Spinal regions involved in baroreflex control of renal sympathetic nerve activity in the rat

Spinal cord injury causes debilitating cardiovascular disturbances. The etiology of these disturbances remains obscure, partly because the locations of spinal cord pathways important for sympathetic control of cardiovascular function have not been thoroughly studied. To elucidate these pathways, we examined regions of the thoracic spinal cord important for reflex sympathetic control of arterial pressure (AP). In anesthetized rats, baroreceptor relationships between pharmacologically induced changes in AP and changes in left renal sympathetic nerve activity (RSNA) were generated in spinally intact rats and after acute surgical hemisection of either the dorsal, left, or right T8 spinal cord. None of these individual spinal lesions prevented the baroreceptor-mediated increases in RSNA caused by decreases in AP. Thus, baroreceptor-mediated increases in RSNA in rats are mediated by relatively diffuse, bilateral, descending, excitatory projections. The ability to reduce RSNA at increased AP was impaired after both dorsal and left hemisections, and baroreceptor gain was significantly decreased. Baroreceptor-induced maximum decreases in RSNA were not affected by right hemisections. However, baroreflex gain was impaired. Because both dorsal and left hemisections, but not right hemisections, attenuated the decrease in RSNA at elevated AP, we conclude that pathways involved in the tonic inhibition of spinal sources of sympathetic activity descend ipsilaterally in the dorsal spinal cord. Our results show that many lesions that do not fully transect the spinal cord spare portions of both descending excitatory pathways that may prevent orthostatic hypotension and descending inhibitory pathways that reduce the incidence of autonomic dysreflexia.     

Adaptive changes of locomotion after central and peripheral lesions

This paper reviews findings on the adaptive changes of locomotion in cats after spinal cord or peripheral nerve lesions. From the results obtained after lesions of the ventral/ventrolateral pathways or the dorsal/dorsolateral pathways, we conclude that with extensive but partial spinal lesions, cats can regain voluntary quadrupedal locomotion on a treadmill. Although tract-specific deficits remain after such lesions, intact descending tracts can compensate for the lesioned tracts and access the spinal network to generate voluntary locomotion. Such neuroplasticity of locomotor control mechanisms is also demonstrated after peripheral nerve lesions in cats with intact or lesioned spinal cords. Some models have shown that recovery from such peripheral nerve lesions probably involves changes at the supra spinal and spinal levels. In the case of somesthesic denervation of the hindpaws, we demonstrated that cats with a complete spinal section need some cutaneous inputs to walk with a plantigrade locomotion, and that even in this spinal state, cats can adapt their locomotion to partial cutaneous denervation. Altogether, these results suggest that there is significant plasticity in spinal and supraspinal locomotor controls to justify the beneficial effects of early proactive and sustained locomotor training after central (Rossignol and Barbeau 1995; Barbeau et al. 1998) or peripheral lesions.     

刺激大鼠外侧缰核对脊髓背角神经元伤害性反应的影响

电刺激大鼠一侧外侧缰核可对脊髓疹角广动力型神经元的伤害性放电产生明显抑制;这种抑制效应可部分地被静脉注射赛庚啶及酚妥拉明所阻断,电解损毁ＬＨｂ对ＷＤＲ神经元的放电无影响,本文结果表明,ＬＨｂ参与了脊髓上结构对脊髓背角ＷＤＲ神经元伤害性反应的下行抑制,这种下行抑制为位相性抑制。     

Dorsal root entry zone lesions for conus medullaris root avulsions

We have found dorsal root entry zone (DREZ) lesions to be an effective treatment of chronic deafferentation pain in patients who have had avulsions of the dorsal rootlets from the spinal cord. Eight patients were operated in whom chronic pain of the lower extremity resulted from dorsal root avulsions from the conus medullaris. In 7 of the 8 patients, the mechanism of injury was a motor vehicle accident; all 7 sustained severe pelvic trauma. Seven of the 8 patients remained pain-free, off all narcotics, with an average follow-up of 33 months. All patients had DREZ lesions of the conus performed by radiofrequency techniques.     

