Myelinated Afferent Fibers Research Articles

Identification of Minimal Neuronal Networks Involved in Flexor-Extensor Alternation in the Mammalian Spinal Cord

Neural networks in the spinal cord control two basic features of locomotor movements: rhythm generation and pattern generation. Rhythm generation is generally considered to be dependent on glutamatergic excitatory neurons. Pattern generation involves neural circuits controlling left-right alternation, which has been described in great detail, and flexor-extensor alternation, which remains poorly understood. Here, we use a mouse model in which glutamatergic neurotransmission has been ablated in the locomotor region of the spinal cord. The isolated invitro spinal cord from these mice produces locomotor-like activity-when stimulated with neuroactive substances-with prominent flexor-extensor alternation. Under these conditions, unlike in control mice, networks of inhibitory interneurons generate the rhythmic activity. In the absence of glutamatergic synaptic transmission, the flexor-extensor alternation appears to be generated by Ia inhibitory interneurons, which mediate reciprocal inhibition from muscle proprioceptors to antagonist motor neurons. Our study defines a minimal inhibitory network that is needed to produce flexor-extensor alternation during locomotion.

Expression of mechanogated two-pore domain potassium channels in mouse lungs: special reference to mechanosensory airway receptors

Afferent activities arising from sensory nerve terminals located in lungs and airways are carried almost exclusively by fibres travelling through the vagus nerve. Based on electrophysiological investigations, intrapulmonary airway-related vagal afferent receptors have been classified into three main subtypes, two of which are myelinated and mechanosensitive, i.e., rapidly and slowly adapting receptors. To allow for a full functional identification of the distinct populations of airway receptors, morphological and neurochemical characteristics still need to be determined. Nerve terminals visualised using markers for myelinated vagal afferents seem to be almost uniquely associated with two morphologically well-formed airway receptor end organs, smooth muscle-associated airway receptors (SMARs) and neuroepithelial bodies (NEBs), localised in airway smooth muscle and epithelium, respectively. Due to the lack of a selective marker for SMARs in mice, no further neurochemical coding is available today. NEBs are extensively innervated diffusely spread groups of neuroendocrine cells in the airway epithelium, and are known to receive at least two separate populations of myelinated vagal afferent nerve terminals. So far, however, no evidence has been reported for the expression of channels that may underlie direct sensing and transduction of mechanical stimuli by the receptor terminals in NEBs and SMARs. This study focused on the expression of mechanogated two-pore domain K(+) (K(2P)) channels, TREK-1 and TRAAK, in mouse airways and more particular in the NEB micro-environment and in SMARs by multiple immunostaining. TREK-1 could be detected on smooth muscle cells surrounding intrapulmonary airways and blood vessels, while TRAAK was expressed on myelinated vagal afferents terminating both in SMARs and in the NEB micro-environment. Co-stainings with known markers for subpopulations of myelinated vagal afferents and general neuronal markers revealed that all identified SMARs exhibit TRAAK immunoreactivity, and that at least three subpopulations exist in mouse airways. Also, the intraepithelial terminals of both subpopulations of NEB-associated myelinated vagal sensory nerve fibres were shown to express TRAAK. In conclusion, the present study finally characterised an intrinsically mechanosensitive ion channel, the K(2P) channel TRAAK, on the terminals of identified myelinated vagal nodose airway afferents, organised as SMARs and as components of the innervation of NEBs. These data support the hypothesis that both SMARs and NEBs harbour the morphological counterparts of electrophysiologically identified myelinated vagal airway mechanoreceptors. TRAAK appears to be strongly involved in regulating airway mechanosensing since it was found to be expressed on the terminals of all subpopulations of potential vagal mechanosensors.

