Stimulation Of Saphenous Nerve Research Articles

Distribution, course, and spatial relationships of the saphenous nerve: A 3D neuroanatomical map for nerve stimulation.

The overall objective of this study was to construct a 3D neuroanatomical map of the saphenous nerve based on cartesian coordinate data to define its course in 3D space relative to bony and soft tissue landmarks. Ten lower limb embalmed specimens were meticulously dissected, digitized, laser scanned, and modelled in 3D. The course of the main branches, number of collateral branches, and relationship of saphenous nerve to the great saphenous vein were defined and quantified using the high-fidelity 3D models. In 60% of specimens, the saphenous nerve was found to have three branches in the leg, infrapatellar, anterior, and posterior. In 40% of specimens, the posterior branch was absent. Three landmarks were found to consistently localize the anterior branch: the medial border of tibia at the level of the tibial tuberosity, the medial border of tibia at the level of the mid-point of leg, and the mid-point of the anterior border of the medial malleolus. The posterior branch, when present, had variable branching patterns but did not extend as far distally as the medial malleolus in any specimen. Anatomically, the anterior and posterior branches at the level of the tibial tuberosity could be most advantageous for nerve stimulation due to their close proximity to the bifurcation of the saphenous nerve where the branches are larger and more readily localizable than distally. Additionally, the tibial tuberosity is a prominent landmark that can be easily identified in most individuals and could be used to localize the anterior and posterior branch using ultrasound or other imaging modalities. These findings will enable implementation of highly realistic computational models that can be used to simulate saphenous nerve stimulation using percutaneous and implanted devices.

Prolonged inhibition of bladder function is evoked by low-amplitude electrical stimulation of the saphenous nerve in urethane-anesthetized rats.

To better understand the effects of saphenous nerve (SN) stimulation on bladder function, we investigated the duration of electrical stimulation as a key variable in eliciting urodynamic changes. SN stimulation is a novel approach to electrically modulating bladder function. In previous animal studies, bladder-inhibitory responses were evoked by low-amplitude (25 μA) stimulus pulses applied in short-duration (10min) trials and at frequencies between 10 and 20 Hz. Experiments were performed in urethane-anesthetized rats that were separated into three groups: intravesical saline infusion + SN stimulation (group A), intravesical 0.1% acetic acid infusion + SN stimulation (group B), and intravesical saline infusion + no SN stimulation (group C). Changes in bladder function- basal bladder pressure (P base ), contraction amplitude (ΔP), and inter-contraction interval (T ICI )-were measured in response to stimulation trials applied for different durations (10, 20, and 40 min). Trials were also repeated at frequencies of 10 and 20 Hz. In group A, longer-duration (40 min) stimulation trials applied at 10Hz evoked overflow incontinence (OI) episodes that were characterized by significant changes in P base (122.7 ± 9.1%, p=0.026), ΔP (-60.8 ± 12.8%, p=0.044), and T ICI (-43.2 ± 13.0%, p=0.031). Stimulation-evoked OI was observed in 5 of 8 animals and lasted for 56.5 ± 10.7min. In contrast, no significant changes in bladder function were observed in either group B or group C. Our findings show that longer-duration trials consisting of electrical pulses applied at 10Hz are important stimulation parameters that elicit inhibitory bladder responses in anesthetized rodents.

Frequency-Dependent Effects on Bladder Reflex by Saphenous Nerve Stimulation and a Possible Action Mechanism of Tibial Nerve Stimulation in Cats.

PurposeThe present study determined the effects of saphenous nerve stimulation (SNS) at different stimulation frequencies on bladder reflex and explored a possible action mechanism of tibial nerve stimulation (TNS) on bladder activity in cats.MethodsTwo bipolar nerve cuff electrodes were implanted on the saphenous nerve and the contralateral tibial nerve in 13 cats, respectively. Multiple cystometrograms were obtained to determine the effects of single SNS at different frequencies and that of combined SNS and TNS on the micturition reflex by infusing normal saline.ResultsSNS at 1 Hz significantly reduced the bladder capacity (BC) to 59.8%±7.7% and 59.3%±5.8% of the control level at the intensity threshold (T) and 2T, respectively (P<0.05), while that at 20 Hz significantly increased the BC to 130.6%±4.2% of the control level at 6T (P<0.05). The TNS and SNS at 20 Hz did not significantly change the BCs at 1T (P>0.05), while combined stimulation at 1T significantly increased the BC to 122.7%±1.9% of the control level and induced an inhibitory effect which was similar to that TNS at 2T.ConclusionsThe current study revealed that SNS reduced and increased BC depending on different stimulation frequencies. The combined SNS and TNS maximized the clinical efficacy at a low intensity. Also, SNS may be a potential therapeutic mechanism of TNS.

