Stimulation Of Sciatic Nerve Research Articles

Kv1.1 knock-in ataxic mice exhibit spontaneous myokymic activity exacerbated by fatigue, ischemia and low temperature

Episodic ataxia type 1 (EA1) is an autosomal dominant neurological disorder characterized by myokymia and attacks of ataxic gait often precipitated by stress. Several genetic mutations have been identified in the Shaker-like K+ channel Kv1.1 (KCNA1) of EA1 individuals, including V408A, which result in remarkable channel dysfunction. By inserting the heterozygous V408A, mutation in one Kv1.1 allele, a mouse model of EA1 has been generated (Kv1.1V408A/+). Here, we investigated the neuromuscular transmission of Kv1.1V408A/+ ataxic mice and their susceptibility to physiologically relevant stressors. By using in vivo preparations of lateral gastrocnemius (LG) nerve–muscle from Kv1.1+/+ and Kv1.1V408A/+ mice, we show that the mutant animals exhibit spontaneous myokymic discharges consisting of repeated singlets, duplets or multiplets, despite motor nerve axotomy. Two-photon laser scanning microscopy from the motor nerve, ex vivo, revealed spontaneous Ca2+ signals that occurred abnormally only in preparations dissected from Kv1.1V408A/+ mice. Spontaneous bursting activity, as well as that evoked by sciatic nerve stimulation, was exacerbated by muscle fatigue, ischemia and low temperatures. These stressors also increased the amplitude of compound muscle action potential. Such abnormal neuromuscular transmission did not alter fiber type composition, neuromuscular junction and vascularization of LG muscle, analyzed by light and electron microscopy. Taken together these findings provide direct evidence that identifies the motor nerve as an important generator of myokymic activity, that dysfunction of Kv1.1 channels alters Ca2+ homeostasis in motor axons, and also strongly suggest that muscle fatigue contributes more than PNS fatigue to exacerbate the myokymia/neuromyotonia phenotype. More broadly, this study points out that juxtaparanodal K+ channels composed of Kv1.1 subunits exert an important role in dampening the excitability of motor nerve axons during fatigue or ischemic insult.

Inhibition by morphine and its analogs of action potentials in adult rat dorsal root ganglion neurons

Although opioids inhibit action potential (AP) conduction in primary-afferent fibers, this has not yet been fully examined. We investigated by using the sharp glass microelectrode technique how opioids (morphine, codeine, and ethylmorphine) affect APs recorded from adult rat dorsal root ganglion (DRG) neurons in response to sciatic nerve stimulation. The DRG neurons were classified into three types, Aα/β, Aδ, and C, according to AP characteristics, including the fiber conduction velocity (CV) of the neuron. AP of the Aα/β neuron was reduced in peak amplitude by each of the opioids in a reversible and concentration-dependent manner. The potency sequence was ethylmorphine > codeine = morphine (IC(50) = 0.70, 2.5, and 2.9 mM, respectively), indicating that this AP inhibition is related to the chemical structure of the opioid. Each of the Aδ and C neuron APs was also inhibited by the opioids; ethylmorphine had a tendency to inhibit APs more effectively than codeine and morphine. This inhibition was variable in extent among neurons and was either comparable to or greater than that of the Aα/β neuron AP. The opioid-induced AP inhibitions were unaffected by nonspecific opioid-receptor antagonist naloxone; opioid-receptor agonists did not affect APs. In conclusion, the opioids inhibited APs in DRG neurons without opioid-receptor activation; this inhibition was different among neurons having different primary-afferent fiber CVs and also among the three kinds of opioid. The inhibition by opioid of primary-afferent fiber AP conduction is suggested to be distinct in extent among fibers conveying distinct types of nociceptive information.

