On the Role of β-Adrenoreceptors in Mechanisms Underlying Neurogenic Dystrophies

Sciatic nerve damage led to a defective functioning of the renal mineralocorticoid receptors due to the disturbed neurotrophic supply of this organ: the reception of distorted nervous stimuli. The pharmacological blockade of both the neurotransmitter and the humoral pathways of the pathological stimuli from the damaged nerve to the kidney prevented the development of trophic disturbances as tested by the state of the renal mineralocorticoid receptor system. At the same time, the pharmacological stimulation of the sympathetic nervous system leads to an even more defective aldosterone reception by the kidney. Propranolol exerted an antidystrophic effect in the case of local damages of the nervous system and, thereby, prevented the development of neurogenic dystrophies.     

Mechanisms of neurogenic dystrophies induced by activation and deprivation of the sympathetic nervous system

Entry of abnormal nervous stimuli after sciatic nerve transection proved to affect the functioning of renal mineralocorticoid receptors as a result of inadequate neurotrophic support of this organ. Drug blockade of both neural and humoral transmission of the abnormal stimuli from the injured nerve to the kidney prevented development of trophic disorders as indicated by the status of the renal mineralocorticoid receptor system. At the same time, drug stimulation of the sympathetic nervous system further affected aldosterone reception by this organ. -Blocker propranolol was shown to exert an antidystrophic effect in the case of local injuries of the neural system and, thus, prevented the development of neurogenic dystrophies.Translated from Izvestiya Akademii Nauk, Seriya Biologicheskaya, No. 2, 2005, pp. 226–231.Original Russian Text Copyright © 2005 by Akimov, Kositsyn.     

Role of the sympathetic nervous system during reparative regeneration and compensation of heart function in experimental myocardial infarct

Experiments on chemically sympathectomized rats have revealed a double effect of the sympathetic nervous system on compensation and adaptation of heart function and reparative regeneration in myocardial infarction. It has been established that if the sympathetic influences are excluded, the elements of the connective tissue are activated, which leads to myocardial infarction healing at a shorter period of time. At the same time it has been demonstrated that sympathectomy inhibits the development of the compensatory reactions and limits adaptation possibilities of the heart.     

Endopeptidase-24.11, a Cell-Surface Peptidace of Central Nervous System Neurons, Is Expressed by Schwann Cells in the Pig Peripheral Nervous System

Endopeptidase-24.11 is a 90-kDa surface glycoprotein with the ability to hydrolyze a variety of biologically active peptides. Interest in this enzyme is based on the consensus that it may play a role in the termination of peptide signals in the central nervous system. In the present study, we have investigated the distribution of endopeptidase-24.11 in two nerves of the peripheral nervous system of newborn pigs: the sciatic, composed of a mixture of myelinated and nonmyelinated axons, and cervical sympathetic trunk in which greater than 99% of the axons are nonmyelinated. The endopeptidase was monitored enzymatically, as well as by immunoblotting and immunocytochemistry using mono- and polyclonal anti-endopeptidase antibodies. Endopeptidase-24.11 was detected in both the sciatic nerve and the cervical sympathetic trunk. Membrane preparations from sciatic nerve hydrolyzed 125I-insulin B-chain, and more than 50% of the activity was inhibited by phosphoramidon with an IC50 concentration of 3.2 nM. Moreover, a 90-kDa polypeptide was detected by immunoblotting of sciatic nerve membranes. The type of cells expressing the endopeptidase was determined by immunohistochemistry. In teased nerve preparations, these cells were identified morphologically as myelin- and non-myelin-forming Schwann cells. Endopeptidase-24.11 was also expressed by cultured Schwann cells from sciatic nerve and cervical sympathetic trunk maintained for 3 h in vitro. The presence of endopeptidase-24.11 on the Schwann cell surface raises the possibility of a potential role for the enzyme in nerve development and/or regeneration.     