Transecting the hypogastric nerve to uncover the bladder-inhibitory pathways involved with saphenous nerve stimulation in anesthetized rats.

Saphenous (SAFN) nerve stimulation was recently shown in anesthetized rats to elicit bladder-inhibitory responses in a frequency-dependent manner; however, the mechanism of action is unknown. The goal of this study was to investigate the potential role of the hypogastric nerve (HGN) in this inhibitory pathway by examining stimulation-evoked changes in bladder function under four different experimental conditions: (1) HGN intact, saline infusion (HGNi-s), (2) HGN transected, saline infusion (HGNt-s), (3) HGN intact, acetic acid (AA) infusion (HGNi-a), and (4) HGN transected, AA infusion (HGNt-a). Experiments were conducted in 33 urethane-anesthetized female rats, where continuous bladder infusion was provided through a suprapubic catheter. The experimental protocol involved two, 40-min stimulation trials in which electrical pulses were applied to the SAFN at a set frequency (10Hz) and two different amplitudes (50μA and 100μA). In all experimental groups, SAFN stimulation resulted in complete suppression of bladder activity with an incidence rate of 25% to 50%. However, significant changes in the measured urodynamic changes (e.g., basal pressure, contraction amplitude, and inter-contraction interval) were found only in the HGNt-a animals. Our findings suggest that the HGN does not mediate the inhibitory effects of SAFN stimulation and that bladder inhibition is achieved through a different mechanism of action.

A pilot feasibility study of treating overactive bladder patients with percutaneous saphenous nerve stimulation.

Effective long-term treatment of overactive bladder (OAB) remains a significant clinical challenge. We present our initial experience with a new bladder neuromodulation method that electrically targets the saphenous nerve (SAFN). A total of 18 OAB patients (female, 55-84 years) were provided with percutaneous SAFN stimulation. The SAFN was targeted with a needle electrode inserted below the medial condyle of the tibia. Activation of the SAFN was confirmed by the patient's perception of paresthesia radiating down the leg. Electrical stimulation was applied for 30 min and subsequently repeated weekly for 3 months. The effects of stimulation were assessed by a 4-day bladder diary and quality-of-life questionaire (OAB-q). Percutaneous SAFN stimulation was confirmed in all 16 patients who completed the study, and no adverse events were reported. Positive response to SAFN stimulation was achieved in 87.5% (14 of 16) of patients, as determined by either a minimum 50% reduction in bladder symptoms or a minimum 10 point increase in the HRQL total score. Electrical activation of the SAFN was consistently achieved using anatomical landmarks and patient feedback. The procedure was well tolerated and, based on our small cohort of patients, appears efficacious, and safe. This pilot study provides early feasibility data that points to a promising new intervention for treating OAB.

Saphenous nerve stimulation normalizes bladder underactivity induced by tibial nerve stimulation in cats.

This study in α-chloralose-anesthetized cats aimed at investigating the bladder responses to saphenous nerve stimulation (SNS). A urethral catheter was used to infuse the bladder with saline and to record changes in bladder pressure. With the bladder fully distended, SNS at 1-Hz frequency and an intensity slightly below the threshold (T) for inducing an observable motor response of the hindlimb muscles induced large amplitude (40-150 cmH2O) bladder contractions. Application of SNS (1 Hz, 2-4T) during cystometrograms (CMGs), when the bladder was slowly (1-3 ml/min) infused with saline, significantly ( P < 0.05) increased the duration of the micturition contraction to >200% of the control without changing bladder capacity or contraction amplitude. Repeated application (1-8 times) of intense (4-8T intensity) 30-min tibial nerve stimulation (TNS) produced prolonged post-TNS inhibition that significantly ( P < 0.01) increased bladder capacity to 135.9 ± 7.6% and decreased the contraction amplitude to 44.1 ± 16.5% of the pre-TNS control level. During the period of post-TNS inhibition, SNS (1 Hz, 2-4T) applied during CMGs completely restored the bladder capacity and the contraction amplitude to the pre-TNS control level and almost doubled the duration of the micturition contraction. These results indicate that SNS at 1 Hz can facilitate the normal micturition reflex and normalize the reflex when it is suppressed during post-TNS inhibition. This study provides an opportunity to develop a novel neuromodulation therapy for underactive bladder using SNS.