Absence of Intraspinal Sprouting in Dorsal Root Axons Caudal to a Partial Spinal Hemisection: A Horseradish Peroxidase Transport Study

Primary afferent sprouting in the spinal cord was evaluated by comparing the central projection of horseradish peroxidase (HRP)-labeled sciatic nerve afferent axons in nonlesioned control rats, and in rats subjected to acute or chronic partial spinal hemisections as adults. The lesions were performed at various levels from T₁₀ to L₃, and removed supraspinal and varying amounts of descending propriospinal afferents to lumbar segments receiving the maximal sciatic projection. The hemisections typically involved all but the dorsal column, although in some cases a portion of the dorsal column, including the corticospinal tract, was also transected.

The distribution pattern and density of spinal HRP reaction product was not significantly different in experimental and control preparations in any segment below the lesion, regardless of the quantity of denervation, or the density of the normal sciatic projection in a given terminal region. These results, together with our previous finding concerning an absence of primary afferent sprouting following long-term dorsal root ganglionectomies, suggest that current concepts concerning collateral sprouting as a factor in functional plasticity in the mature mammalian spinal cord warrant re-evaluation.     

Alteration of sensorineural circuits in spinal cord by chronic contact dermatitis

In the present study, eczema-induced alteration of sensorineural circuits of the spinal dorsal horn was investigated. Eczematous lesions resembling atopic dermatitis were induced by repeated application of diphenylcyclopropenone (DCP) onto murine right hind paws. Immunohistochemical labeling of calcitonin gene-related peptide and substance P was increased in the dorsal horn on the DCP-treated side. Expression of calcium binding proteins, calretinin and calbindin-D28K, normally widely seen in dorsal horn interneurons, was up-regulated on the DCP-treated side. E-Cadherin and alpha-N-catenin, synapse-related molecules, were intensely expressed in the spinal dorsal horn of the DCP-treated side. Interestingly, c-Fos positive cells were also significantly increased in laminae I and III of the DCP-treated side. These results suggest an enhanced release of neuropeptides from peripheral afferents and alterations in the sensorineural circuitry of the dorsal horn. These changes may account for the enhanced sensory sensitivity recognized in patients with chronic eczema and atopic dermatitis.     

Dorsal root entry zone lesions in the treatment of pain following brachial plexus avulsion, spinal cord injury and herpes zoster

This paper details the long-term results in patients treated with dorsal root entry zone (DREZ) lesions for the treatment of pain following brachial plexus avulsion, spinal cord injury, and herpes zoster. With our current operative technique, 82% of patients with brachial plexus avulsion injuries were afforded long-term pain relief. Patients with pain confined to dermatomes just below the level of spinal injury also did well with DREZ lesions, although the results were less good in patients with diffuse pain or with sacral pain. The postoperative results in patients with postherpetic pain were disappointing.     

Functional organization of locomotor interneurons in the ventral lumbar spinal cord of the newborn rat

Although the mammalian locomotor CPG has been localized to the lumbar spinal cord, the functional-anatomical organization of flexor and extensor interneurons has not been characterized. Here, we tested the hypothesis that flexor and extensor interneuronal networks for walking are physically segregated in the lumbar spinal cord. For this purpose, we performed optical recordings and lesion experiments from a horizontally sectioned lumbar spinal cord isolated from neonate rats. This ventral hemi spinal cord preparation produces well-organized fictive locomotion when superfused with 5-HT/NMDA. The dorsal surface of the preparation was visualized using the Ca(2+) indicator fluo-4 AM, while simultaneously monitoring motor output at ventral roots L2 and L5. Using calcium imaging, we provided a general mapping view of the interneurons that maintained a stable phase relationship with motor output. We showed that the dorsal surface of L1 segment contains a higher density of locomotor rhythmic cells than the other segments. Moreover, L1 segment lesioning induced the most important changes in the locomotor activity in comparison with lesions at the T13 or L2 segments. However, no lesions led to selective disruption of either flexor or extensor output. In addition, this study found no evidence of functional parcellation of locomotor interneurons into flexor and extensor pools at the dorsal-ventral midline of the lumbar spinal cord of the rat.     

Regeneration of dorsal column fibers into and beyond the lesion site following adult spinal cord injury.