Simultaneous identification of unmyelinated and myelinated primary somatic afferents by co-injection of isolectin B4 and Cholera toxin subunit B into the sciatic nerve of the rat

Several studies have used the transganglionic tracers cholera toxin subunit B (CTb) and either Bandeiraea simplicifolia isolectin B4 (IB4) or wheat-germ agglutinin (WGA) to label myelinated and unmyelinated afferent fibres respectively. In this study, we aim to determine whether co-injection of CTb and either IB4 or WGA into the sciatic nerve of rat will selectively label myelinated and unmyelinated simultaneously. A double immunofluorescence approach was used to detect these tracers in dorsal root ganglia (DRGs) and afferent fibre terminals in the spinal cord. CTb- and IB4-labelled neurons were seen mainly in L4 and L5 DRGs, with CTb labelling detected primarily in large sized neurons and IB4 staining seen mainly in smaller cells. Only a minority of CTb labelled DRG neuron profiles (5.1%) were also labelled with IB4. In the spinal cord, IB4-labelling was largely confined to lamina II of spinal segments L3–L5, whereas CTb-labelled terminals were seen in all laminae but sparse in lamina II. Confocal microscopy showed no evidence for colocalisation of CTb and IB4 labelling in any terminals in laminae I–III. Although the central distribution of CTb labelling in laminae I and II inner-IV had the same rostro-caudal and medio-lateral coverage as IB4 labelling in spinal segments L3–L5, CTb labelling in ventral laminae (of putative proprioceptor afferents) extended between T12 and S1. Similar patterns of central labelling were found when CTb and WGA were injected together. We therefore concluded that this co-injection approach provides a reliable method to identify both myelinated and unmyelinated somatic primary afferents simultaneously.

Lysophosphatidic acid as an initiator of neuropathic pain: biosynthesis and demyelination

The injury-induced intense stimulation of spinal cord neurons causes lysophosphatidic acid (LPA) synthesis. LPA1 receptor activation causes demyelination and sprouting of sensory fibers, leading to an induction of synaptic reorganization underlying allodynia, a phenomenon that causes intense pain by innocuous stimuli such as touch. the LPA1 receptor signal also initiates the upregulation of Cavα2δ1 in dorsal root ganglia and PKC-γ in the dorsal horn and the downregulation of substance P in the dorsal horn, which are underlying mechanisms for characteristic neuropathic hyperalgesia in myelinated sensory (A-type) fibers and unmyelinated sensory (C-type) fiber hypoesthesia (a type of sensory loss), respectively. On the other hand, the LPA3 receptor mediates microglia activation at the early stage after nerve injury and LPA-induced LPA biosynthesis. Thus, both LPA1 and LPA3 receptors play key roles in the initiation step for neuropathic pain.