Locomotion in intact and in brain cortex-ablated cats

The current decerebration procedures discard the role of the thalamus in the motor control and decortication only rules out the brain cortex part, leaving a gap between the brain cortex and the subthalamic motor regions. In here we define a new preparation denominated Brain Cortex-Ablated Cat (BCAC), in which the frontal and parietal brain cortices as well as the central white matter beneath them were removed, this decerebration process may be considered as suprathalamic, since the thalamus remained intact. To characterize this preparation cat hindlimb electromyograms (EMG), kinematics and cutaneous reflexes (CR) produced by electrical stimulation of sural (SU) or saphenous (SAPH) nerves were analyzed during locomotion in intact and in BCAC. In cortex-ablated cats compared to intact cats, the hindlimb EMG amplitude was increased in the flexors, whereas in most extensors the amplitude was decreased. Bifunctional muscle EMGs presented complex and speed-dependent amplitude changes. In intact cats CR produced an inhibition of extensors, as well as excitation and inhibition of flexors, and a complex pattern of withdrawal responses in bifunctional muscles. The same stimuli applied to BCAC produced no detectable responses, but in some cats cutaneous reflexes produced by electrical stimulation of saphenous nerve reappeared when the locomotion speed increased. In BCAC, EMG and kinematic changes, as well as the absence of CR, imply that for this cat preparation there is a partial compensation due to the subcortical locomotor apparatus generating close to normal locomotion.

Frequency-dependent inhibition of bladder function by saphenous nerve stimulation in anesthetized rats.

Percutaneous tibial nerve stimulation (PTNS) is an effective neuromodulation therapy for treating overactive bladder (OAB). The therapeutic effects are achieved by repeatedly applying electrical stimulation through a percutaneous needle electrode that is used to target the tibial nerve (TN). Anatomical studies indicate there can be multiple saphenous nerve (SAFN) branches located near the site of electrical stimulation, and therefore we investigated the possibility of evoking a bladder-inhibitory reflex by electrically activating the SAFN. Acute experiments were conducted in 26 urethane-anesthetized rats. Changes in bladder contraction rate (BCR) and bladder capacity were measured in response to 10-min SAFN stimulation trials. Electrical pulses were applied at 25 µA and at stimulation frequencies between 2 Hz and 50 Hz. We report that SAFN stimulation at 20 Hz was most effective at reflexively decreasing the BCR (53.8 ± 5.4% from baseline) and also increasing the bladder capacity (145.8 ± 43.5% from baseline). In contrast, SAFN stimulation at other frequencies yielded inconsistent changes in bladder function. Carry-over effects were minimized by randomizing the sequence of SAFN stimulation trials and also by allowing the bladder to return to the baseline conditions. With notable changes in both the BCR and bladder capacity, our findings provide evidence of a novel bladder-inhibitory reflex in anesthetized rats that is mediated by the SAFN. Further work is needed to determine the clinical relevance of this neural pathway.

Endocannabinoids inhibit neurogenic inflammation in murine joints by a non-canonical cannabinoid receptor mechanism

Neurogenic inflammation is a local inflammatory response that is driven by the peripheral release of neuropeptides from small diameter afferents which occurs in many organs including joints. The knee joint has a rich endocannabinoid system which has been shown to decrease acute synovitis. The aim of this study was to investigate the influence of joint afferents on leukocyte-endothelial interactions within the synovial microcirculation of mice and determine the role of endocannabinoids on this inflammatory response. Electrical, antidromic stimulation of the saphenous nerve decreased leukocyte rolling at the lowest frequency tested (0.5Hz), while increasing leukocyte rolling at higher frequencies (2.0 and 5.0Hz). The leukocyte rolling effect of nerve stimulation was completely abolished by pre-treating the knee with the vasoactive intestinal peptide antagonist VIP6–28; however, neither calcitonin gene related peptide nor substance P antagonism had an effect on this neurogenic inflammatory response. Treating knees with the endocannabinoid breakdown inhibitor URB597 completely blocked leukocyte rolling and this effect could be reversed with the non-canonical cannabinoid antagonist O-1918. These results provide evidence that antidromic stimulation of the mouse saphenous nerve promotes leukocyte rolling within the synovial microcirculation, and that endocannabinoids can attenuate this neurogenic inflammatory response.

