Alteration of central excitation circuits in chronic headache and analgesic misuse

Central excitatory circuits could be involved in the pathophysiology of pain; particularly, the genesis of chronic pain. The "second pain" is the sensation that follows the initial pain after an appropriate nociceptive stimulus. The second pain is amplified by repeating the stimulus after brief intervals (temporal summation). This phenomenon is the psychophysical correlate of the excitatory pain circuits. The temporal summation of the second pain was evaluated in four groups of subjects; one group affected by migraine without aura, one by episodic tension headache, one by chronic daily headache, and a group of healthy subjects. A percutaneous electrical shock was used as the nociceptive stimulus. The intensity of the second pain was significantly greater in the group of patients with chronic headache in comparison with the other groups. The patients with chronic headache were subdivided into three groups on the basis of their clinical history: a group with transformed migraine; a group with chronic headache ab initio, a form related to the first one; (both groups suffered from chronic daily headache with a frequent superimposition of episodes of migraine attacks) and the third group consisted of patients with chronic tension headache. The temporal summation of the second pain was altered in the first two groups. The patients with chronic migraine abused ergotamine given as a symptomatic drug. Those who were able to discontinue this drug were retested and reported a decrease of the second pain in comparison to the previous measurements. The results of the present study indicate that central excitatory circuits could be involved in the mechanism leading to the development of chronic daily headache.     

Investigations into the role of nitric oxide and the large intracranial arteries in migraine headache

Previous studies suggest that nitric oxide (NO) is involved in headaches induced by i.v. infusion of the vasodilator and NO donor glyceryl trinitrate (GTN) in healthy subjects. Extending these studies to sufferers of migraine without aura, it was found that migraineurs experienced a stronger headache than non-migraineurs. In addition, most migraineurs experienced a delayed migraine attack at variable times (mean 5.5 h) after GTN provocation. This biphasic headache response in migraineurs may be linked to hypersensitivity in the NO-cGMP pathway. Thus, compared to controls, migraineurs were found to be more sensitive to GTN-induced intracranial arterial dilatation, which is known to be mediated via liberation of NO and subsequent synthesis of cGMP Furthermore, histamine infusions in migraineurs induced headache responses and intracranial arterial responses resembling those induced by GTN in migraineurs. Histamine is known to liberate NO from the endothelium via stimulation of the H1 receptor, which is present in the large intracranial arteries in man. Because both immediate histamine-induced headache and intracranial arterial dilatation and delayed histamine-induced migraine are blocked by H1-receptor blockade, a likely common pathway for GTN and histamine-induced headaches/migraines and intracranial arterial responses may be via activation of the NO-cGMP pathway. The delay in the development of these experimental migraines may reflect activation of multiple physiological processes. The intracranial arteries of migraineurs were found supersensitive to the vasodilating effect of GTN (exogenous NO). This relates to clinical findings suggesting dilatation of the large intracranial arteries on the headache side during spontaneous migraine attacks. The function of arterial regulatory mechanisms involving NO in migraine was therefore studied. In peripheral arteries, no endothelial dysfunction of NO was found and cardiovascular and intracranial arterial sympathetic function was normal. A mild parasympathetic dysfunction may be involved and may, via denervation supersensitivity, be responsible for the observed supersensitivity to NO. Another possibility is that NO initiates a perivascular neurogenic inflammation with liberation of vasoactive peptides. NO also mediates a variety of other physiological phenomena. One of these, the pain-modulating effect observed in animals, was evaluated in a human study using GTN infusion and measurements of pain thresholds. No definite effects of GTN were demonstrated. The precise mechanisms involved in NO-triggered migraines and which part of the NO-activated cascade that is involved remain to be determined. The possibilities for pharmacological stimulation and/or inhibition of several steps of the NO-activated cascade increase rapidly and soon may be available for human studies.     

