Exogenous NT-3 mitigates the transganglionic neuropeptide Y response to sciatic nerve injury

doi:10.1016/0006-8993(95)01021-M

Brain Research

Volume 699, Issue 1, 13 November 1995, Pages 143-148

https://doi.org/10.1016/0006-8993(95)01021-M Get rights and content

Abstract

Peripheral sciatic nerve transection injury produces a marked increase in immunoreactive NPY in rat lumbar DRG and, as a ‘transganglionic’ response, in their central axonal projections to the dorsal spinal cord and gracile nuclei. Local application of neurotrophin-3 (NT-3) using implanted silicone chambers applied to the proximal transected sciatic nerve stump significantly diminished the transganglionic NPY response in the gracile nucleus and spinal cord but did not affect the CGRP transganglionic response. Conversely, local application of NGF affected the transganglionic CGRP response to axotomy but did not substantially affect transganglionic gracile NPY upregulation.

Reference (31)

BarbutD. et al.
Substance P in spinal cord dorsal horn decreases following peripheral nerve injury
Brain Res.
(1981)
DugganA.W. et al.
Microinjection of neuropeptide Y into the superficial dorsal horn reduces stimulus-evoked release of immunoreactive substance P in the anesthetized cat
Neuroscience
(1991)
DiStefanoP.S. et al.
The neurotrophins BDNF, NT-3, and NGF display distinct patterns of retrograde axonal transport in peripheral and central neurons
Neuron
(1992)
HokfeltT. et al.
Messenger plasticity in primary sensory neurons following axotomy and its functional implications
Trends Neurosci.
(1994)
IpN.Y. et al.
Similarities and differences in the way neurotrophins interact with the Trk receptors in neuronal and non-neuronal cells
Neuron
(1993)
LindsayR.M. et al.
Neuropeptide expression in cultures of adult sensory neurons: modulation of substance P and calcitonin gene-related peptide levels by nerve growth factor
Neurosci.
(1989)
RuitK.G. et al.
Selective dependence of mammalian dorsal root ganglion neurons on nerve growt factor during embryonic development
Neuron
(1992)
WakisakaS. et al.
Increased neuropeptide Y (NPY)-like immunoreactivity in rat sensory neurons following peripheral axotomy
Neurosci. Lett.
(1991)
WoolfC.J. et al.
The growth-associated protein GAP-43 appears in dorsal root ganglion cells and in the dorsal horn of the rat spinal cord following peripheral nerve injury
Neuroscience
(1990)
XuX.-J. et al.
The effects of intrathecal neuropeptide Y on the spinal nociceptive flexor reflex in rats with intact sciatic nerves and after peripheral axotomy
Neuroscience
(1994)

ChongM.S. et al.

GAP-43 mRNA in rat spinal cord and dorsal root ganglia neurons: Developmental changes and reexpression following peripheral nerve injury

Eur. J. Neurosci.

(1992)

FunakoshiH. et al.

Differential expression of mRNAs for neurotrophins and their receptors after axotomy of the sciatic nerve

J. Cell Biol.

(1993)

GrattoK.A. et al.

Role of NT-3 in intact and injured primary sensory neurons

Soc. Neurosci. Abstr.

(1994)

HeumannR. et al.

Differential regulation of mRNA encoding nerve growth factor and its receptor in rat sciatic nerves during development, degeneration and regeneration

JellingerK.

Neuroaxonal dystrophy: its natural history and related disorders

Prog. Neuropathol.

(1973)

Cited by (41)