Recording of cord dorsum potentials in calves

Cord dorsum potentials are sensory evoked potentials being used to assess proximal sensory nerve, dorsal nerve root and spinal cord dorsal horn function. The purpose of the present study was to establish normal values for onset latency, peak latency and peak-to-peak amplitude of cord dorsum potentials after saphenous nerve stimulation in 15 healthy calves.Under general anesthesia, the saphenous nerve was stimulated in the periphery and cord dorsum potentials were recorded from the interarcuate space L3–L4, L4–L5, L5–L6 and L6–S1.Cord dorsum potentials were easily recorded at the different recording sites and consisted of a large negative peak followed by a long latency positive phase. The largest responses were recorded at the L5–L6 interarcuate space. Body temperature significantly influenced peak-to-peak amplitude. Onset latency prolonged with increasing limb length.

Peptide-mediated transdermal delivery of botulinum neurotoxin type A reduces neurogenic inflammation in the skin

Release of inflammatory pain mediators from peripheral sensory afferent endings contributes to the development of a positive feedback cycle resulting in chronic inflammation and pain. Botulinum neurotoxin type A (BoNT-A) blocks exocytosis of neurotransmitters and may therefore block the release of pain modulators in the periphery. Subcutaneous administration of BoNT-A (2.5, 5 and 10U) reduced plasma extravasation (PE) caused by electrical stimulation of the saphenous nerve or capsaicin in the rat hindpaw skin (ANOVA, Post hoc Tukey, p<0.05, n=6). Subcutaneous BoNT-A also reduced blood flow changes evoked by saphenous nerve stimulation (ANOVA, Post hoc Tukey, p<0.05, n=6). Subcutaneous BoNT-A had no effect on PE induced by local injection of substance P (SP) or vasodilation induced by local CGRP injection. Although BoNT-A is an effective treatment for a wide range of painful conditions, the toxin’s large size necessitates that it be injected at numerous sites. We found that a short synthetic peptide (TD-1) can facilitate effective transdermal delivery of BoNT-A through intact skin. Coadministration of TD-1 and BoNT-A to the hindpaw skin resulted in a significant reduction in PE evoked by electrical stimulation. The findings show that BoNT-A can be administered subcutaneously or topically with a novel transdermal delivery peptide to reduce inflammation produced by activating nociceptors in the skin. Peptide-mediated delivery of BoNT-A is an easy and non-invasive way of administering the toxin that may prove to be useful in clinical practice.

Frequency dependent changes in mechanosensitivity of rat knee joint afferents after antidromic saphenous nerve stimulation

The aim of the present study was to examine the effect of electrical saphenous nerve stimulation (14 V, 1–10 Hz) on the mechanosensitivity of rat knee joint afferents. The responses to passive joint rotations at defined torque were recorded from slowly conducting knee joint afferent nerve fibres (0.6–20.0 m/s). After repeated nerve stimulation with 1 Hz, the mechanosensitivity of about 79% of the units was significantly affected. The effects were most prominent at a torque close to the mechanical threshold. In about 46% of the examined nerve fibres a significant increase was obtained, whereas about 33% reduced their mechanosensitivity. The sensitisation was prevented by an application of 5 μM phentolamine, an α-adrenergic receptor blocker, together with a neuropeptide Y receptor blocker. An inhibition of N-type Ca 2+ channels by an application of 1 μM ω-conotoxin GVIA caused comparable changes of the mechanosensitivity during the electrical stimulation. Electrical nerve stimulation with higher frequencies resulted in a further reduction of the mean response to joint rotations. After stimulation with 10 Hz, there was a nearly complete loss of mechanosensitivity. In conclusion, antidromic electrical nerve stimulation leads to a frequency dependent transient decrease of the mechanosensitivity. A sensitisation was only obtained at 1 Hz, but this effect may be based on the influence of sympathetic nerve fibres.