Substance P Signaling Controls Mast Cell Activation, Degranulation, and Nociceptive Sensitization in a Rat Fracture Model of Complex Regional Pain Syndrome

Patients with complex regional pain syndrome have increased tryptase in the skin of the affected extremity indicating mast cell (MC) accumulation and degranulation, processes known to be mediated by substance P (SP). The dysregulation of SP release from primary afferent neurons is characteristic of complex regional pain syndrome. The authors hypothesized that SP acting through the neurokinin-1 receptor results in mast cell accumulation, degranulation, and nociceptive sensitization in a rat model of complex regional pain syndrome. Groups of 6-10 rats underwent tibia fracture and hind limb casting for 4 weeks, and the hind paw skin was harvested for histologic and immunohistochemical analysis. The effects of a selective neurokinin-1 receptor antagonist (LY303870) and of direct SP intraplantar injection were measured. Dermal MC degranulation induced by sciatic nerve stimulation and the effects of LY303870 on this process were investigated. Finally, the antinociceptive effects of acute and chronic treatment with a MC degranulator (48/80) were tested. The authors observed that fracture caused MC accumulation, activation, and degranulation, which were inhibited by LY303870; the percentage of MCs in close proximity to peptidergic nerve fibers increased after fracture; electrical stimulation caused MC activation and degranulation, which was blocked by LY303870; intraplantar SP-induced MC degranulation and acute administration of 48/80 caused MC degranulation and enhanced postfracture nociception, but MC-depleted animals showed less sensitization. These results indicate that facilitated peptidergic neuron-MC signaling after fracture can cause MC accumulation, activation, and degranulation in the injured limb, resulting in nociceptive sensitization.

Control of muscle VO2 kinetics: a role for metabolic rate?

Control of skeletal muscle oxygen uptake (VO2) kinetics is mediated by ADP feedback, oxygen and substrate delivery and mitochondrial content. Controversy remains whether mitochondrial enzyme activation at exercise onset contributes to this control. We tested the hypothesis that VO2 kinetics would be speeded by increased metabolic rate, in pump‐perfused, tetanically‐stimulated muscle (i.e. independent of O2 delivery and muscle recruitment dynamics). The gastrocnemius of 6 anaesthetized, ventilated dogs was isolated and the tendon attached to a force transducer. Blood flow was pump‐controlled at a constant flow (1.09 ± 0.25 L.kg−1.min−1; mean ± SD). Isometric tetanic contractions (50 Hz; 200 ms duration) were elicited via supramaximal sciatic nerve stimulation. Metabolic rate was manipulated using 3 min of stimulation at 0.33 Hz (S1) immediately followed by 3 min at 0.67 Hz (S2); also following prior contractions at 0.67 Hz and 2 min recovery (PS1, PS2). Muscle VO2 was determined contraction‐by‐contraction. τVO2 was lower in S1 (11.4±2.4 s; p<0.05) than S2 (17.6±2.9 s), PS1 (16.6±4.6 s) and PS2 (16.1±2.5 s). Unexpectedly VO2 kinetics were fastest at the lowest stimulation frequency without prior contractions. This implies that any putative role of mitochondrial activation in VO2 kinetic control may be countered by a reduction in cellular energy state (e.g. less negative ΔGATP). Supported by BBSRC: BB/F019521/1

Ultrasound-Guided Peripheral Nerve Stimulator Placement in Two Soldiers with Acute Battlefield Neuropathic Pain

Acute peripheral neuropathic pain after combat-related polytrauma is a common occurrence in the United States military that is often refractory to current drugs and regional anesthesia. Both spinal cord and peripheral nerve stimulation are successfully used for chronic neuropathic pain states, but are not reported for acute neuropathic pain. We present 2 cases of percutaneous ultrasound-guided sciatic peripheral nerve stimulation placement in soldiers who had conditions precluding them from spinal cord stimulation placement. Opioid reduction and marked increase in functionality were possible in one case, and cessation of opioid escalation, with eventual reduction after permanent implantation, was possible in the other.

Effect of electrical stimulation of sciatic nerve on synaptic plasticity of spinal dorsal horn and spinal c-fos expression in neonatal, juvenile and adult rats

To explore the response to nociceptive stimuli in spinal cord of immature rat and observe the electrical stimulation of the sciatic nerve on synaptic plasticity of the spinal dorsal horn and spinal c-fos expression in rats of different ages, MK-801 was added to the spinal cord of rats, and the resulting changes in field potential as well as c-fos expression were recorded. LTP in neonatal rats was mainly evoked by A-type nerve fibers, whereas LTP in juvenile and adult rats was mainly evoked by C-type nerve fibers. C-fos expression was significantly increased in the superficial and deep layers of the spinal dorsal horn and in the ventral horn in neonatal rats indicating that the pain signal changed with age.

