluorescent labeling revealed frequent co-localization of Y1 receptor immunoreactivity in vanilloid receptor type 1-immunoreactive neurons, indicating that Y1 agonists may directly modulate the capsaicin-sensitive class of nociceptors. Collectively, these results indicate that NPY is capable of inhibiting capsaicin-sensitive neurons via a Y1 receptor mechanism, suggesting the mechanisms for spinal NPY-induced antinociception is due, at least in part, to inhibition of central terminals of capsaicin-sensitive nociceptors. Keywords superfusion; pain; spinal cord; dorsal root ganglion; exocytosis Neuropeptide Y (NPY) is a 36 amino-acid neuropeptide that is highly expressed throughout the central and peripheral nervous systems (Balasubramaniam, 1997;Larhammar, 1996;Malstrom, 1997). NPY has been proposed to mediate several physiologic systems including the processing of nociceptive signaling at the level of the spinal cord (Duggan et al., 1991;Mark et al., 1997;Balasubramaniam, 1997;Hokfelt et al., 1998). The NPY Y1 and Y2 receptors are expressed in the dorsal horn of the spinal cord as well as in dorsal root ganglia (DRG) (Kar and Quirion, 1992;Mantyh et al., 1994). The NPY Y1 receptor (Y1-R) is expressed primarily in small-and medium-sized neurons that express calcitonin gene related peptide (CGRP) in the DRG as well as in the dorsal spinal cord in inner lamina II . The NPY Y2 receptor is also expressed in DRG neurons, but primarily in large-* Corresponding author. Tel: +1-210-567-6668; fax: +1-210-567-3389. gibbs@uthscsa.edu (J. Gibbs). The intrathecal administration of NPY or its analogs produces both antinociception and antihyperalgesia (Hua et al., 1991;Taiwo and Taylor, 2002). Recent studies utilizing Y1-R knockout mice or specific NPY receptor antagonists indicate that the intrathecal effects of NPY are due primarily to activation of the Y1-R (Naveilhan et al., 2001;Taiwo and Taylor, 2002). However, the target neuronal populations mediating this effect have yet to be determined. HHS Public AccessNumerous studies have demonstrated that CGRP is involved in spinal nociception (see Vasko, 1995; van Rossum et al., 19...

Inflammation enhances Y1 receptor signaling, neuropeptide Y-mediated inhibition of hyperalgesia, and substance P release from primary afferent neurons

“…These results are consistent with the antibody microprobe studies of Duggan et al, who reported that microinjection of NPY into the substantia gelatinosa reduced SP-LI that was released by electrical stimulation of unmyelinated primary afferent nerves (Duggan et al, 1991). Our results also support the findings of Gibbs and Hargreaves, who reported that Y1 activation attenuated capsaicin-evoked mechanical allodynia and release of calcitonin gene-related peptide in dorsal horn slices, and attenuated bradykinin/prostaglandin E2-evoked increases in intracellular calcium levels in trigeminal ganglion neurons (Gibbs et al, 2004, Gibbs et al, 2006, Gibbs et al, 2007). Second, we measured SP release in terms of NK1R internalization, and induced the release by applying a noxious stimulus to one hind paw of the rat.…”

Activity and expression of the vanilloid receptor 1 (TRPV1) is altered by long‐term diabetes in epineurial arterioles of the rat sciatic nerve

“…Another explanation would be that NPY is inhibiting the release of CGRP. Gibbs et al reported that pre-treating rat dorsal spinal cord slices with a NPY agonist inhibited capsaicin-induced release of CGRP [24]. These investigators demonstrated that the Y1 NPY receptor co-localized with VR1 in rat dorsal root ganglion neurons.…”

Spinal inhibitory neurotransmission in neuropathic pain

“…Because NPY inhibits the central release of CGRP from dorsal horn slices [35], these NPY receptors are poised to regulate pronociceptive neurotransmitter release from primary afferent neurons. Furthermore, peripheral nerve injury dramatically increases spinal NPY at the central terminals of low threshold DRG neurons and their central terminals, which appears to be associated with enhanced release in the dorsal horn [36].…”