Release Of Vasoactive Neuropeptides Research Articles

Monocular transcorneal electrical stimulation induces ciliary muscle thickening in contralateral eye

Transcorneal electrical stimulation (TES) is used as therapy for retinal diseases such as retinitis pigmentosa (RP) and was suggested for assessing retinal sensitivity by determining phosphene thresholds, subjective luminance impressions caused by retinal stimulation. Further applications concerned the accommodation process, revealing an improved accommodative amplitude in presbyopic eyes after TES treatment. The respective changes of the ciliary muscle (CM), the structure most important for near vision, during TES are yet unknown. In a pilot study, we aimed to assess whether monocular TES leads to morphological and functional CM changes and whether central accommodation control is affected. Ten healthy, near-emmetropic adults participated in the trial (4 females, age 26.3 ± 3.6 years). Using a wavefront and a stimulus generator, a biphasic square-wave stimulus (2 s positive and 6 s negative amplitude) of 0 μA average current was produced and transferred to the eye by means of a Dawson-Trick & Litzkow electrode. Prior to the stimulation, an individual determination of phosphene thresholds served to define individual TES current amplitudes, which ranged between 60 and 100 μA. Optical coherence tomography (OCT) imaging of the right eye's temporal ciliary muscle was performed before and during ipsi- as well as contralateral monocular TES in randomized order in the morning and afternoon of the same day. During imaging, subjects fixated a target at 4 m distance and refraction was simultaneously recorded via eccentric infrared photorefraction. OCT images were assessed using previously published custom-developed software, allowing the definition of selective CM thickness (CMT) readings, and plotting of continuous CMT profiles along the muscle border. CMT profiles revealed that both stimulations, on the ipsi- and contralateral eye, induced a thickening of the CM compared to the non-stimulated state. The selective CMT readings confirmed a significant increase with ipsi- (31 ± 30 μm; p = 0.010) and contralateral (25 ± 16 μm; p = 0.001) TES. However, refraction during far vision was not significantly affected by either stimulation (ipsilateral [n = 5]: median Δw/-w/o = 0 D; contralateral [n = 7]: Δw/-w/o = 0.13 D). Pupil size on average increased during TES, but without reaching significance (ipsilateral [n = 5] median Δw/-w/o = 0.23 mm, contralateral [n = 7] Δw/-w/o = 0.39 mm). Ipsilateral CM thickening could be explained by local changes within the stimulated ciliary muscle, such as increased blood flow or interstitial fluid rise induced by TES. However, the CMT increase in the right eye when TES was performed contralaterally, on the left eye, indicates an involvement of the central control circuit of accommodation. Further possible explanations for this finding are a synchronization of neuronal activities in the visual pathway, the release of vasoactive neuropeptides, or effects on the central blood pressure regulation. Given a neuromodulation effect on the CM function, TES might have implications for children with accommodation insufficiencies and as additional therapy in myopia control management, e.g. in combination with multifocal contact lens treatment. Our study is important for the clinical application of TES, and the outcome might add crucial knowledge to the current understanding of the accommodation process and inform research and treatment of both myopia and presbyopia.

Vessel-wall MRI in primary headaches: The role of neurogenic inflammation.

The purpose of this study was to investigate if vessel-wall magnetic resonance imaging (VW-MRI) could differentiate among primary headaches disorders, such as migraine and cluster headache (CH), and detect the presence of neurogenic inflammation. The pathophysiology of primary headaches disorders is complex and not completely clarified. The activation of nociceptive trigeminal afferents through the release of vasoactive neuropeptides, termed "neurogenic inflammation," has been hypothesized. VW-MRI can identify vessel wall changes, reflecting the inflammatory remodeling of the vessel walls despite different etiologies. In this case series, we enrolled seven patients with migraine and eight patients with CH. They underwent a VW-MRI study before and after the intravenous administration of contrast medium, during and outside a migraine attack or cluster period. Two expert neuroradiologists analyzed the magnetic resonance imaging (MRI) studies to identify the presence of vessel wall enhancement or other vascular abnormalities. Fourteen out of 15 patients had no enhancement. One out of 15, with migraine, showed a focal parietal enhancement in the intracranial portion of a vertebral artery, unmodified during and outside the attack, thus attributable to atherosclerosis. No contrast enhancement attributable to neurogenic inflammation was observed in VW-MRI, both during and outside the attack/cluster in all patients. Moreover, MRI angiography registered slight diffuse vasoconstriction in one of seven patients with migraine during the attack and in one of eight patients with cluster headache during the cluster period; both patients had taken triptans as symptomatic therapy for pain. These preliminary results suggest that VW-MRI studies are negative in patients with primary headache disorders even during migraine attacks or cluster periods. The VW-MRI studies did not detect signs of neurogenic inflammation in the intracranial intradural vessels of patients with migraine or CH.

