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The role of the p75 neurotrophin receptor for neuronal survival after nerve crush was studied in L5 dorsal root ganglia (DRG) of knockout mice and controls with assumption-free stereological methods. Numbers of neuronal A- and B-cells were obtained using the optical fractionator and optical disector techniques. At birth, the total number of DRG neurons was 10,000 +/- 2,600 in control mice compared with 5,100 +/- 1,300 in p75 knockout mice. During postnatal development, 1,400 neuronal B-cell bodies were lost in p75 knockouts (2P < 0.05) and 1,100 in controls (NS), whereas the A-cell population remained stable. After a sciatic nerve crush, the total neuron loss in controls was 15.4% +/- 3.5% (2P < 0.05) and 22.7% +/- 5.1% (2P < 0.05) at days 14 and 42, respectively. In contrast, there was no loss in total number of neurons after crush in p75 knockout mice. Neuronal A-cell number was unchanged after the crush in p75 knockouts as well as in controls at both times. At 14 days, the population of B-cells was reduced by 24.8% +/- 3.6% in controls and by 6.1% +/- 3.5% in p75 knockouts, this difference being significant (2P < 0.001). At 42 days, the B-cell loss was 29.6% +/- 5.5% in controls and 4.2% +/- 6.4% in p75 knockouts (2P < 0.001). In conclusion, the lack of the p75 receptor results in neuronal DRG cells that are resistant to nerve injury, pointing to a role for the receptor in apoptosis.

TNF-alpha antagonists have been associated with various types of peripheral neuropathies, including multifocal motor neuropathy with conduction block and mononeuropathies [1]. We present two patients treated with infliximab who developed unifocal motor neuropathy with conduction block. A 34-year-old female with Crohn’s disease developed painless weakness of right-hand pincer grip of insidious onset. She had previously received five courses of infliximab infusions (5 mg/kg) and a further dose 3 days after symptom onset. Infliximab partially controlled gastrointestinal symptoms and she was otherwise well. Regular medication included the oral contraceptive pill, levothyroxine, folate, omeprazole, B12 injections, and iron infusions. Examination revealed MRC grade 4 power of the right abductor pollicis brevis, flexor pollicis longus, flexor digitorum profundus (median), and opponens pollicis. Flexor carpi radialis was mildly weak (4?) but forearm pronation remained strong. There were no sensory signs and systemic examination was unremarkable. A detailed four-limb neurophysiological examination 6 weeks after symptom onset revealed isolated severe right median motor conduction block 2.5–6.5 cm proximal to the antecubital fossa skin crease (Fig. 1). Median and other sensory conduction responses were normal. EMG of median innervated forearm muscles including abductor pollicis brevis and flexor pollicis longus was consistent with conduction block, with reduced recruitment of motor units but no spontaneous activity or other evidence of motor axon loss. Right median sympathetic skin response, somatosensory evoked potentials, and thenar thermal threshold testing were all normal. There was evidence for systemic active inflammation with mild leukocytosis, thrombocytosis, and normocytic anemia; ESR 102 mm/h and CRP 51 mg/l. Anti-DNA antibodies, ANCA, ANA, RA latex, glycolipid and antiGAD antibodies, anti-GM1, and anti-GQ1b antibodies were either normal or negative. An MRI with gadolinium showed hyperintensity of the right median nerve in the lower third of the right arm on TIRM and T2-weighted images, with subtle enhancement but no enlargement. This corresponded to the site of conduction block. No specific treatment was given, but there was significant improvement of power in weak muscles within 4 weeks of presentation, and complete recovery at 1 year. Patient 2, a 41-year-old female with ankylosing spondylitis, had been treated with regular infliximab infusions since 2003. In April 2009, she awoke with painless weakness of left finger and wrist extension 3 days after an infliximab infusion (270 mg). Examination revealed MRC grade 0 finger extension and 4wrist extension with radial deviation and no sensory loss. Initial neurophysiological examination 1 week after symptom onset showed profound A. W. Michell (&) Department of Clinical Neurophysiology, Box 124 Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK e-mail: andrew.michell@addenbrookes.nhs.uk

Pain is the most disruptive influence on the quality of life of cancer patients. Although significant advances are being made in cancer treatment and diagnosis, the basic neurobiology of cancer pain is poorly understood. New insights into these mechanisms are now arising from animal models, and have the potential to fundamentally change the way that cancer pain is controlled.

The significance of the p75 low-affinity neurotrophin receptor, for the maintenance and survival of DRG cells, was studied in p75-deficient mice. Perikarya of the L5 DRG of 12-week-old p75 receptor-deficient mice and healthy Balb C mice were compared using stereological techniques. Following systematic sampling, the optical fractionator and the planar vertical rotator were used to estimate the number and mean volume of the cell bodies of the two neuronal subpopulations. The loss of B-cells was 57% (P < 0.00001), numbers being 7300 (CV = 0.12) in controls and 3100 in p75 receptor-deficient mice (CV = 0.18). Also, A-cells showed a significant loss of 39% (P < 0.0001), numbers being 2600 (CV = 0.12) in control mice and 1500 (CV = 0.16) in p75 receptor-deficient mice. The volume of A-cells was reduced by 30% (P < 0.01), from 24.700 µm3 (CV = 0.17) perikarya in p75 knock-out mice to 15.100 µm3 (CV = 0.17) in controls. B-cell volume did not change significantly. It is concluded that the p75 receptor plays a major role in the survival of DRG cells. The predominant loss of small B-cells indicates that the effect of neurotrophins is dependent upon the presence of the p75 low-affinity receptor.

Introduction In threshold-tracking TMS, stimulation intensity is adjusted online to maintain a predefined target MEP response, thus allowing monitoring and controlling for the naturally occurring fluctuations in corticospinal excitability as well as technical errors. Although it is emerging as a useful clinical tool, little is known about its reliability and comparability with conventional techniques. Objectives To evaluate the reproducibility of the threshold-tracking (constant response ) TMS technique for short interval intracortical inhibition (SICI) and compare it with standard (constant stimulus ) measurements. Methods SICI was measured in 12 healthy volunteers (6 males, 31 ± 7.6 years) from the right FDI muscle using an automated stimulation protocol incorporating (i) conventional, fixed-intensity (A-SICI) and (ii) threshold tracking (T-SICI) methods at conditioning stimuli (CS) of 50–80% resting motor threshold (RMT) and interstimulus interval of 2.5 ms. RMT was defined as a stimulation intensity required to evoke a response of 0.2 mV and was determined by threshold tracking. Measurements were repeated on the same day and at least a week later by a single operator. Results No significant differences in mean RMT, A-SICI and T-SICI were observed between sessions. RMT and TS, measured by threshold-tracking technique, showed excellent intra- and adequate interday reproducibility. At 50% RMT CS both types of SICI had poor reproducibility. At all other CS intensities, T-SICI had excellent intraday (intraclass correlation coefficient, ICC 0.81–0.92) and adequate-to-excellent interday (ICC 0.61–0.88) reproducibility, while A-SICI showed poor intraday and poor-to-adequate interday reproducibility (ICC 0.29–0.37 and 0.37–0.51, respectively). Conclusion SICI measured by threshold tracking shows good intra- and interday reproducibility. Automation of the procedure and allowance for naturally occurring fluctuations in cortical excitability by threshold tracking may increase the reproducibility of SICI.

