Substance P: Depletion in the dorsal horn of rat spinal cord after section of the peripheral processes of primary sensory neurons

doi:10.1016/0006-8993(79)90167-7

Brain Research

Volume 168, Issue 2, 25 May 1979, Pages 247-259

https://doi.org/10.1016/0006-8993(79)90167-7 Get rights and content

Abstract

The substance P content, glutamic acid decar☐ylase and choline acetyltransferase activities and the level of [³H]diprenorphine binding were measured in various regions of the lumbar spinal cord of rats after unilateral section of the sciatic nerve or after dorsal rhizotomy. Sciatic nerve section produced a 75–80% depletion of substance P in the dorsal horn but did not change the substance P content of the ventral horn. The onset of substance P depletion occurred within 7 days and was maintained for 2 months. The substance P content of the dorsal root ganglia and both the peripheral and central branches of primary sensory neurons was also reduced after sciatic nerve section. Glutamic acid decar☐ylase and choline acetyltransferase activity were unchanged; however, a small decrease in opiate receptor binding occurred 1 month after nerve section. Dorsal rhizotomy produced an 80% depletion of substance P in the dorsal horn. In addition, the substance P content of the ventral horn was significantly reduced. Glutamic acid decar☐ylase activity in the dorsal horn was unaffected by dorsal rhizotomy whereas opiate receptor binding was reduced by 40%. From these studies it appears that peripheral nerve injury results in the degeneration of primary sensory neurons which contain and release substance P as neurotransmitter.