What does the pathophysiology of migraine tell us about treatment?

Migraine is a primary brain disorder resulting from altered modulation of normal sensory stimuli. It was previously believed that the migraine aura is caused by cerebral vasoconstriction and that the headache is associated with cerebral or meningeal reactive vasodilation [1]. It is now believed that the migraine aura is due to cortical spreading depression, not vasoconstriction; ischemia rarely occurs, if it does at all. Headache starts when cerebral blood flow is reduced, but not to ischemic levels and it is not due to reflex vasodilation [2,3]. Woods and coauthors reported on a PET study of a patient with migraine that showed propagated hypoperfusion during the pain phase of a migraine attack [4]; Denuelle et al. investigated migraine patients using PET and also found cortical hypoperfusion during the pain phase of migraine [5]. The aura is triggered in the hyperexcitable cortex. The fortification spectrum of the visual aura corresponds to an event moving across the cortex at 2–3 mm/min, similar to cortical spreading depression. Cortical spreading depression, originally described by Leao [6], is an intense depolarization of neuronal and glial membranes accompanied by a massive dis ruption of ionic gradients and loss of membrane resistance. Headache and its associated neurovascular changes are subserved by the trigeminal vascular system [7]. Headache probably results from activation of meningeal and blood vessel nociceptors combined with a change in central pain modulation. Trigeminal sensory neurons contain the neuropeptides substance P, cal citonin gene-related peptide and neurokinin A, as well as glutamate [8]. Trigeminal nerve activation is accompanied by the release of vasoactive neuropeptides from the nerve terminals. These mediators produce mast cell activation, sensitization of the nerve terminals, extravasation of fluid into the perivascular space (plasma protein extra­ vasation) around the dural blood vessels and Stephen D Silberstein* Editorial

Vasorelaxation to capsaicin and its effects on calcium influx in arteries

Capsaicin, an activator of the transient potential vanilloid receptor type 1 (TRPV1), is a commonly used pharmacological tool for desensitising sensory nerves. Capsaicin can induce vasorelaxation of isolated blood vessels by activating perivascular TRPV1 receptors, causing the release of vasoactive neuropeptides. This study attempted to characterise the vascular effects of capsaicin in the rat isolated aorta and porcine coronary arteries. Capsaicin elicited concentration-dependent vasorelaxation of both rat aortae and porcine coronary arteries. Capsaicin-induced vasorelaxation of rat aorta was unaffected by a chronic pre-treatment of vessels with capsaicin. Moreover, relaxation was insensitive to the presence of capsazepine, a competitive TRPV1 antagonist, in both the rat aorta and porcine coronary artery. It was hypothesised that capsaicin may be inhibiting calcium influx into smooth muscle cells. Indeed, in vessels incubated in a Ca2+-free high-k+ buffer, the presence of 30μM capsaicin significantly inhibited the contractile response to the re-introduction of Ca2+. In porcine coronary arteries 100μM capsaicin completely abolished the contractile response to the re-introduction of Ca2+. In addition, capsaicin also abolished the concentration-dependent contraction of porcine coronary arteries induced by the L-type calcium activator Bay-K 8644. Therefore, we suggest that capsaicin causes vascular responses in arteries through the inhibition of L-type Ca2+ channels. In summary, we have identified a potential mechanism underlying TRPV1-independent capsaicin-induced vasorelaxation. Our results also question the use of chronic capsaicin pre-treatment in experimental pharmacology in order to elucidate the role of sensory nerves in vascular responses.