Chronic immune sensory polyradiculopathy (CISP) is a recently described restricted form of chronic inflammatory demyelinating polyradiculopathy (CIDP) [1]. It preferentially affects large myelinated fibres of the posterior roots, is associated with normal peripheral nerve conduction studies, and may respond to immunomodulatory treatment. We describe a patient with clinical features of CISP and additional cranial nerve involvement. A 61 year old woman presented with a 10 year relapsing-remitting neurological disorder. She initially presented with nausea, headache and photophobia followed by diplopia and unilateral ptosis consistent with an oculomotor nerve palsy. Intracranial CT, MRI, MRA, catheter angiography and CSF were all normal. Symptoms resolved over 18 months but an inflammatory cause was suspected after a relapse and treatment with 2 g/kg intravenous immunoglobulin (IVIg) was effective. Further relapses with additional poor balance, facial numbness and distal sensory symptoms responded promptly to IVIg. Intravenous methylprednisolone worsened her symptoms. Neurological examination revealed a partial right oculomotor nerve palsy. Pin prick sensation was reduced in a right trigeminal nerve distribution. Limb power was normal but reflexes were reduced in the upper limbs and absent in the lower limbs with flexor plantars. Romberg’s test was positive. Pin prick was reduced on the ulnar aspect of the right forearm and up to the mid-shins bilaterally. Vibration sense was reduced up to both ankles and proprioception impaired up to the right ankle. Examination after IVIg revealed that ophthalmoplegia, ptosis and a timed Romberg’s test had all improved. Systemic inflammatory/autoimmune blood tests were unremarkable and these included full blood count, ESR, CRP, ANA, ANCA, complement, rheumatoid factor, ENA, protein electrophoresis, immunofixation, acetylcholine receptor antibodies, immunoglobulins, ganglioside serology, lyme serology, treponemal serology and anti-neuronal antibodies. CSF was acellular with normal glucose and a raised protein level of 0.71 g/L (normal 0.15–0.65 g/L). Oligoclonal bands were absent. Neurophysiological data are presented in the appendix. In summary, the absolute values of all neurophysiological investigations listed were normal. However, the ulnar nerve SNAPs were significantly asymmetrical and the motor F-waves prolonged. Thermal thresholds were abnormal in the feet and right hand. Somatosensory evoked potentials were poorly formed in the right lower limb. Asymmetry of motor evoked potential latencies following cervical spine stimulation was consistent with a lesion distal to the intervertebral foramina. Electronic supplementary material The online version of this article (doi:10.1007/s00415-011-6326-0) contains supplementary material, which is available to authorized users.

Charcot-Marie-Tooth disease type 1A is the most frequent inherited peripheral neuropathy. It is generally due to heterozygous inheritance of a partial chromosomal duplication resulting in over-expression of PMP22. A key feature of Charcot-Marie-Tooth disease type 1A is secondary death of axons. Prevention of axonal loss is therefore an important target of clinical intervention. We have previously identified a signalling mechanism that promotes axon survival and prevents neuron death in mechanically injured peripheral nerves. This work suggested that Schwann cells respond to injury by activating/enhancing trophic support for axons through a mechanism that depends on upregulation of the transcription factor c-Jun in Schwann cells, resulting in the sparing of axons that would otherwise die. As c-Jun orchestrates Schwann cell support for distressed neurons after mechanical injury, we have now asked: do Schwann cells also activate a c-Jun dependent neuron-supportive programme in inherited demyelinating disease? We tested this by using the C3 mouse model of Charcot-Marie-Tooth disease type 1A. In line with our previous findings in humans with Charcot-Marie-Tooth disease type 1A, we found that Schwann cell c-Jun was elevated in (uninjured) nerves of C3 mice. We determined the impact of this c-Jun activation by comparing C3 mice with double mutant mice, namely C3 mice in which c-Jun had been conditionally inactivated in Schwann cells (C3/Schwann cell-c-Jun(-/-) mice), using sensory-motor tests and electrophysiological measurements, and by counting axons in proximal and distal nerves. The results indicate that c-Jun elevation in the Schwann cells of C3 nerves serves to prevent loss of myelinated sensory axons, particularly in distal nerves, improve behavioural symptoms, and preserve F-wave persistence. This suggests that Schwann cells have two contrasting functions in Charcot-Marie-Tooth disease type 1A: on the one hand they are the genetic source of the disease, on the other, they respond to it by mounting a c-Jun-dependent response that significantly reduces its impact. Because axonal death is a central feature of much nerve pathology it will be important to establish whether an axon-supportive Schwann cell response also takes place in other conditions. Amplification of this axon-supportive mechanism constitutes a novel target for clinical intervention that might be useful in Charcot-Marie-Tooth disease type 1A and other neuropathies that involve axon loss.

Human prion diseases, although variable in clinicopathological phenotype, generally present as neurologic or neuropsychiatric conditions associated with rapid multifocal central nervous system degeneration that is usually dominated by dementia and cerebellar ataxia. Approximately 15% of cases of recognized prion disease are inherited and associated with coding mutations in the gene encoding prion protein (PRNP). The availability of genetic diagnosis has led to a progressive broadening of the recognized spectrum of disease.We used longitudinal clinical assessments over a period of 20 years at one hospital combined with genealogical, neuropsychological, neurophysiological, neuroimaging, pathological, molecular genetic, and biochemical studies, as well as studies of animal transmission, to characterize a novel prion disease in a large British kindred. We studied 6 of 11 affected family members in detail, along with autopsy or biopsy samples obtained from 5 family members.We identified a PRNP Y163X truncation mutation and describe a distinct and consistent phenotype of chronic diarrhea with autonomic failure and a length-dependent axonal, predominantly sensory, peripheral polyneuropathy with an onset in early adulthood. Cognitive decline and seizures occurred when the patients were in their 40s or 50s. The deposition of prion protein amyloid was seen throughout peripheral organs, including the bowel and peripheral nerves. Neuropathological examination during end-stage disease showed the deposition of prion protein in the form of frequent cortical amyloid plaques, cerebral amyloid angiopathy, and tauopathy. A unique pattern of abnormal prion protein fragments was seen in brain tissue. Transmission studies in laboratory mice were negative.Abnormal forms of prion protein that were found in multiple peripheral tissues were associated with diarrhea, autonomic failure, and neuropathy. (Funded by the U.K. Medical Research Council and others.).

Recent observations suggest that glutamate is important in sensory transduction in the periphery, contributing to peripheral sensitization of nociceptors and the hyperalgesia that accompanies inflammation. This study examined the presence of ionotropic glutamate receptors N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methylisoxazolone-4-propionic acid (AMPA) and kainate (KA) in normal human hairy skin (n = 6) using immunohistochemistry at the electron microscopic level. Analysis of labeled axons at the dermal-epidermal junction demonstrated that 26.9 +/- 2, 19.5 +/- 3 and 18.5 +/- 1% of the axons analyzed were labeled for subunits of the NMDA, AMPA or KA receptors, respectively. An occasional Schwann cell process was labeled for either NMDA or KA receptors. The findings support the hypothesis that glutamate and its ionotropic receptors may play a role in the periphery in sensory processing in humans. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.