Regeneration is abortive following adult mammalian CNS injury. We have investigated whether increasing the intrinsic growth state of primary sensory neurons by a conditioning peripheral nerve lesion increases regrowth of their central axons. After dorsal column lesions, all fibers stop at the injury site. Animals with a peripheral axotomy concomitant with the central lesion show axonal growth into the lesion but not into the spinal cord above the lesion. A preconditioning lesion 1 or 2 weeks prior to the dorsal column injury results in growth into the spinal cord above the lesion. In vitro, the growth capacity of DRG neurite is also increased following preconditioning lesions. The intrinsic growth state of injured neurons is, therefore, a key determinant for central regeneration.     

Involuntary movements of the lower extremity following dorsal root entry zone lesions in a man treated for phantom limb pain

A patient developed continuous patterned involuntary movements of abduction-adduction, flexion-extension of his right lower extremity following surgical placement of spinal dorsal root entry zone lesions for the treatment of phantom limb pain. The stereotype movements were monitored by video and electromyographic recording of quadriceps femoris and hamstring muscles. Administration of para-chlorophenylbutyric acid (baclofen) dramatically stopped the involuntary movements and electromyographic silence ensued. Voluntary muscle movements were preserved. The theoretical implications of this unique movement disorder and central patterning of motor activity within the spinal cord are discussed.     

Spontaneous and Experimental Neuritis and the Distribution of the Myelin Protein P2 in the Nervous System

The P2 contents of nervous tissues from the human, rabbit, guinea pig, and Lewis rat were measured by radioimmunoassay. The ventral spinal roots contained more P2 than any other tissue. Human dorsal roots and peripheral nerves contained 41-65% of the amount in human ventral roots. Human olfactory and optic nerves and brain contained 1.1-2.7%, spinal cord, 2.8%, cranial nerve VIII, 11%, and cerebral grey matter, 0%. The relative amounts in the rabbit nervous system were similar except that the spinal cord contained 20% of the amount in the ventral roots. Qualitative estimates in the guinea pig showed that the spinal roots and peripheral nerves contained more P2 than the spinal cord, and that none was present in the brain. In the Lewis rat, P2 could be detected in the spinal roots and peripheral nerves but not in the CNS. The distribution of P2 in the human nervous system parallels the incidence and severity of lesions in acute polyradiculoneuritis. It also explains the absence of any lesions in the CNS when experimental allergic neuritis is induced in the Lewis rat.     

Innervation of the dermatomes in the neck of the mouse

The dorsal rami of the cervical and thoracic spinal nerves were investigated using both the in situ cholinesterase staining technique and cholinesterase staining on serial sections of plastic-embedded embryos. In most cases only the dorsal rami of the 2nd to 5th cervical spinal nerve possess cutaneous branches. The area innervated by the cutaneous branch of the dorsal ramus of the 5th spinal nerve borders on an area innervated by the cutaneous branch of the dorsal ramus of the 1st thoracic spinal nerve. The dorsal rami of the cervical spinal nerves 6-8 show no cutaneous branches. Therefore the gap in the series of the dorsal cutaneous branches is due only to the middle part of the nerves of the brachial plexus, which range from the 5th cervical nerve to the 1st thoracic nerve.     

Experimental deafferentation syndromes

Animal models of dysesthesias have been established, and reveal the following major points. Dysesthesias of peripheral nerve or dorsal root origin have a central neural cause. Chronic dysesthesias of spinal origin have a cause which resides in the brain. The origins of these effects are lesions in the spinothalamic system. The causes of these effects are abnormal functionings among opiate, catecholamine, and purine pathways. Denervation supersensitivity is suggested.     

Three-Dimensional Distribution of Sensory Stimulation-Evoked Neuronal Activity of Spinal Dorsal Horn Neurons Analyzed by In Vivo Calcium Imaging