Early expression of injury-induced neuropeptide Y in primary sensory neurons and the cuneate nucleus in diabetic rats with median nerve transection
2010, Journal of Chemical Neuroanatomy
In this study we examined the temporal changes in neuropeptide Y (NPY) expression in dorsal root ganglion (DRG) neurons and cuneate nucleus (CN) in streptozotocin (STZ)-induced diabetic rats with or without median nerve transection (MNT). Numerous NPY-like immunoreactive (NPY-LI) neurons and fibers were detected in the DRG and CN of the diabetic MNT (DMNT) rats respectively, but not in those with diabetes-alone. Following MNT, the time-course of NPY expression pattern in the diabetic DRG and CN was similar and both peaked at 2 weeks, which was earlier than those in the non-diabetic MNT rats. Consequently, the expression of neurotrophin-3 (NT-3) immunoreactivity in DRG neurons was coincidentally decreased and reached the nadir at 2 weeks in the diabetic MNT rats, which was also earlier than that in the non-diabetic MNT rats. Following electrical stimulation of the injured nerves, the number of NPY-LI fibers became attenuated and the induced c-Fos-LI cells concurrently appeared in the ipsilateral CN. In the diabetic CN, the number of c-Fos-LI cells also peaked at 2 weeks after MNT, which was consistent with the temporal pattern of changes in NPY expression. The results suggest that in diabetes, MNT induced NPY expression via the reduction of NT-3, and electrical stimulation of the injured median nerve evoked the release of NPY and accordingly more c-Fos-LI cells were identified in the CN. Furthermore, this study demonstrated early NPY and c-Fos expression in the diabetic rats after MNT, suggesting that the development of neuropathic signs may be advanced in hyperglycemic rats.
The role of brain-derived neurotrophic factor in different animal models of neuropathic pain
2010, European Journal of Pain
Even in present day pain therapy, neuropathic pain remains a challenge for clinicians to treat and a challenge for researchers to investigate. Different animal models have been developed to mimic neuropathic pain. Neurotrophins such as nerve growth factor, brain-derived neurotrophic factor and neurotrophin 3 have been studied extensively in these models, yet few review articles concerning brain-derived neurotrophic factor have been published. This article reassesses the literature concerning brain-derived neurotrophic factor expression in the sciatic nerve chronic constriction injury model, the sciatic nerve transection model, the spinal nerve ligation model and the spinal nerve transection model and discusses differences in regulation of brain-derived neurotrophic factor between these models and their causality with neuropathic pain.
BDNF in sensory neurons and chronic pain
2006, Neuroscience Research
Neurotrophic factors, which support neuronal survival and growth during development of the nervous system, have been shown to play significant roles in the transmission of physiologic and pathologic pain. Brain-derived neurotrophic factor (BDNF), synthesized in the primary sensory neurons, is anterogradely transported to the central terminals of the primary afferents in the spinal dorsal horn, where it is involved in the modulation of painful stimuli. In models of inflammatory and neuropathic pain, BDNF synthesis is greatly increased in different populations of dorsal root ganglion (DRG) neurons. Furthermore, it is now known that the activation of mitogen-activated protein kinases occurs in these sensory neurons and contributes to persistent inflammatory and neuropathic pain by regulating BDNF expression. The recent discovery that BDNF upregulation in the DRG and spinal cord contributes to chronic pain hypersensitivity indicates that blocking BDNF in sensory neurons could provide a fruitful strategy for the development of novel analgesics.
The effect of site and type of nerve injury on the expression of brain-derived neurotrophic factor in the dorsal root ganglion and on neuropathic pain behavior
2006, Neuroscience
A number of rat neuropathy models have been developed to simulate human neuropathic pain conditions, such as spontaneous pain, hyperalgesia, and allodynia. In the present study, to determine the relative importance of injury site (proximal or distal to the primary afferent neurons) and injury type (motor or sensory), we examined pain-related behaviors and changes of brain-derived neurotrophic factor expression in the dorsal root ganglion in sham-operated rats, and in the L5 dorsal rhizotomy, L5 ventral rhizotomy, L5 dorsal rhizotomy+ventral rhizotomy, and L5 spinal nerve transection models. L5 ventral rhizotomy and spinal nerve transection produced not only mechanical and heat hypersensitivity, but also an increase in brain-derived neurotrophic factor mRNA/protein in the L5 dorsal root ganglion at 7 days after surgery. In contrast, rats in the L5 dorsal rhizotomy and dorsal rhizotomy+ventral rhizotomy groups did not show both pain behaviors at 7 days after surgery, despite brain-derived neurotrophic factor upregulation in medium- and large-size neurons in the L5 dorsal root ganglion. On the other hand, L5 spinal nerve transection, but not dorsal rhizotomy, dorsal rhizotomy+ventral rhizotomy or ventral rhizotomy, increased the expression of brain-derived neurotrophic factor in the L4 dorsal root ganglion at 7 days after surgery. Taken together, these findings suggest that the upregulation of brain-derived neurotrophic factor expression in the L4 and L5 dorsal root ganglion neurons may be, at least in part, involved in the pathophysiological mechanisms of neuropathic pain and that the selective nerve root injury models may be useful for studying the underlying mechanisms of chronic pain after nerve injury.