Interaction between interleukin 1β and endogenous neurokinin 1 receptor agonists in mediating plasma extravasation and neutrophil accumulation in the cutaneous microvasculature of the rat

Interleukin 1β (IL-1β) is a potent mediator of neutrophil accumulation. Antidromic stimulation of the rat saphenous nerve leads to neurogenic oedema formation mediated by endogenous tachykinins. Here, we have investigated links between IL-1β and the tachykinin 1 (NK 1) receptors in microvascular events in rat skin. Saphenous nerve-induced plasma extravasation was not modulated by skin pretreatment with IL-1β (3 pmol/site intradermally). In addition, the long-lasting antidromic electrical stimulation did not induce significant neutrophil accumulation in naive rat skin. By comparison, the effect of IL-1β-induced neutrophil accumulation was significantly potentiated by co-stimulation of the ipsilateral saphenous nerve; an effect prevented by an NK 1 receptor antagonist (SR140333, 480 nmol/kg, i.v.). We conclude that IL-1β-induced neutrophil accumulation can be influenced in a pro-inflammatory manner by ongoing neurogenic inflammation, of relevance to the sensory nerve input that occurs during ongoing inflammatory disease.

Cyclo-oxygenase and lipoxygenase pathways in mast cell dependent-neurogenic inflammation induced by electrical stimulation of the rat saphenous nerve.

1. We investigated the role of arachidonic acid metabolism and assessed the participation of mast cells and leukocytes in neurogenic inflammation in rat paw skin. We compared the effect of lipoxygenase (LOX) and cyclo-oxygenase (COX) inhibitors on oedema induced by saphenous nerve stimulation, substance P (SP), and compound 48/80. 2. Intravenous (i.v.) pre-treatment with a dual COX/LOX inhibitor (RWJ 63556), a dual LOX inhibitor/cysteinyl-leukotriene (CysLt) receptor antagonist (Rev 5901), a LOX inhibitor (AA 861), a five-lipoxygenase activating factor (FLAP) inhibitor (MK 886), or a glutathione S-transferase inhibitor (ethacrynic acid) significantly inhibited (40 to 60%) the development of neurogenic oedema, but did not affect cutaneous blood flow. Intradermal (i.d.) injection of LOX inhibitors reduced SP-induced oedema (up to 50% for RWJ 63556 and MK 886), whereas ethacrynic acid had a potentiating effect. 3. Indomethacin and rofecoxib, a highly selective COX-2 inhibitor, did not affect neurogenic and SP-induced oedema. Surprisingly, the structurally related COX-2 inhibitors, NS 398 and nimesulide, significantly reduced both neurogenic and SP-induced oedema (70% and 42% for neurogenic oedema, respectively; 49% and 46% for SP-induced oedema, respectively). 4. COX-2 mRNA was undetectable in saphenous nerves and paw skin biopsy samples, before and after saphenous nerve stimulation. 5. A mast cell stabilizer, cromolyn, and a H(1) receptor antagonist, mepyramine, significantly inhibited neurogenic (51% and 43%, respectively) and SP-induced oedema (67% and 63%, respectively). 6. The co-injection of LOX inhibitors and compound 48/80 did not alter the effects of compound 48/80. Conversely, ethacrynic acid had a significant potentiating effect. The pharmacological profile of the effect of COX inhibitors on compound 48/80-induced oedema was similar to that of neurogenic and SP-induced oedema. 7. The polysaccharide, fucoidan (an inhibitor of leukocyte rolling) did not affect neurogenic or SP-induced oedema. 8. Thus, (i) SP-induced leukotriene synthesis is involved in the development of neurogenic oedema in rat paw skin; (ii) this leukotriene-mediated plasma extravasation might be independent of mast cell activation and/or of the adhesion of leukocytes to the endothelium; (iii) COX did not appear to play a significant role in this process.