1342 EFFECT OF SACRAL NERVE MODULATION ON SENSORY PERCEPTION OF THE BLADDER, URETHRA AND PERINEUM

You have accessJournal of UrologyUrodynamics/Incontinence/Female Urology: Incontinence—Evaluation & Therapy1 Apr 20111342 EFFECT OF SACRAL NERVE MODULATION ON SENSORY PERCEPTION OF THE BLADDER, URETHRA AND PERINEUM Frank Burks, David Wenzler, Donna Carico, and Kenneth Peters Frank BurksFrank Burks Royal Oak, MI More articles by this author , David WenzlerDavid Wenzler Royal Oak, MI More articles by this author , Donna CaricoDonna Carico Royal Oak, MI More articles by this author , and Kenneth PetersKenneth Peters Royal Oak, MI More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.1163AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Sacral neuromodulation (SNM) is used to treat symptoms of overactive bladder (OAB) refractory to other therapies. SNM is theorized to alter the neural pathways in the spinal cord or brain that mediate bladder and urethral sensation and thereby treat the symptoms of OAB. We hypothesize that SNM affects bladder and urethral current perception thresholds (CPTs) of this sensory pathway. METHODS Ten women were enrolled in this IRB approved study of CPTs before and after SNM therapy. The mean age was 57 (31–73), with 9/10 women being post-menopausal. The Neurometer was used to measure CPTs at 5 Hz (C-fibers), 250 Hz (A-delta fibers), and 2000 Hz (A-beta fibers) on the right and left labia, perineum, urethra and bladder prior to and 1 month after SNM. Index finger readings at 2000 HZ served as controls as they should not be affected by SNM. A greater than 25% increase (less sensitive) in current perception threshold (CPT) is defined as a responder. RESULTS OAB questionnaire scores improved in all subjects. There was no change in CPT of the index finger as expected. Vulvar and perineal CPTs did not change significantly from pre-SNM to post-SNM. Nine of ten subjects agreed to have bladder and urethral CPT testing done. SNM had the greatest effect on the bladder and urethra at 250 Hz (A-delta) and 2000 Hz (A-beta). For the bladder CPTs, 5 of 9 of subjects at 250 Hz and 2000 Hz had at least a 25% increase in CPT (28% and 60% median positive change respectively). Minimal change was seen in the bladder and urethral CPTs at 5 Hz after SNM. The urethral CPT at 250 HZ was increased in 5 of 9 subjects with a median positive change of 43%. CPT testing was well tolerated with minimal adverse events. CONCLUSIONS This is the first attempt at measuring current perception thresholds before and after sacral neuromodulation. With a measurable change in CPT values for A-delta fibers (250Hz) and A-beta fibers (2000Hz), these findings suggest that SNM may modulate these large myelinated afferent fibers particularly in the bladder and urethra impacting the stimulus-response cycle contributing to OAB symptoms. More research is needed with a larger sample size to determine the actual significance of these findings. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e536 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Frank Burks Royal Oak, MI More articles by this author David Wenzler Royal Oak, MI More articles by this author Donna Carico Royal Oak, MI More articles by this author Kenneth Peters Royal Oak, MI More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

The majority of myelinated and unmyelinated sensory nerve fibers that innervate bone express the tropomyosin receptor kinase A

Although skeletal pain is a leading cause of chronic pain and disability, relatively little is known about the specific populations of nerve fibers that innervate the skeleton. Recent studies have reported that therapies blocking nerve growth factor (NGF) or its cognate receptor, tropomyosin receptor kinase A (TrkA) are efficacious in attenuating skeletal pain. A potential factor to consider when assessing the analgesic efficacy of targeting NGF-TrkA signaling in a pain state is the fraction of NGF-responsive TrkA + nociceptors that innervate the tissue from which the pain is arising, as this innervation and the analgesic efficacy of targeting NGF-TrkA signaling may vary considerably from tissue to tissue. To explore this in the skeleton, tissue slices and whole mount preparations of the normal, adult mouse femur were analyzed using immunohistochemistry and confocal microscopy. Analysis of these preparations revealed that 80% of the unmyelinated/thinly myelinated sensory nerve fibers that express calcitonin gene-related peptide (CGRP) and innervate the periosteum, mineralized bone and bone marrow also express TrkA. Similarly, the majority of myelinated sensory nerve fibers that express neurofilament 200 kDa (NF200) which innervate the periosteum, mineralized bone and bone marrow also co-express TrkA. In the normal femur, the relative density of CGRP +, NF200 + and TrkA + sensory nerve fibers per unit volume is: periosteum>bone marrow>mineralized bone>cartilage with the respective relative densities being 100:2:0.1:0. The observation that the majority of sensory nerve fibers innervating the skeleton express TrkA +, may in part explain why therapies that block NGF/TrkA pathway are highly efficacious in attenuating skeletal pain.

