Neuropeptide Y acts at Y1 receptors in the rostral ventral medulla to inhibit neuropathic pain

Abstract

Brain microinjection studies in the rat using local anesthetics suggest that the rostral ventral medulla (RVM) contributes to the facilitation of neuropathic pain. However, these studies were restricted to a single model of neuropathic pain (the spinal nerve ligation model) and to just two stimulus modalities (non-noxious tactile stimulus and heat). Also, few neurotransmitter systems have been shown to modulate descending facilitation. After either partial sciatic nerve ligation (PSNL) or spared nerve injury (SNI), we found that unilateral or bilateral microinjection of lidocaine into the RVM reduced not only mechanical allodynia (decreased threshold to von Frey hairs and/or an automated device) and mechanical hyperalgesia (increased paw lifting in response to a noxious pin), but also cold hypersensitivity (increased lifting in response to the hindpaw application of a drop of acetone). Application of a drop of water did not elicit paw withdrawal, indicating that the acetone test is indeed a measure of cold hypersensitivity. We found significant neuropeptide Y Y1-like immunoreactivity within, and lateral to, the midline RVM. Intra-RVM injection of neuropeptide Y (NPY) dosedependently inhibited the mechanical and cold hypersensitivity associated with PSNL or SNI, an effect that could be blocked by the Y1 receptor antagonist BIBO 3304. We conclude that medullary facilitation spans multiple behavioral signs of allodynia and hyperalgesia in multiple models of neuropathic pain. Furthermore, NPY inhibits behavioural signs of neuropathic pain, possibly by acting at Y1 receptors in the RVM.

Tonic inhibition of chronic pain by neuropeptide Y

“…Microinjection of NPY into the rostral ventral medulla, a key site of descending inhibitory pain control, also reduces signs of allodynia and hyperalgesia following spared nerve injury (29). Indeed, NPY acts at numerous brain regions to inhibit nociception, including the periaqueductal gray, nucleus accumbens, and arcuate nucleus (30)(31)(32)(33).…”

Spinal Processing of Noxious and Innocuous Cold Information: Differential Modulation by the Periaqueductal Gray

“…It is now recognized that alterations in descending controls from brainstem centers, including the PAG, contribute to central sensitization and chronic pain states (Pertovaara et al, 1996;Urban and Gebhart, 1999;Pertovaara, 2000;Monhemius et al, 2001;Pertovaara and Wei, 2003;Vanegas and Schaible, 2004). Indeed, cold allodynia is dependent on descending control systems, since lidocaine block of the rostroventromedial medulla (RVM), a major relay of outflow from the PAG, attenuates cold allodynia in models of neuropathic injury (Taylor et al, 2007). Therefore, knowledge of descending influences on spinal processing of cold information is clinically important, given the heightened cold sensitivity frequently reported by patients with neuropathic injury (Ochoa and Yarnitsky, 1994;Jorum et al, 2003).…”

Changes in neuropeptide Y gene expression in the spinal cord of chronic constrictive injury model rats after electroconvulsive stimulation

“…*P < 0.05, **P < 0.01 compared with values of contralateral on the corresponding days, by a paired t-test; hippocampus. Although NPY is involved in the control of hypothalamic hormones, appetite, memory, and blood pressure, it was also recently suggested that NPY could be related to pain (6,9,23). NPY Y 1 receptors are found in the midline raphe magnus (11), a pain modulation center in the rostral ventromedial medulla (RVM), which contributes to the descending inhibitory system (16,19).…”

“…NPY Y 1 receptors are found in the midline raphe magnus (11), a pain modulation center in the rostral ventromedial medulla (RVM), which contributes to the descending inhibitory system (16,19). Taylor et al showed that an administration of NPY to the RVM improved neuropathic pain, and thus it was supposed that NPY would have an inhibitory action on pain (23). Another report demonstrated that by direct administration of NPY into the subarachnoid space, improvement of pain was achieved (8).…”

“…We previously showed that in a rat model of chronic constrictive injury (CCI), thermal hypersensitivity was improved and the expression of neuropeptide Y (NPY) was increased in the brain of these rats after electroconvulsive shock (ECS) (14). Recent studies have suggested that NPY inhibits pain (8,23); possibly changes in NPY expression in the brain may be related to ECT's mechanism of action for neuropathic pain. Herein, we examined changes in NPY mRNA expression in the dorsal spinal cord after ECS in a rat model of neuropathic pain.…”