Cerebral angiography is associated with a small but definite risk of neurological complications with an unknown incidence of clinically silent embolism. We assessed the neurological complication rate compared with the frequency of silent embolism after angiographyWe used diffusion-weighted magnetic resonance imaging (MRI) before and after angiography to assess embolic events. 100 consecutive angiographies (66 diagnostic and 34 interventional procedures) were done on 91 patients. Patients underwent neurological assessment before, immediately after, and 1 day after angiography.Before angiography, no abnormalities were seen on diffusion-weighted MRI. Diffusion-weighted MRI showed 42 bright lesions in 23 patients after 23 procedures (17 diagnostic, six interventional) in a pattern consistent with embolic events. There was no new neurological deficit after any angiographic procedure. After diagnostic angiography in patients with a history of vasculopathy, the frequency of lesions was significantly higher than in patients without vascular risk factors (12 [44%] of 27 vs five [13%] of 39 patients, p=0.03). In diagnostic angiography, the appearance of lesions was significantly correlated with whether vessels were difficult to probe (p=0.01), amount of contrast medium needed (p0.01), fluoroscopy time (p0.01), and use of additional catheters (p=0.02).After diagnostic and interventional cerebral angiography, embolic events are more frequent than the apparent neurological complication rate. In diagnostic procedures, the incidence of embolism is closely related to a vascular risk profile.

Mice lacking the major Schwann cell myelin component P0 show a severe dysmyelination with pathological features reminiscent of the Déjérine-Sottas syndrome in humans. Previous morphological and electrophysiological studies on these mice did not only demonstrate a compromised myelination and myelin maintenance, but were suggestive of an impairment of axons as well. Here, we studied the axonal pathology in P0-deficient mice by quantitative electron microscopy. In addition, we investigated epidermal receptor end organs by immunocytochemistry and muscle pathology by histochemistry.In proximal sections of facial and femoral nerves, axon calibers were significantly reduced, whereas the number of myelin-competent axons was not diminished in 5- and 17-month-old P0-deficient mice. However, in distal branches of the femoral and sciatic nerve (digital nerves innervating the skin of the first toe) the numbers of myelin-competent axons were reduced by 70% in 6-month-old P0-deficient mice. Immunolabeling of foot pads revealed a corresponding loss of Merkel cells by 75%, suggesting that survival of these cells is dependent on the presence or maintenance of their innervating myelinated axons. In addition, quadriceps and gastrocnemius muscles showed pathological features indicative of denervation and axonal sprouting. These findings demonstrate that loss of an important myelin component can initiate degenerative mechanisms not only in the Schwann cell but also in the distal portions of myelinated axons, leading to the degeneration of specialized receptor end organs and impairment of muscle innervation.

Evidence suggests that nerve growth factor (NGF) is an important mediator in inflammatory pain states: NGF levels increase in inflamed tissue, and neutralization of endogenous NGF prevents the hyperalgesia which normally develops during inflammation of the skin. Here we asked whether NGF contributes to sensitization of primary afferent nociceptors, which are an important component of pain and hyperalgesia in inflamed tissue. An in vitra skin nerve preparation of the rat was used to directly record the receptive properties of thin myelinated (A delta) and unmyelinated (C) nociceptors innervating normal hairy skin, carrageenan-inflamed skin and carrageenan-inflamed skin where endogenous NGF had been neutralized by application of a trkA-IgG (tyrosine kinase A-immunoglobulin Ci) fusion molecule. Following carrageenan inflammation, there was a marked increase in the proportion of nociceptors which displayed ongoing activity (50% of nociceptors developed spontaneous activity compared to 4% of nociceptors innervating normal uninflamed skin), and this was reflected in a significant increase in the average ongoing discharge activity. Spontaneously active fibres were sensitized to heat and displayed a more than twofold increase in their dischargeto a standard noxious heat stimulus. Furthermore, the number of nociceptors responding to the algesic mediator bradykinin increased significantly from 28% to 58%, By contrast, the mechanical threshold of nociceptive afferents did not change during inflammation. When the NGF-neutralizing molecule trkA-IgG was coadministered with carrageenan at the onset of the inflammation, primary afferent nociceptors did not sensitize and displayed essentially normal response:properties, although the inflammation as evidenced by tissue oedema developed normally. We therefore conclude that NGF is a crucial component for the sensitization of primary afferent nociceptors associated with tissue inflammation.

Following peripheral-nerve lesions there are well-documented events that affect the contralateral nonlesioned structures. These contralateral effects are qualitatively similar to those occurring at the ipsilateral side, but are usually smaller in magnitude and have a briefer time course. It is unclear whether the findings are an epiphenomenon or serve a biological purpose, but in either case the existence of these effects implies the presence of unrecognized signalling mechanisms that link the two sides of the body. Strong circumstantial evidence argues against a peripheral mechanism (for example, via circulating factors) and in favour of a central mechanism, in particular signalling via the system of commissural interneurons that is present in spinal cord and brainstem. While an altered pattern of activity in this system might underlie the phenomenon, there are several reasons for proposing that the changes depend upon chemical signals, possibly growth factors. Because of its relative easy access for experimental manipulation, the spinal cord could serve as a model system to study these transmedian signalling systems.

We report a 5-year follow-up of a patient with Ross syndrome. A biopsy of the anhidrotic skin immunostained with protein gene product 9.5 visualized by confocal microscopy revealed selective loss of sudomotor fibers, whereas epidermal innervation remained intact, providing the first morphologic evidence of selective loss of sudomotor fibers in this syndrome. Among the different treatment strategies employed for the patient's disabling segmental hyperhidrosis, intracutaneous injection of botulinum toxin A was the most helpful.

Neurotrophin-4 (NT4) is the most recently discovered neurotrophic factor in mammals and, functionally, the least well understood. Here, we used mice that lack NT4 to determine whether NT4 is required for the survival of functionally identified subclasses of cutaneous sensory neurons. By using three independent methods of histological and electrophysiological analysis, we show that NT4 is specifically required for the survival of down hair (D-hair) receptors that innervate a subpopulation of hair follicles. All other functionally distinct types of afferents neurons innervating hairy skin were not affected in their survival or in their function. Previous studies have shown that BDNF is required for the mechanical sensitivity of slowly adapting (SA) mechanoreceptors but not for the postnatal survival of myelinated cutaneous afferent fibers. In contrast, the receptive properties of SA mechanoreceptors were not impaired in animals lacking NT4. Consequently, these data show that the two trkB ligands, NT4 and BDNF, have distinct and nonoverlapping roles in supporting cutaneous sensory neurons. Whereas NT4 is required for the survival of D-hair receptors, BDNF supports the mechanical function of SA fibers.

Endogenous nerve growth factor (NGF) has been shown to be an important mediator of inflammatory pain and exogenous application of recombinant human NGF (rhNGF) produces pain and hyperalgesia in animals and humans. Since NGF can act through two receptors types, the high affinity tyrosine kinase A (trkA) receptor and the low affinity p75 receptor, we used transgenic mice lacking p75 to analyse the relative importance of these receptors. After systemic injection of rhNGF (5 mg/ kg), pharmacokinetic studies revealed similar serum levels and elimination profiles of exogenously administered rhNGF in both strains of mice. Although animals lacking p75 have increased mechanical and thermal withdrawal thresholds they developed both heat and mechanical hyperalgesia after systemic injection of rhNGF whose magnitude did not differ significantly from wildtype animals. This means that NGF-induced hyperalgesia can occur in the absence of the p75 receptor and suggests that the trkA receptor is sufficient to mediate the acute noxious action of NGF.