Lysophosphatidic Acid as the Initiator of Neuropathic Pain

The injury-induced intense stimulation of spinal cord neurons causes lysophosphatidic acid (LPA) biosynthesis. LPA(1) receptor activation causes demyelination and sprouting of dorsal root fibers, leading to an induction of synaptic reorganization underlying allodynia, in which innocuous (tactile) stimuli cause intense pain. The LPA(1) signal also initiates the up-regulation of Ca(v)α2δ1 in dorsal root ganglion and PKCγ in the dorsal horn, underlying mechanisms for characteristic neuropathic hyperalgesia in myelinated sensory (A-type) fibers. On the other hand, the LPA(3) receptor mediates microglia activation at the early stage after nerve injury and LPA-induced LPA biosynthesis. Thus, both the LPA(1) and LPA(3) receptors play key roles in the initiation step using a feed-forward system for neuropathic pain.

Expression of α1-adrenoceptors on peripheral nociceptive neurons

The purpose of this study was to determine whether α1-adrenoceptors are expressed on primary nociceptive afferents that innervate healthy skin. Skin and dorsal root ganglia were collected from adult male Wistar rats and assessed using fluorescence immunohistochemistry with antibodies directed against α1-adrenoceptors alone or in combination with specific labels including myelin basic protein and neurofilament 200 (markers of myelinated nerve fibres), protein gene product 9.5 (a pan-neuronal marker), tyrosine hydroxylase (sympathetic neurons), isolectin B4 (IB4: non-peptidergic sensory neurons), calcitonin gene related peptide (CGRP) and transient receptor potential vanilloid receptor 1 (TRPV1) (peptidergic sensory neurons). Double labelling in dorsal root ganglia confirmed the expression of α1-adrenoceptors within sub-populations of CGRP, IB4 and TRPV1 immunoreactive neurons. Myelinated and unmyelinated sensory nerve fibres in the skin expressed α1-adrenoceptors whereas sympathetic nerve fibres did not. The expression of α1-adrenoceptors on C- and A-delta nociceptive afferent fibres provides a histochemical substrate for direct excitation of these fibres by adrenergic agonists. This may help to explain the mechanism of sensory-sympathetic coupling that sometimes develops on surviving primary nociceptive afferents in neuropathic pain states.

Axonal thermosensitivity and mechanosensitivity of cutaneous afferent neurons

We hypothesized that cutaneous afferent myelinated fibers (A-fibers) and afferent unmyelinated fibers (C-fibers) respond to the same natural stimuli applied to their axons as to their terminals in the skin. In anesthetized rats, activity was recorded from afferent axons in strands isolated proximally from the sural nerve. Mechanical, cold or heat stimuli were applied to the skin or along a 15-mm length of the distal sural nerve. One-hundred and eighteen A-fibers and 109 C-fibers were characterized by their conduction velocity and/or shape of their action potentials, and by their responses to natural stimulation of the skin. Then, these fibers were tested for their responses to the same stimuli applied to the nerve. In some cases, the nerve was crushed distally after the nerve fibers had been characterized by their responses to physiological stimulation of the skin, and the responses to stimuli applied to the nerve proximal to the lesion were tested again. Almost all non-nociceptive cold-sensitive (type 1) C-fibers (97%) could be activated by cold stimuli applied to the nerve. Of nociceptive cold-sensitive (type 2) C-fibers, 39% were activated by cold stimuli applied to the nerve. Furthermore, 34% of heat-sensitive C-fibers could be activated by heating the nerve. In contrast, only 2-4% of mechanosensitive A-fibers and C-fibers responded to mechanical stimuli applied to the nerve. In conclusion, cold and heat sensitivity of cutaneous afferent neurons is not restricted to their terminals in the skin, but often extends along the axons in the nerve. Mechanosensitivity is restricted to the afferent endings in the skin.