Sodium reabsorption and the aldosterone receptors in the cells of the kidney tubules in a dynamic disorder of the trophic function of the nervous system]

The results are presented of investigations on determining the functional state of mineralocorticoid receptor apparatus in rat kidney at diverse stages of the reflex renal dystrophy per se and that against the background of renal denervation along with propranolol injections produced at different terms following the disturbance of nervous system trophic function. It was shown that simultaneous blockade of neuroconductory and humoral pathways of pathological stimulus transmission from central end of cut ischiatic nerve to the kidney prevents the development of trophic disturbances in the organ as tested by the state of mineralocorticoid receptors, to a more extent than the blockade of neuroconductory pathway only. The activity of molecular structures which determine the mineralocorticoid reception in cells of renal tubules seems to be controlled both by central neuroconductory and humoral mechanisms.     

Abnormal impulse discharge in primary afferent axons injured in the peripheral versus the central nervous system

Chronic injury to sensory axons in the rat peripheral nerve induces pathophysiologic changes in the axolemma at the cut nerve end, which are reflected in spontaneous ectopic impulse discharge and hyperexcitability to a range of depolarizing stimuli. We asked whether sensory axons injured in the central nervous system (CNS) also respond in this way. Primary afferent axons were severed in the sciatic nerve and, alternatively, in the midcervical or upper lumbar dorsal column (DC). Measurements of abnormal discharge from myelinated afferents showed high levels of spontaneous activity generated at the nerve injury site, especially during the period 3-16 days postoperatively, but comparatively little activity generated at the DC lesion site at any postoperative time. There was a corresponding difference in ectopic hyperexcitability to mechanical and adrenergic stimulation, and to depolarization with topical K+. DC lesion sites were not made more excitable by concurrent transection of the sciatic nerve, or by placing an autologous graft of excised sciatic nerve tissue into the DC defect at the time of initial surgery. Transection sites on dorsal roots L4 and L5 yielded abnormal discharge similar to that of sciatic nerve neuromas, indicating that the relative silence of DC transection sites was related to the CNS environment and not to position with respect to the sensory cell body.     

Genetic evidence for an essential role of neuronally expressed IL-6 signal transducer gp130 in the induction and maintenance of experimentally induced mechanical hypersensitivity in vivo and in vitro

Background

A preconditioning stimulus can trigger a neuroprotective phenotype in the nervous system - a preconditioning nerve lesion causes a significant increase in axonal regeneration, and cerebral preconditioning protects against subsequent ischemia. We hypothesized that a preconditioning nerve lesion induces gene/protein modifications, neuronal changes, and immune activation that may affect pain sensation following subsequent nerve injury. We examined whether a preconditioning lesion affects neuropathic pain and neuroinflammation after peripheral nerve injury.

Results

We found that a preconditioning crush injury to a terminal branch of the sciatic nerve seven days before partial ligation of the sciatic nerve (PSNL; a model of neuropathic pain) induced a significant attenuation of pain hypersensitivity, particularly mechanical allodynia. A preconditioning lesion of the tibial nerve induced a long-term significant increase in paw-withdrawal threshold to mechanical stimuli and paw-withdrawal latency to thermal stimuli, after PSNL. A preconditioning lesion of the common peroneal induced a smaller but significant short-term increase in paw-withdrawal threshold to mechanical stimuli, after PSNL. There was no difference between preconditioned and unconditioned animals in neuronal damage and macrophage and T-cell infiltration into the dorsal root ganglia (DRGs) or in astrocyte and microglia activation in the spinal dorsal and ventral horns.

Conclusions

These results suggest that prior exposure to a mild nerve lesion protects against adverse effects of subsequent neuropathic injury, and that this conditioning-induced inhibition of pain hypersensitivity is not dependent on neuroinflammation in DRGs and spinal cord. Identifying the underlying mechanisms may have important implications for the understanding of neuropathic pain due to nerve injury.     

Neural control of the kidney: functionally specific renal sympathetic nerve fibers

The sympathetic nervous system provides differentiated regulation of the functions of various organs. This differentiated regulation occurs via mechanisms that operate at multiple sites within the classic reflex arc: peripherally at the level of afferent input stimuli to various reflex pathways, centrally at the level of interconnections between various central neuron pools, and peripherally at the level of efferent fibers targeted to various effectors within the organ. In the kidney, increased renal sympathetic nerve activity regulates the functions of the intrarenal effectors: the tubules, the blood vessels, and the juxtaglomerular granular cells. This enables a physiologically appropriate coordination between the circulatory, filtration, reabsorptive, excretory, and renin secretory contributions to overall renal function. Anatomically, each of these effectors has a dual pattern of innervation consisting of a specific and selective innervation by unmyelinated slowly conducting C-type renal sympathetic nerve fibers in addition to an innervation that is shared among all the effectors. This arrangement permits the maximum flexibility in the coordination of physiologically appropriate responses of the tubules, the blood vessels, and the juxtaglomerular granular cells to a variety of homeostatic requirements.     