Since the early eighties we have witnessed a surge of major discoveries about mechanisms of a unique plasticity in the central nervous system (CNS) that play an important role in the generation of ongoing pain and hyperalgesia [17]. One spectacular example triggered by short periods of noci­ ceptive activity is the increased efficiency of synaptic transmission at pain-relevant neurons in the dorsal horn of the spinal cord [6,12]. These findings of central hyperexcitability have provided a great advance in our conceptual framework for the explanation of erstwhile enigmatic clinical symptoms such as touch-evoked pain (allodynia). Alterations of the CNS circuitry are also implicated in the consolidation of painful conditions that may persist, perhaps indefinitely, in some situations even in the absence of excitation of nociceptors. Al­ though it has been recognized for some time that changes in the receptive properties of nociceptors are the basis of some forms of hyperalgesia notably to heat [13], the impressive advances in the understanding of CNS plasticity have diverted attention from the periph­ eral events of nociception. It is therefore timely that the article by Carlton and Coggeshall refocuses on the peripheral aspects of nociception. In fact, several lines of evidence now show that changes in the excitability of primary nociceptive afferents may be the single most important factor in the generation and maintenance of acute inflammatory or chronic neuropathic pain in hu­ mans. Thus, local anesthetic blocks of affected nerves or tissues, differential nerve blocks, detailed psychophysi­ cal investigations, and intraneural recording and stimula­ tion experiments using microneurography all converge

This report aims to present an orderly approach to the treatment of Chronic Regional Pain Syndrome (CRPS) types I and II through an algorithm. The central theme is functional restoration: a coordinated but progressive approach that introduces each of the treatment modalities needed to achieve both remission and rehabilitation. Reaching objective and measurable rehabilitation goals is an essential element. Specific exercise therapy to reestablish function after musculoskeletal injury is central to this functional restoration. Its application to CRPS is more contingent on varying rates of progress that characterize the restoration of function in patients with CRPS. Also, the various modalities that may be used, including analgesia by pharmacologic means or regional anesthesia or the use of neuromodulation, behavioral management, and the qualitatively different approaches that are unique to the management of children with CRPS, are provided only to facilitate functional improvement in a stepwise but methodical manner. Patients with CRPS need an individual approach that requires extreme flexibility. This distinguishes the management of these conditions from other well-described medical conditions having a known pathophysiology. In particular, the special biopsychosocial factors that are critical to achieving a successful outcome are emphasized. This algorithm is a departure from the contemporary heterogeneous approach to treatment of patients with CRPS. The underlying principles are motivation, mobilization, and desensitization facilitated by the relief of pain and the use of pharmacologic and interventional procedures to treat specific signs and symptoms. Self-management techniques are emphasized, and functional rehabilitation is the key to the success of this algorithm.

Brain-derived neurotrophic factor (BDNF) is a survival factor for certain sensory neurons during development. Using electrophysiology in BDNF-deficient mice, we show here that slowly adapting mechanoreceptors (SAM), but not other types of cutaneous afferents, require BDNF in postnatal life for normal mechanotransduction. Neurons lacking BDNF did not die, but instead showed a profound and specific reduction in their mechanical sensitivity, which was quantitatively the same in BDNF -/- and BDNF +/- animals. Postnatal treatment of BDNF +/- mice with recombinant BDNF completely rescued the mechanosensitivity deficit. Therefore BDNF is important for regulating SAM mechanosensitivity, independent of any survival-promoting function.

Nerve growth factor (NGF) has a well characterized role in the development of the nervous system and there is evidence that it interacts with nociceptive primary afferent fibres, Here we applied a synthetic tyrosine kinase A IgG (trkA-IgG) fusion molecule for 10-12 days to the innervation territory of the purely cutaneous saphenous nerve in order to bind, and thereby neutralize endogenous NGF in adult Fats. Using neurophysiological analysis of 152 nociceptors we now show that sequestration of NGF results in specific changes of their receptive field properties. The percentage of nociceptors responding to heat dropped significantly from a normal 57% to 32%. This was accompanied by a rightward shift and a reduced slope of the stimulus response function relating the intracutaneous temperature to the neural response. The number of nociceptors responding to application of bradykinin was also significantly reduced from a normal of 28% to 8%, In contrast, the threshold for mechanical stimuli and the response to suprathreshold stimuli remained unaltered, as did the percentage of nociceptors responding to noxious cold. The reduced sensitivity of primary afferent nociceptors was accompanied by a reduction in the innervation density of the epidermis by 44% as assessed with quantitative immunocytochemical analysis of the panaxonal marker PGP 9.5. This demonstrates that endogenous NGF in the adult specifically modulates the terminal arborization of unmyelinated fibres and the sensitivity of primary afferent nociceptors to thermal and chemical stimuli in vivo.

Neurotrophins mediate specific effects on sensory neurons through tyrosine kinase receptors. Most of these neurons also co-express the neurotrophin receptor p75 (p75 NTR ) but its function has remained obscure. We now show that nerve growth factor but not brain-derived neurotrophic factor or neurotrophin-3 selectively increases the expression of bradykinin binding sites on cultured dorsal root ganglion neurons from adult mouse via p75 NTR . This up-regulation of bradykinin binding sites did not occur in neurons from mice lacking p75 NTR or in neurons from wild-type mice treated with p75 NTR -blocking antibody, indicating that tyrosine kinase receptors alone are not sufficient to trigger this physiological neuronal response. Thus, the interaction of nerve growth factor with p75 NTR is an important factor contributing to chronic pain conditions.

We report a patient with an extensive paranasal sinus carcinoma. One year after tumor resection, magnetic resonance imaging (MRI) showed swelling of the ipsilateral masticatory muscles with signal increase on T2-weighted images and gadolinium-DTPA uptake, suggestive of local tumor infiltration. However, electromyography, biopsy, and follow-up MRI confirmed denervation pseudohypertrophy of the muscles innervated by the mandibular nerve and excluded tumor recurrence. Muscle denervation and pseudohypertrophy should be considered in the differential diagnosis of appropriate patients with suspected tumor recurrence.

Mice with a targeted mutation of the p75 low affinity neurotrophin receptor display smaller peripheral nerves and dorsal root ganglia. Here we show that transgenic mice have a significant elevation of thresholds to noxious mechanical and heat stimuli compared with p75+/+ control mice. Immunocytochemical analysis using antibodies against PGP 9.5 (a panaxonal marker) and calcitonin gene related peptide (CGRP, which labels peptidergic neurons) showed a reduction to 73% and 54%, respectively, of the epidermal innervation density. However, analysis of the cell size distribution of toluidine blue-stained dorsal root ganglia showed no selective loss of neurons of particular diameters. Moreover, the neurochemical profile of dorsal root ganglia cells as defined by trkA, CGRP, IB4 and RT97 immunostaining revealed no significant differences in comparison with p75+/+ animals. Staining of the dorsal horn of the spinal cord for CGRP and IB4 was also normal in p75-/- animals. Taking into account a previously reported loss of approximately 50% dorsal root ganglion neurons, we conclude that all types of sensory neurons are equally depleted in p75-/- mice and that the absence of p75 impedes the development of more than one neuronal subtype.