Acid-induced CGRP release from the stomach does not depend on TRPV1 or ASIC3

Acid-sensing and regulating reactions are vitally important in the upper gastrointestinal tract and disturbances are common. Sensory neurons in the mucosa detect the intrusion of hydrogen ions and, by their release of vasoactive neuropeptides, seem to play a predominantly protective role in these tissues. The model to investigate sensory transduction of proton stimuli in the isolated everted mouse stomach was to measure the induced calcitonin gene-related peptide (CGRP) release as an index of neuronal activation. Proton concentrations in the range of pH 2.5-0.5 stimulated the release of CGRP and substance P and profoundly decreased the prostaglandin E2 formation in outbred CD mice. A similar linearly pH-dependent CGRP release was observed in inbred C57BL/6 mice, fully dependent on extracellular calcium at pH 2, partially at pH 1. Both transient receptor potential vanilloid type 1 (TRPV1) and acid-sensing ion channel type 3 (ASIC3) are expressed in the sensory neurons innervating the stomach walls and are responsible for the transduction of acidic stimuli in other visceral organs. However, the proton-induced gastric CGRP release in mice lacking the TRPV1 or the ASIC3 receptor-channels was the same as in corresponding wild-type mice. Nonetheless, the pharmacological blockers N-(4-tertiarybutylphenyl)-4-(3-chlorophyridin-2-yl)tetrahydropyrazine-1(2H)carboxamide and amiloride, respectively, inhibited the acid-stimulated CGRP release, although to the same extend in wild types as TRPV1 and ASIC3 knockout mice. Adequate proton concentrations inhibit prostaglandin and stimulate CGRP release from the stomach wall, however, the transduction mechanism in the gastric sensory neurons remains unclear.

SCN9A Mutations Define Primary Erythermalgia as a Neuropathic Disorder of Voltage Gated Sodium Channels

Primary erythermalgia is a rare disorder characterized by recurrent attacks of red, warm and painful hands, and/or feet. We previously localized the gene for primary erythermalgia to a 7.94 cM region on chromosome 2q. Recently, Yang et al identified two missense mutations of the sodium channel alpha subunit SCN9A in patients with erythermalgia. The presence of voltage-gated sodium channels in sensory neurons is thought to play a crucial role in several chronic painful neuropathies. We examined four different families and two sporadic cases and detected missense sequence variants in SCN9A to be present in primary erythermalgia patients. A total of five of six mutations were located in highly conserved regions. One family with autosomal dominantly inherited erythermalgia was double heterozygous for two separate SCN9A mutations. These data establish primary erythermalgia as a neuropathic disorder and offers hope for treatment of this incapacitating painful disorder.

Wounds increase activin in skin and a vasoactive neuropeptide in sensory ganglia

Successful healing of skin wounds requires sensory innervation and the release of vasoactive neuropeptides that dilate blood vessels and deliver serum proteins to the wound, and that cause pain that protects from further injury. Activin has been proposed as a target-derived regulator of sensory neuropeptides during development, but its role in the mature nervous system is unknown. While adult skin contains a low level of activin, protein levels in skin adjacent to a wound increase rapidly after an excision. Neurons containing the neuropeptide calcitonin gene-related peptide (CGRP) increased in sensory ganglia that projected to the wounded skin, but not in ganglia that projected to unwounded skin, suggesting that neurons respond to a local skin signal. Indeed, many adult sensory neurons respond with increased CGRP expression to the application of activin in vitro and utilize a smad-mediated signal transduction pathway in this response. A second skin-derived factor nerve growth factor (NGF) also increased in wounded skin and increased CGRP in cultured adult dorsal root ganglia (DRG) neurons but with lower efficacy. Together, these data support the hypothesis that activin made by skin cells regulates changes in sensory neuropeptides following skin injury, thereby promoting vasodilation and wound healing.

The pathophysiology of migraine.