NGF receptor-mediated reduction in axonal NGF uptake and retrograde transport following sciatic nerve injury and during regeneration.

Injury to the rat sciatic nerve leads to the induction of nerve growth factor (NGF) receptors on the denervated Schwann cells and their disappearance on the regenerating axons of the axotomized, normally NGF-sensitive sensory and sympathetic neurons. This disappearance in the axonal expression and retrograde transport of NGF receptors is associated with a similarly dramatic reduction in the axonal uptake and retrograde transport of NGF following axotomy and during regeneration. In view of the massive NGF synthesis occurring in the injured nerve, these results suggest that, while sensory and sympathetic neurons are the primary targets of NGF in the normal peripheral nervous system, the denervated Schwann cells may become its primary target in the aftermath of nerve injury.     

DISTRIBUTION AND TURNOVER OF OCTOPAMINE IN TISSUES

Abstract— Octopamine is a normally occurring amine in several species of animals. Particularly high concentrations are found in the crustacean central nerve cord. In the rat it is specifically localized to sympathetic nerve endings, has a subcellular distribution similar to that of norepinephrine, and is asymmetrically distributed in the CNS. It has a turnover rate in heart about six times that of norepinephrine. The physiological role of octopamine has not been established but it appears likely that it is a cotransmitter together with norepinephrine in the peripheral sympathetic nervous system.     

A search for the factors responsible for absence of recovery of the normal vascular response to oxytocin following sympathetic nerve injury.

In dogs following crush injury to the lumbar sympathetic trunk, reflex vasoconstriction reappears in 4-6 months but the normal vasodilator response to oxytocin does not return even 12 months after crush. Histochemical examination of the walls of the blood vessels shows that division or crush of the lumbar sympathetic trunk or removal of terminal ganglia leads to decentralization, not denervation of the blood vessels. True denervation follows division or crush of the sciatic and femoral nerves. Following recovery from sciatic or femoral crush the pattern of peripheral innervation appears histochemically normal. However, there is no return of the normal vasodilator response to oxytocin. It is concluded that a normal response to oxytocin does not return even after long-term recovery from sympathetic injury, nor does its effect depend on a normal pattern of peripheral adrenergic innervation, but on an unknown more central activity of the sympathetic nervous system.     

Assessment of Autonomic Function in Patients with a Parkinsonian Syndrome

The integrity of the autonomic nervous system was assessed in 11 Parkinsonian patients with symptoms suggestive of autonomic dysfunction. Three had the additional clinical features of the Shy-Drager variant of idiopathic orthostatic hypotension and were found to have a gross disturbance of vasomotor, sudomotor, pilomotor, and bladder function; assessment indicated that a lesion was present at sympathetic ganglionic level or beyond in two cases, though a more centrally placed lesion may well have been present also, as in the third case. In the remaining eight patients with paralysis agitans no unequivocal functional disturbance was found except in the bladder; nevertheless, the low resting blood pressure and the supersensitivity to intravenously infused L-noradrenaline in the three patients in whom it was tested is taken to imply defective regulation from higher centres, with a consequent reduction in impulse traffic at sympathetic nerve terminals. Such a concept is supported by experimental studies in animals and would account for the low renin and aldosterone secretion rates and reduced noradrenaline formation reported by others in patients with paralysis agitans.     