The tonic sympathetic input to the cochlear vasculature in guinea pig

Vascular tones is an essential component in maintaining steady regional blood flow and dynamic responsiveness of a vascular bed. Sympathetic innervation can contribute to vascular tone. Although certain studies have reported evoked changes in cochlear blood flow (CBF) with activation of the sympathetic fibers to the cochlear vasculature, other studies have failed to show evidence of sympathetic contribution to CBF regulation when the cervical sympathetic fibers were unilaterally sectioned. We hypothesized that the bilateral 'sympathectomy of the stellate ganglia' would remove sufficient sympathetic input to the cochlea to yield a change in CBF resting level. To test this hypothesis a new technique was used to expose the stellate ganglia (SG) bilaterally and induce a chemical sympathectomy. We observed that unilateral SG blockade with 2 microliters of 4 mM lidocaine hydrochloride on either side produced a 5-10% increase in CBF, which recovered to baseline during the following 2 min. A subsequent blockade of the contralateral SG produced a rapid 25-35% increase, which then recovered partially during the following 3-4 min, remaining 5-15% above the baseline over a 20 min measurement period. Superior cervical ganglion transection did not affect CBF. Our results provide evidence for the existence of a tonic sympathetic component in the control of vascular tone in guinea pig cochlea. This neural effect is derived bilaterally from SG. This result is consistent with previous anatomical studies showing the bilateral innervation of the cochlea by the SG sympathetic fibers and with previous physiological studies on the bilaterality of evoked changes in CBF due to electric stimulation of SG.     

Effects of unilateral stellate ganglion blockade on the arrhythmias associated with coronary occlusion

In anesthetized dogs the circumflex and/or the anterior descending coronary artery were briefly occluded (10 to 90 seconds) and ectopic beats occurring during the occlusion or for 60 seconds following release were counted. Control occlusions were alternated with occlusions performed during complete, reversible, unilateral blockade of either the right or the left stellate ganglion. This was achieved with thermodes through which coolant was circulated. In this way the shortcomings associated with stellectomy, which is irreversible, are avoided. Blockade of the right stellate ganglion increased the number of ectopic beats associated with coronary occlusion. The occurrence of episodes of ventricular tachycardia and fibrillation was also greater. By contrast, blockade of the left stellate ganglion reduced or abolished occlusion-induced arrhythmias. These effects are independent of changes in heart rate or vegal activity; they depend solely upon unilateral alteration in sympathetic tone, and are not demonstrable when such tone is low. We suggest that the right and left cardiac sympathetic nerves have a different influence upon cardiac excitability.     

Combined evaluation of pupillary and cardiovascular responses to cold pressor test in cluster headache patients

Little is known about the structures and mechanisms involved in the pathophysiology of cluster headache (CH). In this study, pupillary and cardiovascular responses to the cold pressor test (CPT) were monitored in CH patients during either an active phase of disease or a remission period in order to evaluate the oculocephalic and cardiovascular functioning of the autonomic nervous system in this form of idiopathic headache. CH patients showed a specific pattern of pupillary response on both sides during both phases of the disease. This response differed from that of controls because of an absent miosis. The pressor response to CPT was more marked in CH patients than in controls. Naloxone pretreatment caused specific and selective changes in both the pupillary and cardiovascular responses of CH patients. These data suggest a systemic sympathetic hyperactivation in response to CPT in CH patients. An oculocephalic sympathetic hypofunction is possibly associated as well as an altered opioid neuromodulation.     

Characterization of prostaglandin production in tissue culture of rat renal medullary cells

The purpose of our studies was to examine the role of the nervous system in arrhythmias produced by digitalis overdose and coronary artery occlusion in the cat. This was done by observing the effect of these arrhythmogenic procedures on cardiac efferent neural activity and then determining whether any observed alteration in neural activity contributed to the cardiac rhythm disturbances evoked by digitalis and coronary artery occlusion. Our data indicate that both procedures used to evoke arrhythmias activate each division of the autonomic nervous system. Activation of the sympathetic nervous system resulted in a deleterious effect on cardiac rhythm whereas activation of the parasympathetic nervous system, in general, resulted in a beneficial effect on cardiac rhythm. With coronary occlusion, the role exerted by the nervous system depended on the anatomic location of the involved myocardium. Studies directed at elucidating the mechanisms whereby the nervous system caused cardiac rhythm disturbances indicated that there may be an important difference between the antiarrhythmic efficacy of beta-adrenergic blockade and bilateral stellate ganglionectomy. The latter procedure proved to be a more effective way of removing deleterious sympathetic neural effects on the heart. In conclusion, our findings suggest that the development of new drugs for treating arrhythmias resulting from digitalis and coronary occlusion should be aimed at finding drugs that act to either depress central sympathetic outflow or enhance parasympathetic effects on the ventricle.     