Impairment of neurovascular coupling in type 1 diabetes mellitus in rats is linked to PKC modulation of BKCa and Kir channels

We hypothesized that chronic hyperglycemia has a detrimental effect on neurovascular coupling in the brain and that this may be linked to protein kinase C (PKC)-mediated phosphorylation. Therefore, in a rat model of streptozotocin-induced chronic type 1 diabetes mellitus (T1DM), and in nondiabetic (ND) controls, we monitored pial arteriole diameter changes during sciatic nerve stimulation and topical applications of the large-conductance Ca(2+)-operated K(+) channel (BK(Ca)) opener, NS-1619, or the K(+) inward rectifier (Kir) channel agonist, K(+). In the T1DM vs. ND rats, the dilatory response associated with sciatic nerve stimulation was decreased by ∼30%, whereas pial arteriolar dilations to NS-1619 and K(+) were largely suppressed. These responses were completely restored by the acute topical application of a PKC antagonist, calphostin C. Moreover, the suffusion of a PKC activator, phorbol 12,13-dibutyrate, in ND rats was able to reproduce the vascular reactivity impairments found in T1DM rats. Assay of PKC activity in brain samples from T1DM vs. ND rats revealed a significant gain in activity only in specimens harvested from the pial and superficial glia limitans tissue, but not in bulk cortical gray matter. Altogether, these findings suggest that the T1DM-associated impairment of neurovascular coupling may be mechanistically linked to a readily reversible PKC-mediated depression of BK(Ca) and Kir channel activity.

Probabilistic modeling of selective stimulation of the human sciatic nerve with a flat interface nerve electrode

Ankle control is critical to both standing balance and efficient walking. The hypothesis presented in this paper is that a Flat Interface Nerve Electrode (FINE) placed around the sciatic nerve with a fixed number of contacts at predetermined locations and without a priori knowledge of the nerve's underlying neuroanatomy can selectively control each ankle motion. Models of the human sciatic nerve surrounded by a FINE of varying size were created and used to calculate the probability of selective activation of axons within any arbitrarily designated, contiguous group of fascicles. Simulations support the hypothesis and suggest that currently available implantable technology cannot selectively recruit each target plantar flexor individually but can restore plantar flexion or dorsiflexion from a site on the sciatic nerve without spillover to antagonists. Successful activation of individual ankle muscles in 90% of the population can be achieved by utilizing bipolar stimulation and/or by using a cuff with at least 20 contacts.

Reference values and clinical application of magnetic peripheral nerve stimulation in cats

Magnetic stimulation of radial (RN) and sciatic (SN) nerves was performed bilaterally in 40 healthy cats. Reference values for onset latency and peak-to-peak amplitude of magnetic motor evoked potentials (MMEPs) were obtained and compared with values of electric motor evoked potentials (EMEPs) in 10/40 cats. Onset latencies and peak-to-peak amplitudes of the MMEPs of three cats with polyneuropathy (PNP) were compared to the reference values. Magnetic motor evoked responses were easily recorded in all normal cats. Significant differences were found in onset latencies between MMEPs and EMEPs, but peak-to-peak amplitudes were equal. The MMEPs of three cats with PNP can be seen as outliers in comparison to the reference values. MMEPs from the RN and SN were easily obtained and reproducible in normal cats. The technique could represent a useful adjunct in the assessment of peripheral nerve disorders.