Alterations in the distribution of stimulus-evoked c- fos in the spinal cord after neonatal peripheral nerve injury in the rat

Neonatal peripheral nerve injury results in a significant rearrangement of the central terminals of surviving axotomized and adjacent intact primary afferents in the dorsal horn of the spinal cord. This study investigates the ability of these afferents to make functional contacts with dorsal horn cells, using c- fos expression as a marker of synaptic activation. Graded electrical stimulation at A- or C-fiber strength of either the neonatally axotomized sciatic nerve or the adjacent uninjured saphenous nerve was performed in adult rats. Stimulation of the contralateral uninjured nerve served as a control. Quantitative examination of the number and distribution of c- fos-labeled cells in the spinal cord laminae was performed. Electrical stimulation of the previously axotomized sciatic nerve at A-fiber intensity resulted in many labeled profiles in laminae I–V of the lumbar spinal cord on the experimental as compared to the contralateral side. Electrical stimulation of uninjured saphenous nerve or saphenous-nerve-innervated skin (using pin electrodes) at A-fiber intensity did not evoke c- fos. Stimulation of the saphenous nerve at C-fiber intensity, however, resulted in a significant increase in the number and distribution of c- fos-labeled profiles in laminae I–V on the experimental side as compared to the contralateral control side. The results show that the distribution of c- fos-expressing cells after neonatal nerve injury is compatible with the previously demonstrated distribution of sprouting of primary afferents belonging to an uninjured nerve adjacent to an injured nerve, and that the surviving axotomized afferents are capable of transmitting signals to postsynaptic cells. These findings indicate that Aβ afferent stimulation of injured but not uninjured afferents elicits c- fos expression in postsynaptic cells. This may reflect an injury-induced maintenance of a normal developmental process whereby Aβ stimulation elicits c- fos in dorsal horn neurons.

Interaction between somatic and vagal afferent inputs in control of ventilation in 2-week-old rabbits

Effects of saphenous nerve stimulation (SNS) on the Hering–Breuer expiratory-promoting reflex evoked by a positive tracheal pressure (P tr; 5 cmH 2O) and on the diaphragmatic EMG (EMG di), inspiratory (T i) and expiratory (T e) time, were studied in 16 urethane-anesthetized (1.2–1.6 g/kg, i.p.) spontaneously breathing 2-week-old rabbits. Positive P tr applied at the end of T i increased the subsequent T e to 255±29% (±S.E.; P<0.0001) of control. SNS (1 sec train, 2 msec pulse, 6 Hz) applied at the onset of T e, shortened this T e by 42±3% ( P<0.0001). When SNS preceded positive P tr or positive P tr preceded SNS, the T e increased to 163±20 and 184±21% of control, respectively. These responses were not different, and smaller than that provoked by the P tr test alone ( P<0.003 and 0.05, respectively). The results show that in newborns somatic afferent stimulation attenuates the vagally mediated respiratory inhibition, whether immediately before or during the vagal stimulation.

Methylprednisolone prevents the development of autotomy and neuropathic edema in rats, but has no effect on nociceptive thresholds

Corticosteroids are probably an effective treatment for some types of neuropathic pain and complex regional pain syndromes. This study examined the effects of systemic methylprednisolone (MP) on acute nociception and on pain behavior and hyperalgesia in normal and neuropathic rats. There was no dose-response to intraperitoneal MP (up to 12 mg/kg) for nociceptive thresholds to heat (Peltier) or mechanical (analgesy-meter and von Frey fibers) stimuli in normal rats. Chronic high dose MP (3 mg/kg per day for 21 days) also had no effect on acute nociceptive thresholds in normal rats. After sciatic nerve section in rats a saphenous nerve mediated hyperalgesia to heat and mechanical stimuli gradually developed over 21 days. High dose MP (3 mg/kg per day for 21 days) had no effect on this adjacent neuropathic hyperalgesia. When systemic MP was started immediately after bilateral sciatic and saphenous nerve transection there was a dose-dependent reduction in autotomy behavior. Substance P has been proposed as a mediator of neuropathic pain and edema. Single dose MP (12 mg/kg) slightly reduced the substance P mediated extravasation induced with electrical stimulation of the saphenous nerve. Chronic MP (3.4 mg/kg per day for 28 days) severely reduced the neurogenic extravasation induced with saphenous nerve stimulation. Sciatic sectioned rats developed hindpaw edema between 7 and 14 days after surgery, and this neuropathic edema did not develop in rats chronically treated with MP (3.4 mg/kg per day). These results demonstrate that corticosteroids did not affect nociceptive thresholds in normal or neuropathic hyperalgesic rats. Chronic steroid treatment did prevent the development of autotomy and neuropathic edema, and completely blocked neurogenic extravasation, findings consistent with the hypothesis that primary afferent substance P release mediates autotomy pain behavior and neuropathic edema. This may be a relevant model for examining the effects of corticosteroids on neuropathic pain and complex regional pain syndromes.