Thermal sensitivity in unilateral headaches

Thermal thresholds were measured in the face (first and second trigeminal area), over the mastoid process (C2-3 area), and in the hands in patients with migraine (n=17), cluster headache (n=22), and cervicogenic headache (n=20). Significant symptomatic versus nonsymptomatic side differences were generally not found for any headache group. Cluster headache patients had significantly higher warm thresholds than controls (n=24) for most of the cephalic points. Cervicogenic headache patients had significantly higher warm and cold thresholds than controls (n=56) at several cephalic and noncephalic points. Warm thresholds over the mastoid process on the symptomatic side were higher in cervicogenic headache patients compared to the other groups. In migraine patients, thermal thresholds were similar to those in controls. Thus, we found no evidence of focal or unilateral peripheral somatic nerve dysfunction involving C or A-delta fibers in any of the studied headache groups, although a C2-3 root dysfunction in cervicogenic headache could not be excluded. A bilateral central sensory dysfunction in cluster headache and cervicogenic headache may be hypothesized but a generalized peripheral dysfunction can also explain our results.     

Treatment of Head Pain With Psychotropics.

There are four general classes of primary headache: migrainous or vascular headache, muscle tension headache, cluster headache, and a miscellaneous class including posttraumatic headache and headache with toxic origin. This article provides an update on the pharmacological treatment of these classes of head pain. In sum, both the pathophysiology and management of migraine and tension headache remain frustratingly vague. Although antidepressants and mood stabilizers are widely used in clinical practice, results of carefully conducted trials reveal in general a more limited role. For acute, episodic attacks of migraine head pain, the triptans will generally yield the best results, but complete elimination of headache is uncommon. Chronic migraine sufferers may benefit from addition of a tricyclic antidepressant (TCA) and possibly a mood stabilizer, although side effects and tolerability are issues. Patients with chronic tension headache may also benefit from an agent of one of these two classes. A comprehensive treatment plan addressing psychosocial stresses and other triggers is essential. Though depression is associated with head pain, effective control of depression with an antidepressant does not predict improvement in head pain. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Visual system dysfunction in migraine: a review of clinical and psychophysical findings

This paper reviews both clinical and experimental literature relating to visual dysfunction in migraine, starting with the eye and progressing via the retina and visual pathways to the visual cortex. Migraine is associated with (i) a pupillary sympathetic hypofunction, and (ii) a cortical hypersensitivity to visual stimuli (perhaps only in migraine with aura), the pathogenesis of which remains to be determined. Various hypotheses are discussed, and it is proposed that the methods of visual psychophysics may represent a useful approach in the future study of cortical hyperexcitability in migraine. Paradoxically, little research has been directed towards understanding (i) the photophobia of migraine attacks, and (ii) how migraine may be triggered by visual stimuli. Research aimed at elucidating the mechanisms of these phenomena may enhance understanding of the pathogenesis of migraine.     