Charcot-Marie-Tooth (CMT) disease type 1A is the most common form of CMT. The main clinical features are distal weakness, sensory loss, and skeletal deformities. Although pain is a frequent complaint, small fiber involvement in CMT1A has not been studied extensively.We assessed pain and small fiber involvement in 49 CMT1A patients using a variety of pain scales, pain questionnaires, and thermal thresholds.Forty-three of 49 patients (88%) complained of pain. The pain was localized to the feet in 61% of patients. Only 18% of patients had neuropathic pain. Cold and warm detection thresholds were elevated in 53% and 12% of patients, respectively.Our findings confirm that CMT1A patients have significant pain, which is more likely to be multifactorial in origin and suggests that a proportion of patients have small fiber dysfunction affecting mainly thinly myelinated Aδ fibers.

With a 3-fold increase in the number of cancer survivors noted since the 1970s, there are now over 28 million cancer survivors worldwide. Accordingly, there is a heightened awareness of long-term toxicities and the impact on quality of life following treatment in cancer survivors. This review will address the increasing importance and challenge of chemotherapy-induced neurotoxicity, with a focus on neuropathy associated with the treatment of breast cancer, colorectal cancer, testicular cancer, and hematological cancers. An overview of the diagnosis, symptomatology, and pathophysiology of chemotherapy-induced peripheral neuropathy will be provided, with a critical analysis of assessment strategies, neuroprotective approaches, and potential treatments. The review will concentrate on neuropathy associated with taxanes, platinum compounds, vinca alkaloids, thalidomide, and bortezomib, providing clinical information specific to these chemotherapies.

Sympathetic reflex responses were elicited in human volunteers by sustained selective excitation of nociceptors by noxious chemicals, namely topical application of mustard oil which elicited burning pain, or histamine which induced itching in a skin area of 5 cm2 on the volar aspect of one forearm. Stimulus-related sympathetic reflex responses were studied by means of computer-assisted infrared thermography of the palmar aspects of both hands. Nociceptive stimulation induced a decrease of skin surface temperature in both hands interpreted as vasoconstriction. The magnitude of the reflex cooling was correlated with the magnitude of the sensation (r = 0.49), but independent of the quality of sensation (itch or pain). The temperature reduction was maintained for more than 30 min and its time-course matched the time-courses of pain or itch sensations. It is concluded that the sustained and selective excitation of nociceptors elicits a sustained sympathetic reflex response, which adapts very slowly. The time-course of the reflexes suggests that these are not arousal responses, but may be indicators of nociceptive processing in conscious humans. Contralateral temperature decreases were consistently smaller than ipsilateral ones. Thus, sustained nociceptive-specific vasoconstrictor reflexes may be somatotopically organised with an emphasis on areas close to the painful stimulus (homotopic), which has so far only been shown in animals. The study thus demonstrates for the first time in humans the presence of a sympathetic reflex asymmetry, which is specific for nociceptive afferent input.

Previous evidence suggests that, in adult animals, nerve growth factor (NGF) can induce hyperalgesia, and may be an endogenous mediator in some persistent pain states. Here we have studied the effects of single intradermal injections of 50-500 ng of human recombinant NGF into the plantar skin of adult rat hindpaws. We found that doses of 250 ng and more produced a prolonged and stable thermal hyperalgesia to radiant heat. NGF did not produce overt pain behaviour as judged by the absence of paw licking or guarding of the injected paw. In animals subjected to surgical or chemical sympathectomy, by repeated systemic guanethidine treatments, the hyperalgesic effects of NGF were markedly reduced. We also found that NGF produced plasma extravasation in rat skin, using the Evan's blue method, with a dose dependency similar to that determined for hyperalgesia. Together, these findings suggest that NGF can lead to a rapid activation and sensitization of cutaneous nociceptors. However, these actions appear at least partly indirect, requiring the presence of normal sympathetic post-ganglionic terminals.

The peripheral nociceptive nervous system is very malleable and following tissue injury, nociceptors often increase their sensitivity. They accomplish this by a leftward-shift of their stimulus response functions to heat stimuli, the acquisition of responses to new modalities, notably algesic mediators or the expansion of mechanosensitive receptive fields. Moreover, a recently discovered class of nociceptors which is unresponsive to transient noxious stimuli in healthy tissue starts to discharge specifically at the onset of tissue inflammation. Persistent increases of nociceptor excitability can occur after nerve lesion and contribute significantly neuropathic pain states in humans.

Sympathelic vasoconstrictor neurons that had previously innervated blood vessels in hairy skin were made to reinnervate the vasculature of the hairless skin of the paw pad by suturing the central stump of the cut sural nerve to the distal stump of the cut tibial nerve. After allowing sufficient time for the reinnervation, electrical stimulation of the vasoconstrictor pathway in the lumbar sympathetic trunk produced a reduction of the blood flow that was significantly greater than in control animals. There was also a clear sign of a “denervation supersensitivity” of the blood vessels as evidenced by a significantly increased vasoconstriction that followed the systemic application of the alpha 1 -adrenoceptor specific agonist phenylephrine. Neurogenic vasodilatation evoked by antidromic excitation of small diameter primary afferent neurones was significantly impaired although myelinated and unmyelinated primary afferents had re-grown into the target tissue. Electrical stimulation of the intact tibial nerve (containing sympathetic vasoconstrictor axons and nociceptive primary afferent fibres) in control animals, always produced vasodilatation indicating that the neurogenic vasodilatation can override the sympathetic vasoconstrictor response. By contrast, electrical stimulation of cross-unioned nerves consistently produced a robust vasoconstriction. We conclude that sympathetic vasoconstrictor neurons have a high capacity to functionally reinnervate autonomic effector organs in the adult cat. Despite this functional recovery, the blood vessels exhibited stronger than normal responses to an alpha 1 -adrenoceptor agonist. The impaired neurogenic vasodilatation mediated by small diameter afferents may be due to their poor ability to re-establish their efferent vasodilatory function. Alternatively it may be masked by the strong vasoconstriction.