Migraine results from episodic changes in central nervous system physiologic function in hyperexcitable brain manifested by abnormal energy metabolism, lowered threshold for phosphene generation, and increased contingent negative variation. Human functional magnetic resonance imaging and magnetoencepholography data strongly suggest that aura is caused by cortical spreading depression. Brain hyperexcitability may be caused by low magnesium levels, mitochondrial abnormalities with abnormal phosphorylation of adenosine 5'-diphosphate, a dysfunction related to nitric oxide, or calcium channelopathy. Low magnesium can result in opening of calcium channels, increased intracellular calcium, glutamate release, and increased extracellular potassium, which may in turn trigger cortical spreading depression. Mitochondrial dysfunction has been suggested by a low phosphocreatine:Pi ratio and a possible response by migraine patients to riboflavin prophylaxis. Nitroglycerine administration results in a delayed migraine-like headache in migraine patients but not in control patients, and a nonspecific nitric oxide synthase inhibitor aborted migraine at 2 hours in the majority of tested migraine patients compared to controls. Many patients with familial hemiplegic migraine have a missense mutation in the P/Q calcium channel, so that this form of migraine, at least, is associated with a demonstrable calcium channelopathy. The generation of migraine occurs centrally in the brain stem, sometimes preceded by cortical spreading depression and aura. Activation of the trigeminovascular system stimulates perivascular trigeminal sensory afferent nerves with release of vasoactive neuropeptides, resulting in vasodilation and transduction of central nociceptive information. There is then a relay of pain impulses to central second- and third-order neurons and activation of brain stem autonomic nuclei to induce associated symptoms.

Reflex sympathetic dystrophy: The clinician's perspective

Theories on the etiology of reflex sympathetic dystrophy (RSD) are reviewed and presented in three categories: peripheral, spinal, and supraspinal. The peripheral pathophysiology involves a prolonged inflammatory response to injury due to the axon reflex with release of vasoactive neuropeptides and sensitized nociceptors. The spinal component of RSD genesis involves nociceptive spinal cord neurons with lowered thresholds due to chronic pain input. These sensitized spinal neurons respond in turn by signaling pain reflexes through the sympathetic system. A physical-emotional diathesis may predispose individuals to respond to stress through autonomic arousal. Autonomic arousal, coupled with injury, signals the supraspinal influence on this syndrome. Since the puzzle of RSD remains to be solved, measurement and treatment strategies are suggested to provide intervention at each level. Measurement techniques should include a battery of static tests and stress tests. Static tests are used to quantify a physiological parameter at one point in time. Stress tests access physiological response to various neuro-vaso-motor challenges. A “hands off” treatment regime is presented that includes pain control, methods to reset sensory thresholds, vasomotor challenges, and an active motion program.

Clinical presentation and treatment of migraine

The pathogenesis of migraine is not completely understood but may involve vasodilation of cerebral blood vessels and/or the release of vasoactive neuropeptides (ie, norepinephrine) from the perivascular axons in the dura mater after activation of the trigeminovascular system. Many environmental factors and physiologic influences may provoke a migraine or increase its severity. The typical migraine headache without aura is unilateral, pulsating, of moderate-to-severe intensity, and aggravated by physical activity. Migraine prevention is best achieved by avoidance of known migraine triggers or enhancers and by reducing the amount of lifestyle stressors. Pharmacotherapeutic options in the treatment of migraine are discussed herein.

Changes in plasma concentrations of vasoactive neuropeptides in patients with sepsis and septic shock

The aim of this work was to study the hypothesis that the release of vasoactive neuropeptides may be related to the hemodynamic changes and severity of disease in human sepsis and septic shock. Twenty-two patients diagnosed with sepsis and treated in medical wards with standard supportive therapy and twenty patients admitted to a medical intensive care unit because of septic shock were studied Twenty healthy volunteers in a similar age range were enrolled as control group. Blood samples were taken at onset and every 12 hours on the following day after hospital admission to measure plasma concentrations of calcitonin gene-related peptide (CGRP), neuropeptide Y (NPY) and substance P (SP). Clinical and biochemical variables were measured simultaneously. The Acute Physiology and Chronic Health Evaluation (APACHE) II score was calculated on admission. From the day of admission, septic shock patients had significantly higher plasma CGRP-like immunoreactivity levels than patients with sepsis, as well as both groups of patients compared to control subjects. Plasma NPY-like immunoreactivity levels in patients with either sepsis or septic shock was significantly increased, and plasma SP-like immunoreactivity levels significantly reduced compared to those in controls. Plasma CGRP levels at study entry correlated with the APACHE II score ( r=0.71, p<0.01) , as well as with the cardiac index ( r=0.61, p<0.05) and systemic vascular resistance index ( r=−0.62, p<0.05) . Our data suggest that both CGRP and NPY, but not SP, are increasedly released into the circulation during the development of human sepsis and septic shock. In patients with sepsis the vasoconstriction mediated by the release of NPY appears to counterbalance the vasodilatory effect of CGRP. In septic shock patients, however, the release of NPY might be inadequately low to overcome the widespread CGRP-induced vasodilation.