Interactions between non-immune host cells and the immune system during periodontal disease: role of the gingival keratinocyte

OBJECTIVE: The role of sympathetic blocks in pain therapy is examined in the light of changing concepts of pain pathophysiology. A critical review of the literature also sought to develop an evidence-based analysis of outcome studies to provide recommendations for appropriate applications of sympathetic blocks, together with ideas for further clinically based research. METHODS: A focus on the pathophysiology of neuropathic and inflammatory pain disorders was used to help redefine what contribution, if any, was provided by the sympathetic system, to chronic pain states. Validation of nerve block therapies based on historical practices and these newer concepts and outcome determinations has then been used to present an overview of clinical nerve block therapies as applied to the sympathetic nervous system. RESULTS: 1. Pain Diagnosis: A reclassification of reflex sympathetic dystrophy (RSD) to the new taxonomy of complex regional pain syndromes (CRPS) is supported, with evidence that only a questionable sympathetic contribution at the dorsal root ganglion level can be ascribed etiologically to this group of disorders. Sympathetic blocks can establish whether pains may be nonresponsive or variably responsive to such blocks, but are considered inappropriate in determining a clinical diagnosis. 2. Neuropathic Pain Therapy: (a) A critical review of the literature regarding the use of sympathetic blocks in the treatment of acute herpes zoster pain and in the treatment of postherpetic neuralgia found little support for the widely held view that sympathetic blocks reduced either the incidence of long-term reduction of pain in these disorders. Further attempts to reduce PHN by the combination of blocks with aggressive drug therapies during acute herpes infection are suggested. (b) CRPS (RSD) treatments are seen as evolutionary at present, with the role of sympathetic blocks being only part of a balanced pain treatment strategy aimed at getting patients activated under cover of good analgesia and improved function. These proposals come as consensus recommendations but are not substantiated by outcome studies. 3. Ischemic Pain: Permanent sympathetic block with neurolytic or thermocoagulation techniques provides up to 50% long-term improved blood flow and reduction of pain and ulceration for patients with advanced peripheral vascular disease. This is particularly appropriate at lumbar levels in which percutaneous techniques are safe when conducted with real time imaging control. CONCLUSIONS: Changes in the understanding of CRPS disorders and the role of the sympathetic nervous system in neuropathic pain has changed both the diagnostic and management strategies for these pain states. The sensitivity and specificity of response to sympathetic blocks in establishing their value at diagnostic aids will not be fully established without further clinical study. Further use of intravenous regional blocks or diagnostic intravenous infusions remains questionable. Preventive and therapeutic use of sympathetic blocks in herpes zoster pain remains open to well-controlled study.     

Prostaglandin E1 suppresses tumor necrosis factor-alpha and interleukin-10 production by lipopolysaccharides-stimulated mononuclear cells

Previous studies have shown that the intravenous administration of yohimbine, an alpha 2 antagonist, increases norepinephrine turnover and has related anxiogenic effects in humans. We herein report that yohimbine also increases plasma neuropeptide Y (NPY) in healthy human subjects. This finding is consistent with previous reports in animals, but contrasts with a previously reported study in humans. NPY is a 36 amino acid peptide neurotransmitter located in sympathetic and nonsympathetic nerve fibers, as well as in brain structures such as the locus coeruleus, where it is colocalized with norepinephrine. NPY has been shown to inhibit locus coeruleus neuronal firing, decrease norepinephrine release, and increase postsynaptic noradrenergic signal transduction. When administered centrally, NPY also has anxiolytic properties. This study therefore suggests that yohimbine challenge may be useful in assessing NPY and noradrenergic system interactions in neuropsychiatric disorders such as panic disorder or post traumatic stress disorder in which noradrenergic system dysfunction has been observed.     