Renal nerves and hypertension: an update

Increased efferent renal sympathetic nerve activity could facilitate the development of hypertension by shifting the arterial pressure-renal sodium excretion curve to the right. Accordingly, interruption of the renal nerves should prevent the development of hypertension in animal models in which increased sympathetic nervous system activity has been implicated. Renal denervation delays the development of hypertension and results in greater sodium excretion in the Okamoto and New Zealand spontaneously hypertensive rat and in the deoxycorticosterone acetate-salt-treated rat, which suggests that these responses result from, at least in part, loss of efferent renal nerve activity. Similar sympathetically mediated renal vasoconstriction has been implicated in the pathogenesis of early essential hypertension in humans. The efferent renal sympathetic nerves play a diminishing role once hypertension is established in these models. Renal denervation in established one-kidney, one-clip and two-kidney, one-clip Goldblatt hypertension in the rat and chronic coarctation in the dog results in an attenuation of the hypertension. The depressor effect of renal denervation in these models is not caused by changes in renin activity or sodium excretion but is associated with decreased sympathoadrenal activity. These findings suggest that the afferent renal nerves contribute to the pathogenesis of renovascular hypertension by enhancing the activity of the sympathetic nervous system. Interruption of afferent renal fibers also appears to be the mechanism by which renal denervation prevents or reverses the normal increase in arterial pressure seen after aortic baroreceptor deafferentation in the rat.     

Spatiotemporal Expression of PSD-95 and nNOS After Rat Sciatic Nerve Injury

Neuronal nitric oxide synthase (nNOS) has been implicated to influence peripheral nerve lesion and regeneration. Post-synaptic density-95 (PSD-95) is one of nNOS-anchoring proteins and plays an important role in specifying the sites of reaction of NO in nervous system. Here we established a rat sciatic nerve crush (SNC) model to examine the spatiotemporal expression of PSD-95 and nNOS. At gene levels, PSD-95 mRNA diminished shortly after crush, and significantly elevated from 2 days to 2 weeks, whereas nNOS decreased progressively post-operation, reached the valley at 1 day, and markedly up-regulated from 1 to 2 weeks after SNC. The expression of both molecules returned to the control level at 4 weeks post-injury. At protein levels, PSD-95 and nNOS underwent the similar changes as their gene expression except for a time lag during up-regulating. At their peak expression, PSD-95 co-labeled with nNOS in Schwann cells (SCs) of sciatic nerve within 0.5 mm from the lesion site, but had few colocalization in axons. In addition, the interaction between PSD-95 and nNOS enhanced significantly at 2 weeks after SNC. These results suggest a correlation of PSD-95 up-regulation with nNOS in reactive SCs of crushed sciatic nerve, which may lead to understanding the function of PSD-95 during peripheral nerve regeneration. Shangfeng Gao and Min Fei contributed equally to this work.     

PK (‘peripheral benzodiazepine’) – binding sites in the CNS indicate early and discrete brain lesions: microautoradiographic detection of [3H]PK 11195 binding to activated microglia

The isoquinoline PK 11195 has been suggested as a marker of glial pathology in the lesioned brain. The aim of the present study is to clarify the precise cellular location of its binding site in the central nervous system. Here, we report that in the facial nucleus after facial nerve axotomy–a lesion causing a retrograde neuronal reaction without nerve cell death while keeping the blood–brain barrier intact–activated microglia are the predominant source of lesion-induced increases of PK 11195 binding. Likewise, increased PK 11195 binding is seen in the gracile nucleus after anterograde neuronal injury following sciatic nerve transection. The peak of PK 11195 binding, using the single isomer R-PK 11195, was observed 4 days after the peripheral nerve lesion, consistent with the well-known time course of microglial activation. Photoemulsion microautoradiography confirmed the restriction of PK 11195 binding to activated microglia. The increase of PK 11195 binding in the facial nucleus seen after selective cell death of facial motoneurons by retrograde suicide transport of toxic ricin, a lesion that is accompanied by the rapid transformation of microglia into phagocytes, was no higher than that seen following axotomy. This suggests that the full transformation of microglia into parenchymal phagocytes is not necessary to reach maximal levels of PK 11195 binding. PK 11195, therefore, is a well-suited marker to detect microglial activation in areas of subtle brain pathology, where neither a disturbance of the blood–brain barrier function nor the presence of macrophages and inflammatory cells indicate an on-going disease process.     