The spinal dorsal horn comprises heterogeneous populations of interneurons and projection neurons, which form neuronal circuits crucial for processing of primary sensory information. Although electrophysiological analyses have uncovered sensory stimulation-evoked neuronal activity of various spinal dorsal horn neurons, monitoring these activities from large ensembles of neurons is needed to obtain a comprehensive view of the spinal dorsal horn circuitry. In the present study, we established in vivo calcium imaging of multiple spinal dorsal horn neurons by using a two-photon microscope and extracted three-dimensional neuronal activity maps of these neurons in response to cutaneous sensory stimulation. For calcium imaging, a fluorescence resonance energy transfer (FRET)-based calcium indicator protein, Yellow Cameleon, which is insensitive to motion artifacts of living animals was introduced into spinal dorsal horn neurons by in utero electroporation. In vivo calcium imaging following pinch, brush, and heat stimulation suggests that laminar distribution of sensory stimulation-evoked neuronal activity in the spinal dorsal horn largely corresponds to that of primary afferent inputs. In addition, cutaneous pinch stimulation elicited activities of neurons in the spinal cord at least until 2 spinal segments away from the central projection field of primary sensory neurons responsible for the stimulated skin point. These results provide a clue to understand neuronal processing of sensory information in the spinal dorsal horn.     

Peculiarities of spinal hyperreflexia after combined synchronous transection of the sciatic nerve and chordotomy in rats

Parameters of the reflex discharges evoked by spinal dorsal root stimulation were measured in rats with the sciatic nerve and spinal cord (at low thorasic level) transected five days earlier. Monosynaptic discharges in the ventral roots were found to increase after the operation; the degree of increase was significantly higher as compared with that observed after isolated transections of the spinal cord or the nerve. The combined lesion of the nerve and spinal cord could result in the appearance of high-amplitude reflex discharge components, probably of a polysynaptic nature. We concluded, from the comparison of modifications of reflex discharges, that the mechanisms underlying spinal hyperreflexia after nerve or spinal cord lesions differ considerably from each other.Neirofiziologiya/Neurophysiology, Vol. 26, No. 3, pp. 197–202, May–June, 1994.     

The Inhibition of Subchondral Bone Lesions Significantly Reversed the Weight-Bearing Deficit and the Overexpression of CGRP in DRG Neurons,GFAP and Iba-1 in the Spinal Dorsal Horn in the Monosodium Iodoacetate Induced Model of Osteoarthritis Pain

Background

Chronic pain is the most prominent and disabling symptom of osteoarthritis (OA). Clinical data suggest that subchondral bone lesions contribute to the occurrence of joint pain. The present study investigated the effect of the inhibition of subchondral bone lesions on joint pain.

Methods

Osteoarthritic pain was induced by an injection of monosodium iodoacetate (MIA) into the rat knee joint. Zoledronic acid (ZOL), a third generation of bisphosphonate, was used to inhibit subchondral bone lesions. Joint histomorphology was evaluated using X-ray micro computed tomography scanning and hematoxylin-eosin staining. The activity of osteoclast in subchondral bone was evaluated using tartrate-resistant acid phosphatase staining. Joint pain was evaluated using weight-bearing asymmetry, the expression of calcitonin gene-related peptide (CGRP) in the dorsal root ganglion (DRG), and spinal glial activation status using glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule-1 (Iba-1) immunofluorescence. Afferent neurons in the DRGs that innervated the joints were identified using retrograde fluorogold labeling.

Results

MIA injections induced significant histomorphological alterations and joint pain. The inhibition of subchondral bone lesions by ZOL significantly reduced the MIA-induced weight-bearing deficit and overexpression of CGRP in DRG neurons, GFAP and Iba-1 in the spinal dorsal horn at 3 and 6 weeks after MIA injection; however, joint swelling and synovial reaction were unaffected.

Conclusions

The inhibition of subchondral bone lesions alleviated joint pain. Subchondral bone lesions should be a key target in the management of osteoarthritic joint pain.     