Sustained blockade of neurotrophin receptors TrkA, TrkB and TrkC reduces non-malignant skeletal pain but not the maintenance of sensory and sympathetic nerve fibers

Current therapies for treating skeletal pain have significant limitations as available drugs (non-steroidal anti-inflammatory drugs and opiates) have significant unwanted side effects. Targeting nerve growth factor (NGF) or its cognate receptor tropomysin receptor kinase A (TrkA) has recently become an attractive target for inhibition of adult skeletal pain. Here we explore whether sustained administration of a selective small molecule Trk inhibitor that blocks TrkA, TrkB and TrkC kinase activity with nanomolar affinity reduces skeletal pain while allowing the maintenance of sensory and sympathetic neurons in the adult mouse. Twice-daily administration of a Trk inhibitor was begun 1 day post fracture and within 8 h of acute administration fracture pain-related behaviors were reduced by 50% without significant sedation, weight gain or inhibition of fracture healing. Following administration of the Trk inhibitor for 7 weeks, there was no significant decline in the density of unmyelinated or myelinated sensory nerve fibers, sympathetic nerve fibers, measures of acute thermal pain, acute mechanical pain, or general neuromuscular function. The present results suggest that sustained administration of a peripherally selective TrkA, B and C inhibitor significantly reduces skeletal pain without having any obvious detrimental effects on adult sensory and sympathetic nerve fibers or early fracture healing. As with any potential therapeutic advance, understanding whether the benefits of Trk blockade are associated with any risks or unexpected effects will be required to fully appreciate the patient populations that may benefit from this therapeutic approach.

Cutaneous silent period changes in Type 2 diabetes mellitus patients with small fiber neuropathy

Small myelinated (A-delta) and unmyelinated (C) somatic sensory fibers are initially affected and may be the earliest exhibited sign of neuropathy in glucose dysmetabolism. Cutaneous silent period (CSP) is an inhibitory spinal reflex and its afferents consist of A-delta nerve fibers. The aim of this study was to evaluate CSP changes in Type 2 diabetic patients with small fiber neuropathy. Forty-three patients and 41 healthy volunteers were included. CSP latency and duration, as well as CSP latency difference of the upper and lower extremities, were examined. Nerve conduction studies were within normal limits in both groups. Lower extremity CSP latency was longer (122.1+/-15.5 vs. 96.4+/-6.4 ms; p<0.001), CSP duration was shorter (29.5+/-8.9 vs. 43.1+/-5.0 ms; p<0.001), and latency difference was longer (48.1+/-12.6 vs. 22.7+/-3.7; p<0.001) in patients than controls. The difference was more significant in patients with neuropathic pain. No significant difference existed in upper extremity on CSP evaluation. The CSP evaluation together with nerve conduction study, has been demonstrated to be beneficial and performance of latency difference in addition to CSP latency and duration may be a valuable parameter in electrophysiological assessment of diabetic patients with small fiber neuropathy. An additional CSP evaluation may be considered in cases which nerve conduction studies do not provide sufficient information.

Mechano- and thermosensitivity of regenerating cutaneous afferent nerve fibers

Crush lesion of a skin nerve is followed by sprouting of myelinated (A) and unmyelinated (C) afferent fibers into the distal nerve stump. Here, we investigate quantitatively both ongoing activity and activity evoked by mechanical or thermal stimulation of the nerve in 43 A- and 135 C-fibers after crush lesion of the sural nerve using neurophysiological recordings in anesthetized rats. The discharge patterns in the injured afferent nerve fibers and in intact (control) afferent nerve fibers were compared. (1) Almost all (98%) A-fibers were mechanosensitive, some of them exhibited additionally weak cold/heat sensitivity; 7% had ongoing activity. (2) Three patterns of physiologically evoked activity were present in the lesioned C-fibers: (a) C-fibers with type 1 cold sensitivity (low cold threshold, inhibition on heating, high level of ongoing and cold-evoked activity; 23%): almost all of them were mechanoinsensitive and 40% of them were additionally heat-sensitive; (b) C-fibers with type 2 cold sensitivity (high cold threshold, low level of ongoing and cold-evoked activity; 23%). All of them were excited by mechanical and/or heat stimuli; (c) cold-insensitive C-fibers (54%), which were heat- and/or mechanosensitive. (3) The proportions of C-fibers exhibiting these three patterns of discharge to physiological stimuli were almost identical in the population of injured C-fibers and in a population of 91 intact cutaneous C-fibers. 4. Ongoing activity was present in 56% of the lesioned C-fibers. Incidence and rate of ongoing activity were the same in the populations of lesioned and intact type 1 cold-sensitive C-fibers. The incidence (but not rate) of ongoing activity was significantly higher in lesioned type 2 cold-sensitive and cold insensitive C-fibers than in the corresponding populations of intact C-fibers (42/93 fibers vs. 11/72 fibers).