Accumulating evidence shows that adhesion molecules are critically involved in inflammatory demyelination in the focusing of systemic immune responses into the target tissue, the nervous system.Adhesion molecules are upregulated through the action of cytokines. Tumor necrosis factor alpha appears to be of prime importance. Circulating adhesion molecules probably reflect acute inflammatory episodes in the central and peripheral nervous system, but may also function to modulate ongoing inflammatory responses. Cytokines released by T H 1 cells render resident and immigrant macrophages, as well as microglia, activated to synthesize and release increased amounts of inflammatory mediators, such as oxygen radicals, nitric oxide metabolites, and components of the complement system. A more detailed understanding of the sequence of immunopathologic events that culminate in myelin damage in the central and peripheral nervous systems has revealed several sites to which more specific and effective immunointervention can be targeted. NEUROLOGY 1995;45(Suppl 6): S22-S32

Aim To evaluate the reproducibility of a threshold-tracking (constant response) TMS technique for short interval intracortical inhibition (SICI) and compare it with standard (constant stimulus) measurements. Methods SICI was measured in 12 healthy volunteers (31 ± 7.6 years) from the right FDI muscle using an automated stimulation protocol incorporating (i) conventional, fixed-intensity (A-SICI) and (ii) threshold tracking (T-SICI) methods at conditioning stimuli (CS) of 50–80% resting motor threshold (RMT) and interstimulus interval of 2.5 ms. Measurements were repeated on the same day and at least a week later by a single operator. Results No significant differences in RMT, A-SICI and T-SICI were observed between sessions. At 50% RMT CS both types of SICI had poor reproducibility. At all other CS intensities, T-SICI had excellent intraday (intraclass correlation coefficient, ICC 0.81–0.92) and adequate-to-excellent interday (ICC 0.61–0.88) reproducibility, while A-SICI showed poor intraday and poor-to-adequate interday reproducibility (ICC 0.29–0.37 and 0.37–0.51, respectively). Conclusion SICI measured by threshold tracking shows good intra- and interday reproducibility. Key message Automation of the procedure and allowance for naturally occurring fluctuations in cortical excitability by threshold tracking may increase the reproducibility of SICI.

The authors report three patients with chronic sciatic pain without focal neurologic deficit. Sitting or lying on the affected side provoked pain, and standing and walking relieved it. MRI revealed varicotic gluteal vessels compressing the sciatic nerve. Decompression of the nerve resulted in complete and permanent pain relief. Sciatic or buttock pain in patients with varicosities and pain provocation in the sitting or lying position suggests this neurovascular compression syndrome.

BackgroundBing-Neel syndrome (BNS) is a rare manifestation of Waldenstrom's Macroglobulinaemia (WM) due to direct infiltration of the central nervous system. Isolated peripheral nerve infiltration has not been described but as the blood-nerve-barrier has similar characteristics to the blood-brain-barrier, CNS-penetrating chemotherapy would be required.CaseA 43 year-old man was diagnosed with WM after presenting with constitutional symptoms; IgMk paraprotein (34.6 g/L) and lymphoplasmacytoid cells in the bone marrow. He received R-CVP (Rituximab, Cyclophosphamide, Vincristine, and Prednisolone) with good partial haematological response and minimal distal sensory vincristine-related neuropathy. Ten months later he developed a rapidly progressive, symmetric sensorimotor deficit in all four limbs with impairment of walking and hand clumsiness, MRC sum score=61/70. Electrophysiology showed a non-length dependant axonal neuropathy with patchy slowing. Sural nerve biopsy revealed a patchy infiltrate WM cells. He tolerated 4 cycles of blood-nerve-barrier penetrating multi-agent chemotherapy, IDARAM (idarubicin, dexamethasone, cytosine arabinoside, methotrexate, cytosine arabinoside plus intrathecal methotrexate). A marked improvement was seen during treatment and by 3 months later MRC score was 70/70. No electrophysiological difference was detectable at this stage.DiscussionPeripheral BNS is not a recognised neurological manifestation of WM but with appropriate treatment a good outcome may be achieved.

We investigated the ability of human nociceptive primary afferent neurons to encode mechanical pain and to produce vasodilatation. Pain was induced by shooting a light metal cylinder (0.3 g) at different velocities (6–18 m/sec) perpendicularly against the hairy skin of the hand. When single impact stimuli were applied, monotonically increasing stimulus-response functions were obtained in 10 psychophysical experiments using magnitude estimation techniques. In 35 microneurographic experiments nine unmyelinated afferents were recorded from the superficial radial nerve. All units responded readily to impact stimulation even at stimulus intensities that were not rated as painful. However, there was a close linear correlation between the number of action potentials evoked from the nociceptors and the psychophysical magnitude estimates of the perceived sensation or the stimulus intensity. This was also reflected by a corresponding increase of neurogenic vasodilatation. While two thin myelinated afferents displayed qualitatively similar responses 12 low-threshold mechanosensitive afferents (4 rapidly adapting, 5 slowly adapting type 1, 3 slowly adapting type II) failed to encode the intensity of the applied impact force and often became desensitized. This indicates that the total number of action potentials is the determinant of the magnitude of mechanical pain and the associated vasodilatation following single brief stimuli. By contrast, the close correlation between nociceptor activity and sensation changed when trains of mechanical impact stimuli (five stimuli of constant intensity, intratrain frequency of 1/32 to 2 Hz) were applied. Magnitude estimates of pain intensity were frequency dependent and stimuli with short interstimulus intervals were perceived as more painful than those delivered with long intervals. However, the total number of action potentials evoked from C-fibers was higher at longer interstimulus intervals than shorter intervals, thus yielding a negative correlation between the magnitude estimates of the perceived painful sensation and the number of action potentials elicited from nociceptive afferents. This suggests that temporal summation of the nociceptive discharge at central neurons becomes increasingly more important for the sensory discriminative experience of pain evoked by repetitive stimulation. We conclude that human nociceptive C-fibers signal brief noxious mechanical stimuli by the total number of action potentials evoked during a short period of time. However, with repetitive stimulation the total number of action potentials evoked from nociceptors is less important for evoking pain and temporal summation of the nociceptive primary afferent discharge becomes the crucial factor for signaling the magnitude of sensation.

Different types of hyperalgesia were studied after experimental induction of inflammation in small skin areas of healthy volunteers either by topical application of capsaicin solution (1% in 70% ethanol) or by briefly freezing a skin area of similar size to -28 degrees C. Sensory tests were performed 30 min after capsaicin application and 22 h after freeze lesions. Heat pain thresholds were lowered after both treatments, probably due to nociceptor sensitization. Hyperalgesia to four types of mechanical stimulation was studied. (i) Hyperalgesia to punctate stimuli was encountered at the skin site directly affected by the noxious chemical or freeze stimulus (1 degree zone) and in the surrounding skin (2 degrees zone) in both models though the area of 2 degrees hyperalgesia to punctate stimuli after freezing was smaller than after capsaicin. (ii) Hyperalgesia to gently brushing the skin was prominent after capsaicin in 1 degree and 2 degrees zone, but almost absent after freezing. It was concluded that both hyperalgesia to punctate stimuli and brush-evoked pain are due to central nervous plasticity changes rather than nociceptor sensitization. As revealed by differential nerve blocks, brush-evoked pain is mediated by low threshold mechanosensitive A beta-fibres, whilst hyperalgesia to punctate stimuli can be elicited when only C-fibres conduct. In contrast to hyperalgesia to punctate stimuli it requires continuous background discharges in nociceptor units. (iii) Pressure hyperalgesia to tonic stimulation with a blunt probe was encountered in the 1 degree zone of both types of inflammation and is probably due to recruitment of sensitized nociceptor units. (iv) Impact hyperalgesia was studied by shooting small bullets against the skin at predetermined velocities. It was found in the 1 degree zone after freezing and absent in the capsaicin model. Differential nerve blocks revealed that it is probably mediated by sensitized C-fibres. In conclusion, different types of inflammatory changes may result in characteristic different patterns of hyperalgesia.

Acute palsies of the peroneal nerve may have a variety of causes. In many patients, the cause remains undetermined. The authors report a patient with a thrombosis of a crural vein causing an acute peroneal nerve palsy. If the clinical history of patients with an acute peroneal nerve lesion is suggestive of venous thrombosis an appropriate diagnostic workup should be considered.