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The neuropeptide substance P (SP) was identified in a plexus of axons in the superficial dorsal horn (SDH; laminae I-II) by Hokfelt et al. (1975), who showed that some of these axons originated from a population of SP-expressing primary afferent neurons. A series of studies involving Tom Jessell published over the next few years demonstrated that SP was located in axon terminals in the dorsal horn (Cuello et al., 1977), that it could be released in response to capsaicin (Theriault et al., 1979), and that it was substantially depleted from the dorsal horn by treatment with capsaicin, as well as by peripheral nerve section or dorsal rhizotomy (Jessell et al., 1978; Jessell et al., 1979; Yaksh et al., 1979). However, following rhizotomy (which should destroy central terminals of primary afferents), the SP concentration in the ipsilateral dorsal horn was ∼20% of that seen in unoperated animals (Jessell et al., 1979), suggesting that some of the peptide is derived from non-primary sources.
The tachykinin peptide substance P (SP) is expressed by many interneurons and some projection neurons in the superficial dorsal horn of the spinal cord. We have recently shown that SP-expressing excitatory interneurons in lamina II correspond largely to a morphological class known as radial cells. However, little is known about their function, or their synaptic connectivity. Here we use a modification of the Brainbow technique to define the excitatory synaptic input to SP radial cells. We show that around half of their excitatory synapses (identified by expression of Homer) are from boutons with VGLUT2, which are likely to originate mainly from local interneurons. The remaining synapses presumably include primary afferents, which generally have very low levels of VGLUT2. Our results also suggest that the SP cells are preferentially innervated by a population of excitatory interneurons defined by expression of green fluorescent protein under control of the gene for gastrin-releasing peptide, and that they receive sparser input from other types of excitatory interneuron. We show that around 40% of lamina I projection neurons express Tac1, the gene encoding substance P. Finally, we show that silencing Tac1-expressing cells in the dorsal horn results in a significant reduction in reflex responses to cold and radiant heat, but does not affect withdrawal to von Frey hairs, or chloroquine-evoked itch.
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It is debatable whether peripheral nerve injury could cause up-regulation of SP and CGRP in axotomized myelinated afferents. Many investigators reported that peripheral nerve injury caused down-regulation of SP (Hofmann et al., 2003; Hökfelt et al., 1994, 1997, 2006; Honore et al., 2000; Jessell et al., 1979; Ji et al., 1996; McGregor et al., 1984; Rydh-Rinder et al., 1996; Sanderson Nydahl et al., 2004; Shehab and Atkinson, 1986a,b; Siri et al., 2001; Wang et al., 2002; Xiao et al., 2002; Zhang et al., 1995a) and CGRP (Dumoulin et al., 1991; Hofmann et al., 2003; Noguchi et al., 1990; Zhang et al., 1995b). However other investigators reported an up-regualtion of SP and CGRP in the DRG and gracile nucleus where myelinated primary afferent neurons originate and terminate respectively (Fukuoka et al., 1998; Ma and Bisby, 1998; Ma et al., 1999; Marchand et al., 1994; Miki et al., 1998; Noguchi et al., 1995, 1994; Weissner et al., 2006) suggesting that this up-regulation might be involved in mechanisms of the development of allodynia and hyperalgesia.
Previous investigations of the anatomical basis of the neuropathic-like manifestations in the spinal nerve ligation animal model have shown that the central terminations of the unmyelinated primary afferents of L5 spinal nerve are not restricted to the corresponding L5 spinal segment, and rather extend to two spinal segments rostrally and one segment caudally where they intermingle with primary afferents of the adjacent L4 spinal nerve. The aim of the present study was to investigate the neurochemical changes in the dorsal horn of the spinal cord and DRGs after L5 nerve injury in rats. In the first experiment, the right L5 nerve was ligated and sectioned for 14 days, and isolectin B4 (IB4, a tracer for unmyelinated primary afferents) was injected into the left L5 nerve. The results showed that the vasoactive intestinal peptide (VIP) was up-regulated in laminae I–II of L3–L6 spinal segments on the right side in exactly the same areas where IB4 labelled terminals were revealed on the left side. In the second experiment, L5 was ligated and sectioned and the spinal cord and DRGs were stained immunocytochemically with antibodies raised against various peptides known to be involved in pain transmission and hyperalgesia. The results showed that L5 nerve lesion caused down-regulation of substance P, calcitonin-gene related peptide and IB4 binding and up-regulation of neuropeptide Y and neurokinin-1 receptor in the dorsal horn of L4 and L5 spinal segments. Similar neurochemical changes were observed only in the corresponding L5 DRG with minimal effects observed in L3, L4 and L6 DRGs. Although, L5 nerve injury caused an up-regulation in NPY, no change in SP and CGRP immunoreactivity was observed in ipsilateral garcile nucleus. These neuroplastic changes in the dorsal horn of the spinal cord, in the adjacent uninjured territories of the central terminations of the adjacent uninjured nerves, might explain the mechanism of hyperalgesia after peripheral nerve injury.
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Peripheral nerve injuries induce plastic changes on primary afferent fibers and on the spinal circuitry, which are related to the emergence of neuropathic pain. In this study we compared three models of sciatic nerve injury in the rat with different degrees of damage and impact on regeneration capability: crush nerve injury, chronic constriction injury (CCI) and spared nerve injury (SNI). All three models were characterized by means of nerve histology, in order to describe the degenerative and regenerative process of injured axons. Nociceptive responses were evaluated by mechanical and thermal algesimetry tests. Crush animals displayed higher withdrawal thresholds on the ipsilateral paw compared to the contralateral during the time of denervation, while CCI and SNI animals showed mechanical and thermal hyperalgesia. Central plasticity was evaluated by immunohistochemical labeling of non-peptidergic (IB4-positive) and peptidergic (substance P-positive) nociceptive C-fibers on L4–L6 spinal cord sections. After crush nerve injury and SNI, we observed progressive and sustained reduction of IB4 and SP immunolabeling at the sciatic projection territory in the superficial laminae of the dorsal horn, which affected only the tibial and peroneal nerves projection areas in the case of SNI. After CCI, changes on SP-immunoreactivity were not observed, and IB4-immunoreactive area decreased initially but recovered to normal levels on the second week post-injury. Thus, nociceptive responses depend on the type of injury, and the immunoreactivity pattern of afferent fibers at the spinal cord display changes less pronounced after partial than complete sciatic nerve injury. Although signs of neuropathic pain appear in all three lesion models, nociceptive responses and central plasticity patterns differ between them.
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Neurons in the spinal cord use a variety of neurotransmitters to carry out their functions, and they in turn receive a variety of neurotransmitter inputs. For the most part these neurotransmitters show distinct patterns of distribution within the spinal cord that are similar across different species. Furthermore, specific neurotransmitter systems in the spinal cord are often associated with specific functions. This chapter focuses on the distribution of acetylcholine (ACh) and substance P (SP) within the spinal cord, and examines the serotoninergic (5-HT), noradrenergic (NA), and dopaminergic (DA) projections from the brain to the spinal cord. Cholinergic neurons are found throughout the longitudinal extent of the spinal cord from cervical to coccygeal segments. In most species, they are localized to the gray matter of the spinal cord. Substance P (SP), a member of the tachykinin neuropeptide family, is an important signaling molecule that has been associated with functionally distinct spinal cord systems. SP is involved in sensory, autonomic, and motor functions of the spinal cord. Noradrenergic (NA) containing fibers to the spinal cord originate from the locus coeruleus (LC), and other NA cell groups, namely the locus subcoeruleus (SC) and the A5 and A7 cell groups of the lateral tegmentum. All NA in the spinal cord comes from these four areas. The serotoninergic projections from ventral medullary raphe nuclei arise from raphe magnus (RMg), raphe pallidus (RPa), and raphe obscurus (ROb) nuclei; they terminate in all laminae of the spinal cord.
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Substance P: Depletion in the dorsal horn of rat spinal cord after section of the peripheral processes of primary sensory neurons

Abstract

Brain Research

Brain Research

Brain Research

Brain Research

Brain Research

Brain Research

Brain Research

Brain Research

Int. Rev. Neurobiol.

J. biol. Chem.

Brain Research

Brain Research

Brain Research

Brain Research

Brain Research

Life Sci.

Nerve cell degeneration and death in the trigeminal ganglion of the adult rat following peripheral nerve transection

J. Neurocytol.

Quantitative effects of the peripheral innervation area on nerves and spinal ganglion cells

J. comp. Neurol.

Ultrastructural identification of substance P cells and their processes in rat sensory ganglia and their terminals in the spinal cord by immunocytochemistry

Substance P: localization in synaptic vesicles in rat central nervous system

J. Neurochem.

A rapid radiochemical method for the determination of choline acetyltransferase

J. Neurochem.

Quantitative study of trigeminal ganglion response to peripheral nerve trauma

J. Dental Res.