Algesic agents exciting muscle nociceptors

Morphologically, muscle nociceptors are free nerve endings connected to the CNS by thin myelinated (group III) or unmyelinated (group IV) afferent fibers. Not all of these endings are nociceptive; approximately 40% have a low mechanical threshold and likely fulfill non-nociceptive functions. Two chemical stimuli are particularly relevant as causes of muscle pain. The first is a drop in tissue pH, i.e. an increase in proton (H+) concentration. A large number of painful patho(physio)logical alterations of muscle tissue are associated with an acidic interstitial pH (e.g. tonic contractions, spasm, inflammation). The second important cause of muscle pain is a release of adenosine triphosphate (ATP). ATP is present in all body cells, but in muscle its concentration is particularly high. Any damage of muscle cells (trauma, necrotic myositis) is accompanied by a release of ATP from the cells. Therefore, ATP is considered a general pain stimulus by some. ATP and protons are relatively specific stimuli for muscle pain; in cutaneous pain they play a less important role. The numerous agents that are released in pathologically altered muscle include substances that desensitize mechanosensitive group IV receptors. Capsaicin has a long-lasting desensitizing action, brain-derived neurotrophic factor, and tumor necrosis factor-alpha, a short-lasting one. Most of the agents exciting group IV units (e.g. low pH, ATP, capsaicin) activate not only nociceptive endings but also non-nociceptive ones. The only substance encountered that excites exclusively nociceptive group IV receptors is nerve growth factor (NGF). In rat muscle chronically inflamed with complete Freund's adjuvant, most group IV endings are sensitized to mechanical (and to some) chemical stimuli. However, stimulants such as ATP, NGF, and solutions of low pH were found to be less effective in inflamed muscle. A possible explanation for this surprising finding is that in inflamed muscle the concentrations of ATP and NGF and H+ are increased. Therefore, experimental administration of these agents is a less effective stimulus.

Caudal end of the rat spinal dorsal horn

We have previously demonstrated that the transformation of the caudal spinal cord through the conus medullaris to the filum terminale takes place in three steps. In the conus medullaris the twin layers of CGRP-immunoreactive and IB4-labeled primary afferent fibers as well as the translucent portion of the superficial dorsal horn equivalent to the substantia gelatinosa discontinue before the complete removal of the dorsal horn. Parallel with these changes VGLUT1-immunoreactive myelinated primary afferent fibers arborize not only in the deep layers but also in the entire extension of the remaining dorsal horn, while scattered CGRP fibers still remains at the margin of and deep in the dorsal horn. PKCgamma-immunoreactive dorsal horn neurons discontinue parallel with the disappearance of the IB4-labeled nerve fibers. These observations suggest that in the dorsal horn certain neurons are linked to the substantia gelatinosa, while others are substantia gelatinosa-independent neurons.