Signaling downstream of receptor tyrosine kinases controls cell differentiation and survival. How signals from different receptors are integrated is, however, still poorly understood. In this work, we have identified Kidins220 (Kinase D interacting substrate of 220 kDa)/ARMS (Ankyrin repeat-rich membrane spanning) as a main player in the modulation of neurotrophin and vascular endothelial growth factor (VEGF) signaling in vivo, and a primary determinant for neuronal and cardiovascular development. Kidins220(-/-) embryos die at late stages of gestation, and show extensive cell death in the central and peripheral nervous systems. Primary neurons from Kidins220(-/-) mice exhibit reduced responsiveness to brain-derived neurotrophic factor, in terms of activation of mitogen-activated protein kinase signaling, neurite outgrowth and potentiation of excitatory postsynaptic currents. In addition, mice lacking Kidins220 display striking cardiovascular abnormalities, possibly due to impaired VEGF signaling. In support of this hypothesis, we demonstrate that Kidins220 constitutively interacts with VEGFR2. These findings, together with the data presented in the accompanying paper, indicate that Kidins220 mediates the integration of several growth factor receptor pathways during development, and mediates the activation of distinct downstream cascades according to the location and timing of stimulation.

Objective. Animals with transected nerves may develop self-mutilating behavior (autotomy) directed at the denervated body part. Autotomy is often thought to be a response to deafferentation pain produced by pathological changes in the dorsal horn, and self-mutilation after dorsal rhizotomy has consequently been used as an outcome measure for the investigation of chronic pain in animal models. A less recognized hypothesis suggests that autotomy is simply an animal's efforts to remove the useless part. We report a case of self-mutilation of the thumb and fingers in a patient with loss of all sensory modalities in the arm after brachial plexus avulsion. Conclusion. Asking the patient about the reasons for his self-mutilation provides insights into the cause of autotomy which cannot be established from animal studies. We suggest that autotomy may not be a result of chronic pain, and discuss the human experience and alternative underlying pathological processes.

MRI may provide treatment outcome measures in neuromuscular conditions. The authors assessed MRI magnetisation transfer ratios (MTRs) in lower-limb musculature as markers of pathology in peripheral neuropathies and compared the findings with associated clinical data. Ten patients with Charcot-Marie-Tooth disease type 1A (CMT1A) and nine patients with chronic inflammatory demyelinating polyneuropathy (CIDP) were compared with 10 healthy subjects. The MTR in the calf muscles was significantly lower than controls in the two patient groups (both p

Nerve growth factor (NGF) was originally discovered as a neurotrophic factor essential for the survival of sensory and sympathetic neurons during development. However, in the adult NGF has been found to play an important role in nociceptor sensitization after tissue injury. The authors outline mechanisms by which NGF activation of its cognate receptor, tropomyosin-related kinase A receptor, regulates a host of ion channels, receptors, and signaling molecules to enhance acute and chronic pain. The authors also document that peripherally restricted antagonism of NGF-tropomyosin-related kinase A receptor signaling is effective for controlling human pain while appearing to maintain normal nociceptor function. Understanding whether there are any unexpected adverse events and how humans may change their behavior and use of the injured/degenerating tissue after significant pain relief without sedation will be required to fully appreciate the patient populations that may benefit from these therapies targeting NGF.

The cytoplasmic dynein complex is fundamentally important to all eukaryotic cells for transporting a variety of essential cargoes along microtubules within the cell. This complex also plays more specialized roles in neurons. The complex consists of 11 types of protein that interact with each other and with external adaptors, regulators and cargoes. Despite the importance of the cytoplasmic dynein complex, we know comparatively little of the roles of each component protein, and in mammals few mutants exist that allow us to explore the effects of defects in dynein-controlled processes in the context of the whole organism. Here we have taken a genotype-driven approach in mouse (Mus musculus) to analyze the role of one subunit, the dynein light intermediate chain 1 (Dync1li1). We find that, surprisingly, an N235Y point mutation in this protein results in altered neuronal development, as shown fromin vivostudies in the developing cortex, and analyses of electrophysiological function. Moreover, mutant mice display increased anxiety, thus linking dynein functions to a behavioral phenotype in mammals for the first time. These results demonstrate the important role that dynein-controlled processes play in the correct development and function of the mammalian nervous system.

To improve the accuracy of genotype prediction and guide genetic testing in patients with muscle channelopathies we applied and refined specialized electrophysiological exercise test parameters.We studied 56 genetically confirmed patients and 65 controls using needle electromyography, the long exercise test, and short exercise tests at room temperature, after cooling, and rewarming.Concordant amplitude-and-area decrements were more reliable than amplitude-only measurements when interpreting patterns of change during the short exercise tests. Concordant amplitude-and-area pattern I and pattern II decrements of20% were 100% specific for paramyotonia congenita and myotonia congenita, respectively. When decrements at room temperature and after cooling were20%, a repeat short exercise test after rewarming was useful in patients with myotonia congenita. Area measurements and rewarming distinguished true temperature sensitivity from amplitude reduction due to cold-induced slowing of muscle fiber conduction. In patients with negative short exercise tests, symptomatic eye closure myotonia predicted sodium channel myotonia over myotonia congenita. Distinctive "tornado-shaped" neuromyotonia-like discharges may be seen in patients with paramyotonia congenita. In the long exercise test, area decrements from pre-exercise baseline were more sensitive than amplitude decrements-from-maximum-compound muscle action potential (CMAP) in patients with Andersen-Tawil syndrome. Possible ethnic differences in the normative data of the long exercise test argue for the use of appropriate ethnically-matched controls.Concordant CMAP amplitude-and-area decrements of20% allow more reliable interpretation of the short exercise tests and aid accurate DNA-based diagnosis. In patients with negative exercise tests, specific clinical features are helpful in differentiating sodium from chloride channel myotonia. A modified algorithm is suggested.

The growth factor family of neurotrophins has major roles both inside and outside the nervous system. Here, we report a detailed histological analysis of key phenotypes generated by the ablation of the Kinase D interacting substrate of 220 kDa/Ankyrin repeat-rich membrane spanning (Kidins220/ARMS) protein, a membrane-anchored scaffold for the neurotrophin receptors Trk and p75(NTR). Kidins220 is important for heart development, as shown by the severe defects in the outflow tract and ventricle wall formation displayed by the Kidins220 mutant mice. Kidins220 is also important for peripheral nervous system development, as the loss of Kidins220 in vivo caused extensive apoptosis of DRGs and other sensory ganglia. Moreover, the neuronal-specific deletion of this protein leads to early postnatal death, showing that Kidins220 also has a critical function in the postnatal brain.

