Tonic inhibition of chronic pain by neuropeptide Y

Abstract

Dramatically up-regulated in the dorsal horn of the mammalian spinal cord following inflammation or nerve injury, neuropeptide Y (NPY) is poised to regulate the transmission of sensory signals. We found that doxycycline-induced conditional in vivo (Npy tet/tet ) knockdown of NPY produced rapid, reversible, and repeatable increases in the intensity and duration of tactile and thermal hypersensitivity. Remarkably, when allowed to resolve for several weeks, behavioral hypersensitivity could be dramatically reinstated with NPY knockdown or intrathecal administration of Y1 or Y2 receptor antagonists. In addition, Y2 antagonism increased dorsal horn expression of Fos and phosphorylated form of extracellular signal-related kinase. Taken together, these data establish spinal NPY receptor systems as an endogenous braking mechanism that exerts a tonic, long-lasting, broad-spectrum inhibitory control of spinal nociceptive transmission, thus impeding the transition from acute to chronic pain. NPY and its receptors appear to be part of a mechanism whereby mammals naturally recover from the hyperalgesia associated with inflammation or nerve injury.N europeptide Y (NPY) is a 36-aa peptide that acts at Gprotein-coupled Y receptors to initiate cellular signaling. NPY systems modulate a variety of physiological processes, including somatosensation (1). Expressed in neurons and terminals of the spinal cord dorsal horn (2), and up-regulated by peripheral inflammation or nerve injury, NPY is poised to inhibit the spinal transmission of sensory signals. For example, nerve injury elicits a profound de novo synthesis of NPY in large-diameter neurons of dorsal root ganglion (DRG) and their terminal regions in the dorsal horn (3-7), perhaps serving as an adaptive compensatory response to increased excitatory signaling (8). Increases in NPY last at least 24 wk, indicating that it is temporally available to confer long-lasting inhibition of pronociceptive neurotransmission (9), but this hypothesis has not been tested.Of the five NPY receptors cloned in the mouse, only Y1 and Y2 are expressed in the adult DRG (they colocalize with peptides that are predominantly found in unmyelinated to thinly myelinated neurons) and dorsal horn (10-12). Y1-ir is found in cells and terminals of lamina II i , whereas Y2-ir is found in terminals of I-II o (13-15). Numerous studies using an intrathecal delivery approach have demonstrated that exogenous delivery of NPY reduces hypersensitivity to tactile and thermal stimulation in models of chronic pain, including the spared nerve injury (SNI) model of neuropathic pain; Y1 and Y2 receptor antagonists reverse these antiallodynic actions (16)(17)(18)(19)(20). However, the use of receptor-selective antagonists to evaluate the intrinsic actions of NPY is uncommon, perhaps because behavioral thresholds demonstrate a floor effect in major animal models. For example, although the Y1 receptor antagonist BIBO3304 slightly but significantly increased heat hyperalgesia when administered during the peak of complete Freund'...

The Shared Neuroanatomy and Neurobiology of Comorbid Chronic Pain and PTSD

“…[25][26][27][28] In addition, and as discussed in the remainder of this review, there are PTSD-related neurohormones, neurotransmitters, and inflammatory system factors that impact pain transmission and/or amplification along the neuroaxis from the periphery to the brain and behavioral reactions that result. NPY and the GABAergic neuroactive steroids, [29][30][31][32][33][34][35][36][37][38] as well as the opioid and endocannabinoid systems, immune factors, and specific cellular second messenger systems (see below) thus appear to play roles in the pathophysiology of both PTSD and CP. As such, these systems may constitute pathophysiological domains that promote the comorbidity of these conditions.…”

Neuropeptide Y and posttraumatic stress disorder

“…Conditional knockout mice lacking NPY in the spinal cord and sensory neurons in adulthood lack tonic, long-lasting inhibitory control of spinal nociceptive transmission by NPY. 140 NPY administration in rats attenuates morphine-induced tolerance and withdrawal symptoms in neuropathic pain model, suggesting an interaction with the endogenous opioid system. 141 The antinociceptive actions of NPY are described to be similar to the opioid family in pain alleviation.…”

Involvement of Neuropeptide Y in Post-Incisional Nociception in Rats

“…What could be the functional significance of expression of NPY? Data from several studies, including experiments using doxycycline-induced knockdown of NPY, convincingly showed that NPY could act as an "endogenous braking mechanism" and suppress transmission of noxious stimuli at the spinal cord level [29][30][31]. The initial decrease of NPY immunostaining between 1 and 3 h after incision, when nociception was at its highest level, can be correlated with the release of NPY from synaptic terminals as well as extrasynaptic sites [32].…”