Innocuous, Not Noxious, Input Activates PKCγ Interneurons of the Spinal Dorsal Horn via Myelinated Afferent Fibers

Protein kinase C gamma (PKCgamma), which is concentrated in interneurons of the inner part of lamina II of the dorsal horn, has been implicated in injury-induced allodynia, a condition wherein pain is produced by innocuous stimuli. Although it is generally assumed that these interneurons receive input from the nonpeptidergic, IB4-positive subset of nociceptors, the fact that PKCgamma cells do not express Fos in response to noxious stimulation suggests otherwise. Here, we demonstrate that the terminal field of the nonpeptidergic population of nociceptors, in fact, lies dorsal to that of PKCgamma interneurons. There was also no overlap between the PKCgamma-expressing interneurons and the transganglionic tracer wheat germ agglutinin which, after sciatic nerve injection, labels all unmyelinated nociceptors. However, transganglionic transport of the beta-subunit of cholera toxin, which marks the medium-diameter and large-diameter myelinated afferents that transmit non-noxious information, revealed extensive overlap with the layer of PKCgamma interneurons. Furthermore, expression of a transneuronal tracer in myelinated afferents resulted in labeling of PKCgamma interneurons. Light and electron microscopic double labeling further showed that the VGLUT1 subtype of vesicular glutamate transmitter, which is expressed in myelinated afferents, marks synapses that are presynaptic to the PKCgamma interneurons. Finally, we demonstrate that a continuous non-noxious input, generated by walking on a rotarod, induces Fos in the PKCgamma interneurons. These results establish that PKCgamma interneurons are activated by myelinated afferents that respond to innocuous stimuli, which suggests that injury-induced mechanical allodynia is transmitted through a circuit that involves PKCgamma interneurons and non-nociceptive, VGLUT1-expressing myelinated primary afferents.

Reflex Sympathetic Activity After Intravenous Administration of Midazolam in Anesthetized Cats

Although intrathecal midazolam has been reported to produce antinociceptive effects mediated by gamma-aminobutyric acid type A-benzodiazepine receptor complexes in the spinal cord, the effects of systemic midazolam on nociception remain unclear. We performed this study to examine the effects of IV-administered midazolam on somatosympathetic Adelta and C reflex discharges in brain-intact cats and decerebrate cats (with transection at midbrain level). Somatosympathetic Adelta and C reflexes were elicited in the inferior cardiac sympathetic nerve by electrical stimulation of myelinated (Adelta) and unmyelinated (C) afferent fibers of the superficial peroneal nerve in 28 mature cats. After control somatosympathetic reflex responses were obtained, midazolam was administered IV to four groups of randomly allocated cats as follows: brain-intact cats at a dose of 0.03 mg/kg, brain-intact cats at a dose of 0.1 mg/kg, brain-intact cats at a dose of 0.5 mg/kg, and decerebrate cats at a dose of 0.1 mg/kg. C reflex discharges were significantly augmented at the dose of 0.03 mg/kg and significantly depressed at the dose of 0.1 and 0.5 mg/kg in brain-intact cats. C reflex discharges were also significantly depressed at the dose of 0.1 mg/kg in decerebrate cats. We have demonstrated that IV midazolam produces dose-related effects on somatosympathetic reflex discharges. The clinical implication of these findings is that the effect of midazolam on nociception depends on its dosage. It also appears that the infra-midbrain region plays a major role in mediating the depressive effects of midazolam on somatosympathetic C reflex discharges.

Small‐fiber involvement in spinobulbar muscular atrophy (Kennedy's disease)

We assessed the involvement of cutaneous innervation in two subjects with a molecularly confirmed diagnosis of spinobulbar muscular atrophy (SBMA) using antidromic nerve conduction studies, quantitative sensory testing, and sweat tests, as well as immunohistochemical techniques and confocal microscopy of glabrous and hairy skin biopsy. Both patients showed a marked reduction in amplitude of sensory action potentials and moderate or severe abnormalities of tactile thresholds and mechanical pain perception. A severe reduction of sweat drops on the Silastic imprint test and a widespread loss of small myelinated and unmyelinated fibers in hairy skin were also observed. Fiber loss involved either somatic or autonomic fibers and did not show any distal-proximal gradient. These results, together with loss of Meissner corpuscles and their large myelinated afferent fibers in glabrous skin, confirmed the extensive involvement of sensory neurons of large and small size and revealed an autonomic skin denervation in SBMA.