Effect of Treadmill Exercise on Serotonin Immunoreactivity in Medullary Raphe Nuclei and Spinal Cord Following Sciatic Nerve Transection in Rats

The serotoninergic system modulates nociceptive and locomotor spinal cord circuits. Exercise improves motor function and changes dopaminergic, noradrenergic, and serotonergic central systems. However, the direct relationship between serotonin, peripheral nerve lesion and aerobic treadmill exercise has not been studied. Using immunohistochemistry and optic densitometry, this study showed that the sciatic nerve transection increased the serotoninergic immunoreactivity in neuronal cytoplasm of the magnus raphe nuclei of trained and sedentary rats. In the dorsal raphe nucleus the increase only occurred in sedentary-sham-operated rats. In the spinal cord of trained, transected rats, the ventral horn showed significant changes, while the change in dorsal horn was insignificant. Von Frey’s test indicated analgesia in all exercise-trained rats. The sciatic nerve functional index indicated recovery in the trained group. Thus, both the aerobic treadmill exercise training and the nervous lesion appear to contribute to changes in serotonin immunoreactivity.     

Effect of β Adrenoreceptor Blocker Propranolol during Reflex Renal Dystrophy Induced by Sciatic Nerve Cutting

We present the data on the functional status of the mineralocorticoid receptor system in the rat kidney in the course of renal reflex dystrophy induced by sciatic nerve cutting against the background of both renal denervation and injections of propranolol, a -adrenoreceptor blocker. According to the state of renal mineralocorticoid receptors, the simultaneous block of both neural and humoral pathological stimuli coming to the kidney after the nerve injury prevented cytochemical changes in the organ more effectively than the block of neural transmission alone. We propose that both the central neural transmission and humoral mechanisms control the activity of the molecular structures responsible for aldosterone reception in the cells of renal tubules.     

Renal reflexes in the regulation of blood pressure and sodium excretion

The rich innervation of the kidney is distributed to all structures of renal parenchyma thus providing important anatomical support to the functional evidence that the renal nerves can control kidney functions and send signals on the kidney environment to the central nervous system. Efferent renal nerve fibres are known to influence renal haemodynamics by modifying arteriolar vascular tone, renin release by a direct action on juxtaglomerular cells, and the excretion of sodium and water by changing tubular reabsorption of sodium and water at the different tubular levels. Mechano- and chemo-receptors have been shown in the kidney. Afferent fibres connected with renal receptors convey signals to the central nervous system both at spinal and supraspinal levels. The central areas receiving inputs from the kidney are those involved in the control of cardiovascular homeostasis and fluid balance. Activation of renal receptors by the electrical stimulation of renal afferent fibres were found to elicit both excitatory and inhibitory sympathetic responses. Although the existence of excitatory renorenal reflexes has been suggested, electrophysiological and functional data demonstrate that neural renorenal reflexes exert a tonic inhibitory influence on the tubular sodium and water reabsorption and on the secretion of renin from the juxtaglomerular cells.     

Role of renal sympathetic nerve activity in hypertension induced by chronic nitric oxide inhibition

Nitric oxide levels are diminished in hypertensive patients, suggesting nitric oxide might have an important role to play in the development of hypertension. Chronic blockade of nitric oxide leads to hypertension that is sustained throughout the period of the blockade in baroreceptor-intact animals. It has been suggested that the sympathetic nervous system is involved in the chronic increase in blood pressure; however, the evidence is inconclusive. We measured renal sympathetic nerve activity and blood pressure via telemetry in rabbits over 7 days of nitric oxide blockade. Nitric oxide blockade via N(omega)-nitro-L-arginine methyl ester (L-NAME) in the drinking water (50 mg x kg(-1) x day(-1)) for 7 days caused a significant increase in arterial pressure (7 +/- 1 mmHg above control levels; P < 0.05). While the increase in blood pressure was associated with a decrease in heart rate (from 233 +/- 6 beats/min before the L-NAME to 202 +/- 6 beats/min on day 7), there was no change in renal sympathetic nerve activity (94 +/- 4 %baseline levels on day 2 and 96 +/- 5 %baseline levels on day 7 of L-NAME; baseline nerve activity levels were normalized to the maximum 2 s of nerve activity evoked by nasopharyngeal stimulation). The lack of change in renal sympathetic nerve activity during the L-NAME-induced hypertension indicates that the renal nerves do not mediate the increase in blood pressure in conscious rabbits.