Somatotopic redistribution of c-fos expressing neurons in the superficial dorsal horn after peripheral nerve injury

The functional somatotopic reorganization of the lumbar spinal cord dorsal horn after nerve injury was studied in the rat by mapping the stimulus-evoked distribution of neurons expressing proto-oncogene c-fos. In three different nerve injury paradigms, the saphenous nerve was electrically stimulated at C-fibre strength at survival times ranging from 40 h to more than six months: 1) Saphenous nerve stimulation from three weeks onwards after ipsilateral sciatic nerve transection resulted in an increase in the number of Fos-immunoreactive neurons within the dorsal horn saphenous territory in laminae I–II, and an expansion of the saphenous territory into the denervated sciatic territory until 14 weeks postinjury. 2) Saphenous nerve stimulation from five days onwards after ipsilateral sciatic nerve section combined with saphenous nerve crush resulted in an increase in the number of Fos-immunoreactive neurons within the dorsal horn saphenous nerve territory, and an expansion of the saphenous nerve territory into the denervated sciatic nerve territory. 3) Stimulation of the crushed nerve (without previous adjacent nerve section) at five days, but not at eight months resulted in a temporary increase in the number of Fos-immunoreactive neurons within the territory of the injured nerve, and no change in area at either survival time. The results indicate that nerve injury results in an increased capacity of afferents in an adjacent uninjured, or regenerating nerve, to excite neurons both in its own and in the territory of the permanently injured nerve in the dorsal horn. The onset and duration of the increased postsynaptic excitability and expansion depends on the types of nerve injuries involved. These findings indicate the complexity of the central changes that follows in nerve injuries that contain a mixture of uninjured, regenerating and permanently destroyed afferents.

Stimulation of saphenous afferent nerve produces vasodilatation of the vasa nervorum via an axon reflex-like mechanism in the sciatic nerve of anesthetized rats

The present study was intended to examine the physiological relevance of peptidergic afferent vasodilative fibers in the regulation of blood flow in the vasa nervorum, with special reference to the axon reflex. The response of nerve blood flow (NBF) in the sciatic nerve to electrical stimulation of saphenous nerve afferents was examined using laser Doppler flowmetry in anesthetized rats whose lumbosacral afferents and efferents had been disconnected from the spinal cord. Repetitive electrical stimulation of unmyelinated fibers in the central cut end of the saphenous nerve produced an increase in NBF in the sciatic nerve ipsilateral to the stimulation, independent of changes in mean arterial blood pressure. This increase was abolished by topical application of a calcitonin gene-related peptide (CGRP) receptor antagonist, hCGRP (8–37). In conclusion, NBF in the sciatic nerve is regulated via an axon reflex-like mechanism by unmyelinated afferent CGRP containing vasodilators with collaterals in the saphenous nerve.

Topical glucocorticoids inhibit neurogenic inflammation: involvement of lipocortin 1

Topical glucocorticoid treatment (betamethasone-17-valerate (0.018 mg/cm 2, 3 h pretreatment) significantly inhibited neurogenic oedema formation induced by electrical antidromic stimulation (2 Hz, 15 V, 0.1 ms for 5 min) of the rat saphenous nerve; a response mediated by neuropeptides released from activated capsaicin-sensitive sensory C-fibres. Oedema formation was estimated by measurement of extravasation of i.v. injected 125I-albumin into skin. The inhibitory effect of the topical glucocorticoid was reversed by passive immunisation of rats with polyclonal antibody to the glucocorticoid-inducible anti-inflammatory protein lipocortin 1 (1 ml/kg, s.c., 24 h pretreatment) whilst a non-immune serum was without effect. Similarly the glucocorticoid receptor antagonist RU38486 (20 mg/kg, 2 and 20 h pretreatment) abrogated the response indicating specific binding to glucocorticoid receptors. Topical glucocorticoid treatment also inhibited the oedema produced by intradermal substance P (0.1 nmol) in the dorsal skin of rats. Topical glucocorticoid inhibited neurogenic oedema formation partly through a mechanism dependent upon lipocortin 1. This inhibition may be partly due to a post-junctional effect upon substance P activity/binding however a pre-junctional component cannot be excluded.