Denervation supersensitivity to 5-hydroxytryptophan in rats following spinal transection and 5,7-dihydroxytryptamine injection

doi:10.1016/0028-3908(81)90216-1

Neuropharmacology

Volume 20, Issue 6, June 1981, Pages 611-616

https://doi.org/10.1016/0028-3908(81)90216-1 Get rights and content

Abstract

Within 3 days after transection of the spinal cord in rats, a single injection of 5-hydroxytryptophan (5-HTP) or of the serotonin agonist, quipazine, induced a small increase of the spontaneous electromyographic (EMG) activity recorded in the paralyzed hindlimbs. The amplitude of the response increased progressively with time. It reached a maximum 30 days after the transection.

Similarly, the amplitude of the flexor contraction in response to electrical stimulation of the paw also increased progressively after the transection. In contrast, when the transection was performed 20 days following the intraventricular injection of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT), 5-HTP increased markedly the spontaneous level of EMG activity in the hindlimbs 1 day following the transection, but the flexor response was not modified significantly.

These results support the hypothesis that a specific supersensitivity to serotonin develops after a spinal cord transection. They also suggest that the supersensitivity of the 5-KT receptors is only one of the mechanisms that can explain the hyperreactivity that develops after cord transection.

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Following spinal cord injury in adult mammals, descending serotonergic projections are partially interrupted and 5-HT concentration is significantly reduced caudal to the lesion (Carlsson et al., 1963; Hadjiconstantinou et al., 1984). As a consequence, the locomotor network develops a denervation supersensitivity to 5-HT (Barbeau and Bédard, 1981; Shibuya and Anderson, 1968) reviewed in (Husch et al., 2012), leading to several plastic changes at the cellular level, including constitutive activity of 5-HT2C receptors in motoneurons (Berg et al., 2001), enhanced bistable firing properties in motoneurons (Anelli et al., 2007; Bennett et al., 2001; Harvey et al., 2006) and 5-HT supersensitivity in V2a interneurons (Husch et al., 2012). Such changes could easily promote an increase in the 5-HT sensitivity of the locomotor CPG.
The spinal locomotor central pattern generator (CPG) in neonatal mice exhibits diverse output patterns, ranging from sub-rhythmic to multi-rhythmic to fictive locomotion, depending on its general level of excitation and neuromodulatory status. We have recently reported that the locomotor CPG in neonatal mice rapidly recovers the ability to produce neurochemically induced fictive locomotion following an upper lumbar spinal cord compression injury. Here we address the question of recovery of multi-rhythmic activity and the serotonin-sensitivity of the CPG. In isolated spinal cords from control and 3 days post-injury mice, application of dopamine and NMDA elicited multi-rhythmic activity with slow and fast components. The slow component comprised 10–20 s episodes of activity that were synchronous in ipsilateral or all lumbar ventral roots, and the fast components involved bursts within these episodes that displayed coordinated patterns of alternation between ipsilateral roots. Rhythm strength was the same in control and injured spinal cords. However, power spectral analysis of signal within episodes showed a reduced peak frequency after recovery. In control spinal cords, serotonin triggered fictive locomotion only when applied at high concentration (30 µM, constant NMDA). By contrast, in about 50% of injured preparations fictive locomotion was evoked by 2–3 times lower serotonin concentrations (10–15 µM). This increased serotonin sensitivity was correlated with post-injury changes in the expression of specific serotonin receptor transcripts, but not of dopamine receptor transcripts.
The time course of serotonin 2A receptor expression after spinal transection of rats: An immunohistochemical study
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There may be several reasons for the return of plateau potentials and the development of a spastic syndrome. Earlier studies have estimated the effects of 5-HT (and its precursors and agonists) on rather indirect measures of muscle contraction and behaviors following 5-HT-denervation (either with a spinal transection or by specific toxin-evoked destruction of the 5-HT neurons in the brain stem) and have described a powerful supersensitivity (Shibuya and Anderson, 1968; Trulson et al., 1976; Bedard et al., 1979; Barbeau and Bedard, 1981; Li et al., 2007). Several 5-HT receptors, including 5-HT1A, 2A and 2C, have been demonstrated to be upregulated in spinal motoneurons and/or interneurons in response to spinal lesions (e.g. Giroux et al., 1999; Fuller et al., 2005; Lee et al., 2007; Otoshi et al., 2009; Hayashi et al., 2010; Kong et al., 2010).