Sciatic nerve stimulation for injection of the piriformis muscle: safety and efficacy

Sciatic nerve stimulation for injection of the piriformis muscle: safety and efficacy

Electrical stimulation at distinct peripheral sites in spinal nerve injured rats leads to different afferent activation profiles

The neurophysiological basis by which neuromodulatory techniques lead to relief of neuropathic pain remains unclear. We investigated whether electrical stimulation at different peripheral sites induces unique profiles of A-fiber afferent activation in nerve-injured rats. At 4–6 weeks after subjecting rats to L5 spinal nerve injury (SNL) or sham operation, we recorded the orthodromic compound action potential (AP) at the ipsilateral L4 dorsal root in response to (1) transcutaneous electrical nerve stimulation (TENS, a patch electrode placed on the dorsum of the foot), (2) subcutaneous electrical stimulation (SQS, electrode inserted subcutaneously along the dorsum of the foot), (3) peroneal nerve stimulation (PNS, electrode placed longitudinally abutting the nerve), and (4) sciatic nerve stimulation (SNS). The area under the Aα/β compound AP was measured as a function of the bipolar, constant-current stimulus intensity (0.02–6.0 mA, 0.2 ms). In both nerve-injured and sham-operated groups, the stimulus-response (S-R) functions of the Aα/β compound APs differed substantially with the stimulation site; SNS having the lowest threshold and largest compound AP waveform, followed by PNS, SQS, and TENS. The S-R function to PNS was shifted to the right in the SNL group, compared to that in the sham-operated group. The Aα/β-threshold to PNS was higher in the SNL group than in the sham-operated group. The S-R functions and Aα/β-thresholds to TENS and SQS were comparable between the two groups. Electrical stimulation of different peripheral targets induced distinctive profiles of A-fiber afferent activation, suggesting that the neuronal substrates for the various forms of peripheral neuromodulatory therapies may differ.

Effects of Ozone on Sciatic Nerve in Rat

This study evaluated the influence of ozone on rat sciatic nerve structure and function. Thirty Wistar rats were randomly divided into six groups (n = 5). In groups I to IV, 1ml of ozone (O(3)) 10 μg/ml, 30 μg/ml, 50 μg/ml, 8 0 μg/ml was injected at the junction of gluteus maximus margin and lateral edge of the long head of biceps femoris respectively, in group V, 1 ml of pure O(2) was injected at the same point, and group V had puncture without any injection. Ozone was manufactured by an ozone generator (Ozone Line Co, Italy). The rats were investigated by both gross measurement and behavioral changes. One day, one week and three weeks after injection, rat hindlimb footprints were measured and the sciatic nerve function index (SFI) was calculated, and after three weeks, all right sciatic nerves were exposed under anesthesia. Near neural stimulation of the rat sciatic nerve was calculated and nerve conduction velocity, latency and maximum amplitude recorded. Animals were sacrificed for pathology, and ipsilateral triceps surae were taken for wet weight. No serious behavioral abnormalities were observed in any animal. SFI comparison in the various times and various groups showed no significant differences (p<0.05), and nerve conduction velocity, latency and maximum amplitude difference amongst the groups was not significant (p<0.05). There were no abnormalities in peripheral nerves pathologically after injection. Our initial study suggests that ozone concentrations from 10 μg/ml to 80 μg/ml injected around rat's peripheral nerve will not cause serious sequelae or serious damage to the structure and function of peripheral nerve. This finding provides evidence of the safety of ozone injected around the peripheral nerve.

T713 SCIATIC NERVE STIMULATION FOR INJECTION OF THE PIRIFORMIS MUSCLE: SAFETY AND EFFICACY

European Journal of Pain SupplementsVolume 5, Issue S1 p. 98-99 T713 SCIATIC NERVE STIMULATION FOR INJECTION OF THE PIRIFORMIS MUSCLE: SAFETY AND EFFICACY M. Mayo-Moldes, M. Mayo-Moldes Anaesthesia, Meixoeiro Hospital, Vigo, SpainSearch for more papers by this authorA. Carregal, A. Carregal Anaesthesia, Meixoeiro Hospital, Vigo, SpainSearch for more papers by this authorT. Fernandez, T. Fernandez Anaesthesia, Meixoeiro Hospital, Vigo, SpainSearch for more papers by this authorM. Corujeira, M. Corujeira Anaesthesia, Meixoeiro Hospital, Vigo, SpainSearch for more papers by this authorJ. Carballo, J. Carballo Anaesthesia, Meixoeiro Hospital, Vigo, SpainSearch for more papers by this author M. Mayo-Moldes, M. Mayo-Moldes Anaesthesia, Meixoeiro Hospital, Vigo, SpainSearch for more papers by this authorA. Carregal, A. Carregal Anaesthesia, Meixoeiro Hospital, Vigo, SpainSearch for more papers by this authorT. Fernandez, T. Fernandez Anaesthesia, Meixoeiro Hospital, Vigo, SpainSearch for more papers by this authorM. Corujeira, M. Corujeira Anaesthesia, Meixoeiro Hospital, Vigo, SpainSearch for more papers by this authorJ. Carballo, J. Carballo Anaesthesia, Meixoeiro Hospital, Vigo, SpainSearch for more papers by this author First published: 30 January 2012 https://doi.org/10.1016/S1754-3207(11)70336-4Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume5, IssueS1September 2011Pages 98-99 RelatedInformation