Noradrenergic mediation of traumatic spinal cord autodestruction

Acute spinal injury initiates hemorrhagic necrosis (HN), a novel tissue destructive process, within traumatized cord tissues. HN assures permanent paralysis within 24 hours by locally destroying the injured cord. It results from microvascular failure and subsequent lethal tissue hypoxia. Norepinephrine (NE) a normal spinal cord transmitter material rapidly increases (four to tenfold) at the injury site. This vasoactive substance has been implicated in post wounding vascular stasis and permanent spinal paralysis because: 1. Direct spinal NE injections reproduce histological HN. 2. Phenoxybenzamine (alpha receptor blockade) pretreatment significantly diminishes traumatic lesion size. 3. NE synthesis inhibition by alpha methyl tyrosine (acts upon tyrosine hydroxylase), alpha methyl dopa (acts upon L dopa decarboxylase) and FLA-63 (acts upon dopamine beta hydroxylase) all variously protect the wounded cord against HN traumatic lesions. 4. Reserpine (NE depletion) provides significant tissue protection. This drug restores some useful spinal function after severe experimental injuries which consistently paralyze untreated animals.NE bulbospinal fibers are modulated, as determined by tissue lesion size, by two other neural systems. 1. Facilitation occurs from afferent dorsal rootposterior spinal column fibers (non-catecholamine) because prior surgical interruptions significantly diminish traumatic lesions. 2. Inhibition by dopaminergic (DA) fibers was detected by: a. Cord protection with apomorphine DA receptor stimulation. b. Aggravation of traumatic lesions by Pimozide DA receptor blockade. Although these studies are early and incomplete, there is convincing evidence for NE post wounding involvement. As this system is better understood we believe treatments will be developed for spinal injured man.     

Metformin attenuates increase of synaptic number in the rat spinal dorsal horn with painful diabetic neuropathy induced by type 2 diabetes: a stereological study

In our previous study, we have shown that number of synapses in the L5 segment of spinal dorsal horn increased significantly in a rat model of painful diabetic neuropathy (PDN) induced by high-dose of streptozotocin (an animal model of type 1 diabetes). The aims of this study were: (1) to determine whether high fat diet/low dose streptozotocin-diabetes, a rat model for type 2 diabetes, related PDN was also associated with this synaptic plasticity, (2) to reveal the range of this synaptic plasticity change occurred (in the whole length of spinal dorsal horn or only in the L5 lumbar segment of spinal dorsal horn) and (3) to discover whether treatment with metformin had effect on this synaptic plasticity. Male adult Sprague–Dawley rats were randomly allocated into the control group (n?=?7), the PDN group (n?=?6) and the PDN treated with metformin (PDN?+?M) group (n?=?7), respectively. 28 days after medication, synaptic and neuronal numbers in the whole length of spinal dorsal horn or in 1 mm length of the L5 segment of spinal dorsal horn were estimated by the optical disector (a stereological technique). Compared to the control group and the PDN?+?M group, number of synapses in the L5 segment of spinal dorsal horn increased significantly in the PDN group (P?<?0.05). There was no significant change between the control group and the PDN?+?M group in terms of the parameters in the L5 segment of the spinal dorsal horn (P?>?0.05). Parameters of the whole length of spinal dorsal horn showed no significant changes (P?>?0.05). Our results suggest that high fat diet/low dose streptozotocin diabetes related PDN is also associated with a numerical increase of synapses in the L5 segment of spinal dorsal horn but not in the whole length of spinal dorsal horn. Furthermore, the analgesic effect of metformin against PDN is related to its inhibition of numerical increase of synaptic number in the rat spinal dorsal horn.     

福尔马林致痛后大鼠中脑导水管周围灰质甲啡肽及脊髓背角P物质含量的变化

本文用免疫组化方法结合计算机图像处理技术观察大鼠后脚掌皮下注射福尔马林后脊髓背角Ｐ物质免疫阳性反应（ＳＰＬＩ）变化的节段性分布及中脑导水管周围灰质（ＰＡＧ）内甲啡肽样免疫阳性反应（ＭＥＬＩ）的变化。结果显示,注射福尔马林后,脊髓腰段（Ｌ１－２,Ｌ４－５）背角ＳＰＬＩ显著增强（Ｐ＜．０５）,３０ｍｉｎ组与６０ｍｉｎ组相比较无显著变化（Ｐ＞０．０５）;胸脊髓（Ｔ８）无显著变化（Ｐ＞０．０５）;颈脊髓背角ＳＰＬＩ有增强趋势（０．０５＜Ｐ＜０．１）;ＰＡＧ中ＭＥＬＩ减弱,腹外侧部３０ｍｉｎ组比６０ｍｉｎ组变化更大（Ｐ＜０．０５）。ＰＡＧ中ＭＥＬＩ与脊髓背角ＳＰＬＩ变化的时相关系提示福尔马林致痛引起的脊髓背角Ｐ物质的增多可能与ＰＡＧ中甲啡肽及阿片受体活动有关。