Hyperexcitability of motoneurons is one of the key mechanism that has been demonstrated to underlie the pathogenesis of spasticity after spinal injury. Serotonin (5-HT) denervation supersensitivity is one of the mechanisms underlying this increased motoneuron excitability. In this study, to examine whether the supersensitivity is caused by 5-HT receptor upregulation we investigated changes in levels of 5-HT2A receptor immunoreactivity (5-HT2AR-IR) following a spinal transection in the sacral spinal cord of rats at seven different time points post injury: 2, 8, 16 h, and 1, 2, 7 and 28 days, respectively. 5-HT2AR-IR density was analyzed in motoneurons (regions containing their somata and dendrites) in the spinal segments below the lesion. The results showed no significant changes in 5-HT2AR-IR in the motoneurons up to 16 h following the transection. After 1-day, however the levels of 5-HT2AR-IR increased in the motoneurons and their dendrites, with the density level being 3.4-fold higher in spinalized rats than in sham-operated rats. The upregulation increased progressively until a maximal level was reached at 28 days post-injury. We also investigated 5-HT and 5-HT transporter expressions at five different post injury time points: 1, 2, 7, 21 and 60 days and they showed concurrent down-regulation changes after 2 days. These results suggest that the upregulation of 5-HT2ARs may at least partly underlie the development of 5-HT denervation supersensitivity in spinal motoneurons following spinal injury and thereby implicates their involvement in the pathogenesis of the subsequent development of spasticity.
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Thus it cannot be ruled out that a small number of 5-HT2AR-positive dendrites from sources other than from motoneurons were included in the circumscribed region in the lateral funiculus. Our findings may provide a basis for the explanation of the supersensitivity of spinal motoneurons below a spinal transection to systemic 5-HTP and/or tryptophan administration (Shibuya and Anderson, 1968; Bedard et al., 1979; Barbeau and Bédard, 1981). Although the supersensitivity to 5-HTP may depend on an increased pre-motoneuronal activity the main attention has focused on the motoneurons themselves.
It is well known that spinal motoneurons below a spinal transection become supersensitive to a systemic administration of serotonin (5-HT) precursors, such as 5-hydroxytryptophan. This supersensitivity has been implicated in both the process of functional recovery following chronic lesions, and also in the development of symptoms such as hyperreflexia and spasticity. However, the mechanisms of this denervation supersensitivity are still largely unknown. In this study we have investigated the changes in 5-HT2A receptor immunoreactivity following chronic spinal transections at the level of the sacrocaudal spinal cord. The results show that in the spinalized rats the immunoreactivity of 5-HT2A receptors below the lesion is dramatically increased in the motoneuron soma and its proximal dendritic territory, most likely also in their distal dendritic territory, to a level 3–5-fold higher than that of sham-operated rats. We also found a small number of intraspinal 5-HT neurons and clusters of 5-HT fibers and their varicosities in the spinal cord caudal to the lesion, which may provide an intrinsic source of 5-HT to act upon the upregulated 5-HT2A receptors. These results indicate that the upregulation of 5-HT2A receptors at least partly underlies the 5-HT denervation supersensitivity of spinal motoneurons after a complete spinal transection.
The spastic rat with sacral spinal cord injury
2005, Movement Disorders
The Spastic Rat with Sacral Spinal Cord Injury
2004, Movement Disorders: Genetics and Models: Second Edition
The role of serotonin in reflex modulation and locomotor rhythm production in the mammalian spinal cord
2000, Brain Research Bulletin
Over the past 40 years, much has been learned about the role of serotonin in spinal cord reflex modulation and locomotor pattern generation. This review presents an historical overview and current perspective of this literature. The primary focus is on the mammalian nervous system. However, where relevant, major insights provided by lower vertebrate models are presented. Recent studies suggest that serotonin-sensitive locomotor network components are distributed throughout the spinal cord and the supralumbar regions are of particular importance. In addition, different serotonin receptor subtypes appear to have different rostrocaudal distributions within the locomotor network. It is speculated that serotonin may influence pattern generation at the cellular level through modulation of plateau properties, an interplay with N-methyl-D-aspartate receptor actions, and afterhyperpolarization regulation. This review also summarizes the origin and maturation of bulbospinal serotonergic projections, serotonin receptor distribution in the spinal cord, the complex actions of serotonin on segmental neurons and reflex pathways, the potential role of serotonergic systems in promoting spinal cord maturation, and evidence suggesting serotonin may influence functional recovery after spinal cord injury.

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^☆: Supported by the Medical Research Council of Canada.

^†: Scholar of the Canadian Life Insurance Association.

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Denervation supersensitivity to 5-hydroxytryptophan in rats following spinal transection and 5,7-dihydroxytryptamine injection☆

Abstract

Neuropharmacology

Brain Res.

Eur. J. Pharmac.

Int. J. Neuropharmac.

Brain Res.

Spinal reflexes and monoamine liberation

Nature, Lond.