Aging of the Somatosensory System: A Translational Perspective

Balance in the elderly population is a major concern given the often catastrophic and disabling consequences of fall-related injuries. Structural and functional declines of the somatosensory system occur with aging and potentially contribute to postural instability in older adults. The objectives of this article are: (1) to discuss the evidence regarding age-related anatomical and physiological changes that occur in the peripheral proprioceptive and cutaneous systems, (2) to relate the basic science research to the current evidence regarding clinical changes associated with normal aging, and (3) to review the evidence regarding age-related proprioceptive and cutaneous clinical changes and relate it to research examining balance performance in older adults. The article is organized by an examination of the receptors responsible for activating afferent pathways (muscle spindle, golgi tendon organ, and articular and cutaneous receptors) and the corresponding sensory afferent fibers and neurons. It integrates basic science laboratory findings with clinical evidence suggesting that advanced aging results in a decline in cutaneous sensation and proprioception. The potential relationship between postural instability and sensory impairments in older adults also is discussed. Current laboratory and clinical evidence suggests that aging results in: (1) diverse and nonuniform declines in the morphology and physiological function of the various sensory structures examined, (2) preferential loss of distal large myelinated sensory fibers and receptors, and (3) impaired distal lower-extremity proprioception, vibration and discriminative touch, and balance. These findings provide foundational knowledge that emphasizes the importance of using reliable and valid sensory testing protocols for older adults and the need for further research that clarifies the relationship between sensory impairment and balance.

Anhidrosis: A clue to an underlying autonomic disorder

We describe a patient with Ross syndrome who had the classic triad of segmental anhidrosis, tonic pupils and hyporeflexia. Dilute pilocarpine (0.1%) instillation in both eyes revealed parasympathetic denervation hypersensitivity. There was evidence of cardiac dysautonomia in the form of a decrease in heart rate variability with deep breathing and an abnormal Valsalva response. A thermoregulatory sweat test showed the presence of sweating in the right cheek, neck and upper one-third of the left arm and shoulder only. Sympathetic skin responses were absent in the affected segments of the upper limb. Ross syndrome is a degenerative disorder that progressively involves different fibre populations, starting with autonomic fibres and then involving the unmyelinated and myelinated sensory fibres. A careful clinical examination and simple bedside autonomic tests can confirm the diagnosis.

Distribution of synaptic field potentials induced by TTX-resistant skin and muscle afferents in rat spinal segments L4 and L5

Previous results from our group and others showed that skin and muscle afferents are equipped with tetrodotoxin-resistant (TTX-r) channels. The great majority of the TTX-r fibres are unmyelinated (C or group IV) and are assumed to have nociceptive functions. Therefore, a block of the TTX-sensitive (TTX-s) fibres offers the possibility to study reactions of central nervous neurones to a purely nociceptive input. The present study compared spinal synaptic field potentials (SFPs) evoked by electrical stimulation of TTX-r afferent fibres from skin and muscle at various depths of the spinal segments L4 and L5 in the rat. Cutaneous input was produced by stimulation of the sural nerve (SU), input from muscle by stimulation of the gastrocnemius-soleus nerves (GS). To block the (non-nociceptive) TTX-s afferents, a pool containing TTX (concentration 1 μM) was built around the dorsal roots L3–L6. As a measure of synaptic activity, the area of averaged SFPs was determined. After TTX application, the SFPs of fast conducting myelinated afferent fibres vanished completely. Simultaneously, the size of the potentials evoked by electrical stimulation of slowly conducting TTX-r skin and muscle afferents increased significantly. The field potentials of TTX-r GS afferents had a maximum in laminae IV–VI of the dorsal horn, whereas the SFPs induced by SU stimulation were more evenly distributed over all laminae. The results are a further indication that nociceptive input from skin and muscle is differently processed at the spinal level.