Immune and glial cell factors as pain mediators and modulators
2005, Experimental Neurology
A decade ago the attention of pain scientists was focused on a small number of molecules such as prostaglandin and bradykinin as peripheral pain mediators or modulators. These factors were known to be produced by tissue damage or inflammation, and considered responsible for the activation and sensitization of peripheral pain signaling sensory neurons. A small number of molecules were also identified as central pain mediators, most notably glutamate and substance P released from central nociceptive nerve terminals, and, starting at that time, appreciation that nitric oxide might be produced by dorsal horn neurons and act as a diffusible transmitter to increase excitability of central pain circuits.
During the last decade evidence has emerged for many novel pain mediators. The old ones have not disappeared, although their roles have been redefined in some cases. Prostaglandin E2 (PGE2), for instance, is now recognized as playing a prominent role in CNS as well as peripheral tissues. The newly identified mediators include a variety of factors produced and released from nonneuronal cells—predominantly immune and glial cells. The evidence is now growing apace that these are important mediators of persistent pain states and can act at a number of loci.
Here we review the actions of several of these factors—the pro-inflammatory cytokines, some chemokines, and some neurotrophic factors, which, in addition to their traditionally recognized roles, are all capable of changing the response properties of peripheral and central pain signaling neurons. We review these actions, first in periphery, where a substantial literature has accumulated, and then in spinal cord, where the role of factors from nonneuronal cells has only recently been identified as of considerable importance.
Expression of axotomy-inducible and apoptosis-related genes in sensory nerves of rats with experimental diabetes
2004, Molecular Brain Research
Citation Excerpt :
Of course, NGF is not the only neurotrophic factor with a candidacy for activating axotomy-induced changes, and neurotrophin 3 has been shown to contribute, but the neuropeptide NPY appears to be the only respondent characterised so far. As with NGF, this neuropeptide change is reduced expression reversed by administration of NT-3 [30]. The reductions in expression of the genes coding for these neuropeptides and the p75 receptor are definitely part of the diabetes-induced sensory neurone phenotype and in this situation can be ascribed to the neurotrophic deficits endemic to this model (see Introduction and Ref. [8]).
In diabetes, peripheral nerves suffer deficient neurotrophic support—a situation which resembles axotomy. This raises the question: does inappropriate establishment of an axotomised neuronal phenotype contribute to diabetic neuropathy, and in extremis, does this provoke apoptosis? We hybridized reverse-transcribed RNA, from the dorsal root ganglia (DRG) of 8-week streptozotocin (STZ)-induced diabetic rats, to Affymetrix Rat Genome U34A chips and scanned the array for expression of (a) genes that are upregulated by axotomy, (b) proapoptotic and (c) anti-apoptotic genes. Expression of the axotomy-responsive genes coding for growth-associated protein 43 (GAP-43), galanin, neuropeptide Y (NPY), pre-pro-vasoactive intestinal polypeptide (pre-pro-VIP), neuronal nitric oxide synthase (nNOS), protease nexin 1, heat-shock protein 27 (HSP 27) and myosin light chain kinase II (MLCK II) was unaffected in ganglia from diabetic rats compared to controls; thus, no axotomised phenotype was established. The expression of the majority of proapoptotic genes in the DRG was also unaltered (bax, bad, bid, bok, c-Jun, p38, TNFR1, caspase 3 and NOS2). Similarly there was no change in expression of the majority of antiapoptotic genes (bcl2, bcl-xL, bcl-w, NfkappaB). These alterations in gene expression make it clear that neither axotomy nor apoptotic phenotypes are established in neurones in this model of diabetes.

View all citing articles on Scopus

View full text

Exogenous NT-3 mitigates the transganglionic neuropeptide Y response to sciatic nerve injury

Abstract

Brain Res.

Neuroscience

Neuron

Trends Neurosci.

Neuron

Neurosci.

Neuron

Neurosci. Lett.

Neuroscience

Neuroscience

GAP-43 mRNA in rat spinal cord and dorsal root ganglia neurons: Developmental changes and reexpression following peripheral nerve injury

Eur. J. Neurosci.

Differential expression of mRNAs for neurotrophins and their receptors after axotomy of the sciatic nerve

J. Cell Biol.

Role of NT-3 in intact and injured primary sensory neurons

Soc. Neurosci. Abstr.

Differential regulation of mRNA encoding nerve growth factor and its receptor in rat sciatic nerves during development, degeneration and regeneration

Neuroaxonal dystrophy: its natural history and related disorders

Prog. Neuropathol.