The role of neuroeffector mechanisms in cerebral hyperperfusion syndromes

Cerebral hyperperfusion, a state in which blood flow exceeds the metabolic needs of brain, may complicate a number of neurological and neurosurgical conditions. It may account for the propensity with which hemorrhage, cerebral edema, or seizures follow embolic stroke, carotid endarterectomy, or the excision of large arteriovenous malformations, and for some of the morbidity that accompanies acute severe head injury, prolonged seizures, and acute severe hypertension. Hyperperfusion syndromes have in common acute increases in blood pressure, vasodilatation, breakdown of the blood-brain barrier, and the development of cerebral edema. These common features suggest the possibility that they share the same pathogenic mechanisms. It was believed until recently that reactive hyperemia was caused primarily by the generation of vasoactive metabolites, which induced vasodilatation through relaxation of vascular smooth muscle. However, the authors have recently established that the release of vasoactive neuropeptides from perivascular sensory nerves via axon reflex-like mechanisms has a significant bearing upon a number of hyperperfusion syndromes. In this article, the authors summarize their data and discuss possible therapeutic implications for blockade of these nerves or their constituent neuropeptides.

Neurogenic inflammation in the airways. I. Neurogenic stimulation induces plasma protein extravasation into the rat airway lumen.

Activation of sensory nerves in rodent airways results in microvascular permeability and edema formation, presumably due to release of vasoactive neuropeptides from the nerve endings. We examined the possibility that neurogenic stimulation may also induce movement of plasma proteins into the airway lumen. Neurogenic plasma protein extravasation (PPE) was induced in Sprague-Dawley rats by electrical stimulation of both vagal nerves (EVS) at 10 V, 5 ms, 20 Hz. After 90 s of EVS, histologic examination showed Monastral blue B, a macromolecular tracer, extravasated within the endothelium of vessels in the subepithelial layer of the tracheobronchial mucosa. In animals given 125I-labeled albumin intravenously, PPE was quantitated as microliters of plasma deposited into the airways, lung, and tracheobronchial (TB) and bronchoalveolar (BA) lavages. One minute of EVS induced an immediate increase in PPE in the tracheal (+117%) and bronchial wall (+125%) but not in the peripheral lung. There was a concomitant increase in the 125I-labeled albumin recovered from both TB fluid (net increase, 1.29 microliter of plasma = +259%) and BA fluid (net increase, 2.79 microliters of plasma = +107%). In addition, both total protein and endogenous albumin concentrations in TB fluid also increased after EVS. The albumin/total protein ratio (the albumin percentage) in TB lavages was also significantly increased (1.4 x, 1.7 x, and 2.5 x in three separate experiments, respectively), indicating the vascular origin of the increased luminal proteins. Neither cholinergic (atropine) nor adrenergic blockade (phentolamine + propranolol) influenced EVS-induced PPE into the airway walls or movement of radiolabeled albumin into the airway lumen.(ABSTRACT TRUNCATED AT 250 WORDS)

Capsaicin and blood-brain barrier permeability

The influence of perivascular sensory afferent nerve fibres upon the permeability of the blood-brain barrier was examined in halothane-anaesthetised rats. Blood-brain barrier permeability was assessed by the rate of transfer of the small neutral amino acid, [ 14C]α-aminoisobutyric acid, from blood to brain and by gross extravasation of Evans blue albumin. In every brain area examined, the acute administration of capsaicin (0.15–5 μmol/kg, i.v.) failed to alter significantly the passage into the brain of the small neutral amino acid tracer or to effect dye extravasation. Capsaicin, at concentrations which cause the release of vasoactive neuropeptides from nerve endings and increase vascular permeability in peripheral tissues, does not increase the permeability of the blood-brain barrier.