1. A total of sixty-five sacral afferent neurones with myelinated fibres supplying the urinary bladder was recorded from the sacral roots S2 in anaesthetized cats. All afferent units were identified with electrical stimulation of the pelvic nerve. The discharge properties were quantitatively evaluated using slow filling at rates of 1-2 ml min-1 and isotonic distension to preset pressure levels. Eight afferents were studied prior to and after acute sacral de-efferentation of the urinary bladder. 2. All afferent units were silent when the bladder was empty and responded in a graded manner to an increase of intravesical pressure. During slow filling the level of afferent activity correlated closely with the level of the intravesical pressure. All afferents behaved like slowly adapting mechanoreceptors with both a dynamic and static component of their discharge. With the exception of two units the intraluminal pressure threshold was below 25 mmHg. Thus virtually all myelinated afferents respond in the pressure range that is reached during a non-painful micturition cycle. 3. The stimulus-response functions of the afferents were similar regardless of whether intravesical pressure was increased by slow filling or by distension. However, during slow filling stimulation response functions often exhibited steeper slopes between 5 and 25 mmHg indicating that relatively small changes of intravesical pressure result in large changes of afferent activity. Nevertheless, all units displayed monotonically increasing stimulus response functions throughout the innocuous and noxious pressure level. 4. The stimulus-response functions of the afferent neurones did not change after acute de-efferentation of the urinary bladder, although the rapid phasic fluctuations of afferent activity that are produced by small contractions of the urinary bladder under normal conditions largely disappeared. This means that contractions and distension activate the afferent endings by a common mechanism. 5. It is concluded that the myelinated sacral afferents of the urinary bladder form a homogeneous population which encodes all information necessary for the normal regulation of this organ. Furthermore, this set of afferents mediates all sensations which may reach consciousness within a normal micturition cycle.

We have investigated the ability of humans to localise noxious stimuli on the dorsum of the hand. Pin-prick (non-penetrating needle prick), noxious heat (round 1 cm2 copper probe heated to 50 degrees C), mustard oil (100% applied topically in a small cotton ball, diameter 5 mm) and histamine (iontophoresis of 20 mC delivered to an area of 75 mm2) were applied to skin with intact innervation and during a differential nerve compression block of the superficial radial nerve when only C-fibres were conducting. The mean mislocalisation (+/- S.E.M.; n = 8) of all stimuli was 9.5 +/- 0.8 mm with normal nerve conduction and 8.9 +/- 1.2 during the differential nerve block. There was no significant difference between the noxious submodalities. By contrast, when nerve conduction was intact, purely tactile stimulation (7 mN von Frey hair) was significantly better localised having a mean error of 5.5 +/- 0.4 mm. We conclude that focal stimuli evoking itch or pain can be localised with high precision which is only marginally worse than for tactile stimuli. This suggests the existence of a somatotopical representation for noxious inputs in the brain similar to that found for tactile stimuli.

Measurements of the cross sectional area of the sciatic nerve are described in a group of 10 patients with genetically confirmed Charcot-Marie-Tooth disease type 1A (CMT1A), nine patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and 10 healthy controls using MRI. One mid-thigh of each individual was imaged using a short tau inversion recovery sequence and the nerve appearance evaluated radiologically with respect to the signal intensity and visibility of the internal neural structure. The cross sectional area of the sciatic nerve of each individual was measured by defining irregular enclosing regions of interest on the MRI images. The sciatic nerve area was enlarged in both CMT1A (p

The principle finding of the present study is that there are two types of mechanical hyperalgesia developing in human hairy skin following injurious stimuli. Mechanical hyperalgesia comprises a dynamic component (brush-evoked pain, allodynia) signalled by large myelinated afferents and a static component (hyperalgesia to pressure stimuli) signalled by unmyelinated afferents. While the static component is only found in the injured area, the dynamic component also extends into a halo of undamaged tissue surrounding the injury. The irritant chemicals, mustard oil or capsaicin, were applied transdermally in 20 subjects to a patch (2 x 2 cm) of hairy skin. Both substances evoked burning pain and hyperalgesia to mechanical stimuli. While stroking normal skin with a cotton bud was perceived only as touch prior to chemical stimulation, there was a distinctly unpleasant sensation afterwards. This component of mechanical hyperalgesia persisted for at least 30 min and was present in the skin exposed to the irritants (primary hyperalgesia) as well as in a zone of untreated skin surrounding the injury (secondary hyperalgesia) measuring 38 +/- 4 cm2 after capsaicin. Pressure pain thresholds dropped to 55 +/- 8% of baseline level after mustard oil and to 46 +/- 9% after capsaicin. However, this drop of thresholds was short-lived, lasting 5 min following mustard oil but persisting more than 30 min following capsaicin treatment. The reduction of pressure pain thresholds was only observed for treated skin areas, but not in the surrounding undamaged tissue from where brush-evoked pain could be evoked. When pressure pain thresholds were lowered, the pain had a burning quality which differed distinctly from the quality of brush-evoked pain. On-going burning pain and both types of mechanical hyperalgesia were critically temperature dependent. Mildly cooling the skin provided instant relief from on-going pain, abolished brush-evoked pain and normalized pressure pain thresholds. Rewarming resulted in a reappearance of on-going pain and hyperalgesia. The effect of a nerve compression block of the superficial radial nerve on these sensations was tested in 14 experiments. When the ability to perceive light touch had been abolished, there was also no touch-evoked pain, indicating that this component of mechanical hyperalgesia is mediated by large-diameter primary afferents. At a later stage of the block when the subjects' ability to perceive cold stimuli had also been lost, application of cool stimuli still eliminated on-going burning pain, suggesting that pain relief afforded by cooling the skin acts at the peripheral receptor level and not by central masking.(ABSTRACT TRUNCATED AT 400 WORDS)

1. The purpose of the present study was to compare the responsiveness unmyelinated cutaneous units in vivo and in vitro and to determine the proportion of primary afferents innervating the rat hairy skin that do not respond to transient mechanical or thermal stimuli. We have adopted electrical search strategies to locate the terminal arborization of unmyelinated fibers before testing the sensitivity to adequate stimuli. 2. A total of 144 unmyelinated units were studied, of which 31 were obtained from in vivo and 113 from in vitro experiments. 55 afferents were investigated after chronic surgical sympathectomy. Units recorded from sympathectomized rats did not differ in their conduction velocity, electrical thresholds, or receptive properties from units in intact animals. 3. There were only minor differences between the properties of units recorded in vivo and in vitro. This probably reflects technical differences of the setups rather than biological changes introduced by the in vitro conditions. Except for a higher prevalence of mechano-cold sensitive units in vitro, there was no significant difference between the distributions of receptor types. 4. Eight of 31 units (26%) recorded in vivo and 17 of 113 units (15%) obtained from in vitro experiments failed to respond to transient mechanical or thermal stimuli. In vivo, one of eight initially unresponsive units was activated by repeated mechanical and thermal stimulation. Two further units became responsive after topical application of mustard oil. In vitro, 2 of 17 unresponsive units were activated by repeated stimulation. Ten of the remaining unresponsive units were treated with a combination of inflammatory mediators. Four of these units were activated: three developed ongoing activity, and two of them also became responsive to mechanical and/or heat stimuli. The fourth unit responded to probing but was not spontaneously active. 5. We conclude that transient mechanical or thermal stimuli can excite the majority of unmyelinated cutaneous units. However, in vivo and in vitro, part of unmyelinated units are initially unresponsive even to noxious forms of stimulation. Because those unresponsive units were also encountered in sympathectomized preparations, and because some units can be recruited with repeated noxious stimuli or inflammatory agents, it is unlikely that all of them are sympathetic efferents. The same substances that cause sensitization of "normal" nociceptors are capable of recruiting initially unresponsive unmyelinated afferents.