Drugs and toxins associated with myopathies

BACKGROUND: The sympathetic nervous system has long been believed to be involved in the pathogenesis of panic disorder, but studies to date, most using peripheral venous catecholamine measurements, have yielded conflicting and equivocal results. We tested sympathetic nervous function in patients with panic disorder by using more sensitive methods. METHODS: Sympathetic nervous and adrenal medullary function was measured by using direct nerve recording (clinical microneurography) and whole-body and cardiac catecholamine kinetics in 13 patients with panic disorder as defined by the DSM-IV, and 14 healthy control subjects. Measurements were made at rest, during laboratory stress (forced mental arithmetic), and, for 4 patients, during panic attacks occurring spontaneously in the laboratory setting. RESULTS: Muscle sympathetic activity, arterial plasma concentration of norepinephrine, and the total and cardiac norepinephrine spillover rates to plasma were similar in patients and control subjects at rest, as was whole-body epinephrine secretion. Epinephrine spillover from the heart was elevated in patients with panic disorder (P=.01). Responses to laboratory mental stress were almost identical in patient and control groups. During panic attacks, there were marked increases in epinephrine secretion and large increases in the sympathetic activity in muscle in 2 patients but smaller changes in the total norepinephrine spillover to plasma. CONCLUSIONS: Whole-body and regional sympathetic nervous activity are not elevated at rest in patients with panic disorder. Epinephrine is released from the heart at rest in patients with panic disorder, possibly due to loading of cardiac neuronal stores by uptake from plasma during surges of epinephrine secretion in panic attacks. Contrary to popular belief, the sympathetic nervous system is not globally activated during panic attacks.     

Clinical features of daily chronic headache

INTRODUCTION: Although the International Headache Society considers chronic tension headache to be a chronic headache, patients with daily chronic headache may have pain which is not only due to tension but also has migrainous features. OBJECTIVE: To evaluate the clinical differences and abuse of drugs in a group of patients with chronic daily headache who were consecutively evaluated in the Neurology Clinic. MATERIAL AND METHODS: We consider the patients to have daily chronic headache when they have had pain at least 6 days a week for the past 6 months. Using this criterion, we studied 112 patients, of whom 90 (80.4%) were women and 22 (19.6%) men. Results. Sixty nine (61.6%) had transformed migraine and 43 (38.4%) tension headache. There were no differences in their current ages but the age of onset of the headaches varied (p = 0.000,t). Unilateral pain, trigger factors and a family history were more frequent in the cases of transformed migraine. Eighty four patients (75%) abused analgesics. Although we found different pain intensities (p = 0.000, chi 2) there was no difference in the weekly consumption of analgesics (p = 0.64, t) in the mg/week of ergotamine (p = 0.96, t) nor in absence from work between the two types of headache. CONCLUSIONS: In spite of clinical differences between transformed migraine and tension headache, which may help diagnosis, in our series abuse of analgesics (including ergotamine) was a common characteristic.     

Anatomical study of the cervical sympathetic trunk and ganglia in the albino rat (Mus norvegicus albinus)

Nine adult albino rats of both sexes were studied. 16 sympathetic trunks and ganglia were dissected in detail in eight rats. The right and left superior cervical ganglion and the sympathetic trunk below the ganglion were removed from an additional rat. The cell bodies of these ganglia and the axons of the trunks were counted with the aid of light and electron microscopy. Considering the number and location of ganglia and patterns of branching, the rat's cervical sympathetic nervous system compares closely with man's. There appears to be a relationship between body size and myelination of preganglionic neurons in the cervical sympathetic trunks, with smaller animals having the least number of myelinated fibers.     

Is it migraine?

BACKGROUND: Migraine is a common disorder affecting 8-10% of the population. It results in significant morbidity and has social and economic consequences. Vascular and neurogenic mechanisms are involved in the genesis of migraine. Serotonin plays an important part. Attacks are brought on by internal (not identified) and external (identified) trigger factors in people predisposed to the condition, often on an hereditary basis. OBJECTIVE: The diagnosis of migraine depends on the recognition of the features specific to the condition. This article aims to define these features. DISCUSSION: There are diagnostic criteria which define the two main types of migraine--migraine with aura and migraine without aura. The variants of migraine need to be recognised and migraine needs to be distinguished from cluster headache. It is also important to recognise and exclude sinister causes of headache. Treatment is not discussed.     

Myelination in organotypic cultures of sympathetic ganglia

Explants of mouse superior cervical ganglion (SCG), co-cultured with dorsal spinal cord, were grown for up to 4 weeks in vitro. In such cultures, scattered internodes of peripheral nervous system (PNS) myelin were observed, apparently associated with SCG neurites. Although rare, the incidence of PNS myelination in this system might merit further experimentation to provide a model facilitating the evaluation of postganglionic sympathetic myelination, which in vivo may be both extensive and morphologically unusual.     

Headache and the cervical spine: a critical review

Headache related to the cervical spine is often misdiagnosed and treated inadequately because of confusing and varying terminology. Primary headaches such as tension-type headache and migraine are incorrectly categorized as "cervicogenic" merely because of their occipital localization. Cervicogenic headache as described by Sjaastad presents as a unilateral headache of fluctuating intensity increased by movement of the head and typically radiates from occipital to frontal regions. Definition, pathophysiology; differential diagnoses and therapy of cervicogenic headache are demonstrated. Ipsilateral blockades of the C2 root and/or greater occipital nerve allow a differentiation between cervicogenic headache and primary headache syndromes such as migraine or tension-type headache. Neither pharmacological nor surgical or chiropractic procedures lead to a significant improvement or remission of cervicogenic headache. Pains of various anatomical regions possibly join into a common anatomical pathway, then present as cervicogenic headache, which should therefore be understood as a homogeneous but also unspecific pattern of reaction.     

Insulin modulates circulating endothelin-1 levels in humans

Nitroglycerin, which may be regarded as a prodrug for nitric oxide, induces a mild to moderate headache in healthy subjects. In order to study whether migraine patients are more sensitive to nitric oxide than non-migrainous subjects, four different doses of intravenous nitroglycerin were given in a double blind design to 17 migraine patients, 17 age and sex matched healthy controls and 9 subjects with tension-type headache. The nitroglycerin-induced headache was significantly more severe in migraine sufferers, lasted longer and fulfilled diagnostic criteria for migraine more often. We have previously shown a similar supersensitivity to histamine which in human cerebral arteries activates endothelial H1 receptors and causes endothelial production of nitric oxide. Migraine patients are thus supersensitive to exogenous nitric oxide from nitroglycerin as well as to endothelially produced nitric oxide. It is suggested that nitric oxide may be partially or completely responsible for migraine pain.     

Quality of life in migraine and chronic daily headache patients

Primary chronic headache can affect a patient's health-related quality of life (HQL). The Medical Outcomes Study Short Form (SF-36) questionnaire has been used to address this issue. We compare the impact of headache on the HQL of patients with migraine and chronic daily headache (CDH) using the SF-36 instrument. We analyzed a group of 115 consecutive patients; 62 migraine patients and 53 CDH patients completed the questionnaire. Patterns of disability were similar between the two groups, but CDH was marked by a lower level of health scales. Patients with CDH had a significantly worse pain score in physical functioning, role functioning (physical), bodily pain, general health perceptions, and mental health than patients with migraine headache. Our results in the migraine group were similar to findings in other publications, with the lowest scores in role functioning (physical) and bodily pain. There is no previous experience in CDH patients, but the present data suggest that the SF-36 questionnaire is valuable in determining the differences in functional status among headache types. These data suggest that the SF-36 is a reliable and valid measure of the HQL of patients with CDH, and may indeed prove to be valuable in studying the efficacy of therapeutic agents for this type of headache.     

Distribution of CD9 in the developing and mature rat nervous system

CD9 is a cell surface protein implicated in intercellular signaling that has been identified in selected cell types of the hematopoietic system. To begin a study of the role of CD9 in the developing and adult nervous system, we used the anti-rat CD9 monoclonal antibody ROCA2 to determine the distribution of this protein. The identity of the antigen in these tissues was confirmed by immunoblotting and peptide sequencing. Early embryonic sympathetic and dorsal root ganglion sensory neurons and adrenal chromaffin cells all express CD9. ROCA2 also labels the somas, axons, and growth cones of cultured sympathetic and sensory neurons. In the central nervous system (CNS), CD9 is transiently and specifically expressed in embryonic spinal motoneurons. In the adult, central and peripheral glia intensely express CD9. Thus, CD9 is developmentally regulated in a variety of peripheral and central neurons and glia, including proliferating progenitors as well as mature cells. These findings suggest that CD9 may have diverse roles in the nervous system.