Kinetic control of oxygen consumption during contractions in self‐perfused skeletal muscle

Fast kinetics of muscle oxygen consumption (VO2) is characteristic of effective physiological systems integration. The mechanism of VO2 kinetic control in vivo is equivocal as measurements are complicated by the twin difficulties of making high-frequency direct measurements of VO2 and intramuscular metabolites, and in attaining high [ADP]; complexities that can be overcome utilising highly aerobic canine muscle for the investigation of the transition from rest to contractions at maximal VO2. Isometric tetanic contractions of the gastrocnemius complex of six anaesthetised, ventilated dogs were elicited via sciatic nerve stimulation (50 Hz; 200 ms duration; 1 contraction s(−1)). Muscle VO2 and lactate efflux were determined from direct Fick measurements. Muscle biopsies were taken at rest and every ∼10 s during the transient and analysed for [phosphates], [lactate] and pH. The temporal VO2 vs. [PCr] and [ADP] relationships were not well fitted by linear or classical hyperbolic models (respectively), due to the high sensitivity of VO2 to metabolic perturbations early in the transient. The time course of this apparent sensitisation was closely aligned to that of ATP turnover, which was lower in the first ∼25 s of contractions compared to the steady state. These findings provide the first direct measurements of skeletal muscle VO2 and [PCr] in the non-steady state, and suggest that simple phosphate feedback models (which are adequate for steady-state observations in vitro) are not sufficient to explain the dynamic control of VO2 in situ. Rather an allosteric or 'parallel activation' mechanism of energy consuming and producing processes is required to explain the kinetic control of VO2 in mammalian skeletal muscle.

Patterning of somatosympathetic reflexes reveals nonuniform organization of presympathetic drive from C1 and non-C1 RVLM neurons

To determine the organization of presympathetic vasomotor drive by phenotypic populations of rostral ventrolateral medulla (RVLM) neurons, we examined the somatosympathetic reflex (SSR) evoked in four sympathetic nerves together with selective lesions of RVLM presympathetic neurons. Urethane-anesthetized (1.3 g/kg ip), paralyzed, vagotomized and artificially ventilated Sprague-Dawley rats (n = 41) were used. First, we determined the afferent inputs activated by sciatic nerve (SN) stimulation at graded stimulus intensities (50 sweeps at 0.5-1 Hz, 1-80 V). Second, we recorded sympathetic nerve responses (cervical, renal, splanchnic, and lumbar) to intensities of SN stimulation that activated A-fiber afferents (low) or both A- and C-fiber afferents (high). Third, with low-intensity SN stimulation, we examined the cervical SSR following RVLM microinjection of somatostatin, and we determined the splanchnic SSR in rats in which presympathetic C1 neurons were lesioned following intraspinal injections of anti-dopamine-β-hydroxylase-saporin (anti-DβH-SAP). Low-intensity SN stimulation activated A-fiber afferents and evoked biphasic responses in the renal, splanchnic, and lumbar nerves and a single peak in the cervical nerve. Depletion of presympathetic C1 neurons (59 ± 4% tyrosine hydroxylase immunoreactivity profiles lesioned) eliminated peak 2 of the splanchnic SSR and attenuated peak 1, suggesting that only RVLM neurons with fast axonal conduction were spared. RVLM injections of somatostatin abolished the single early peak of cervical SSR confirming that RVLM neurons with fast axonal conduction were inhibited by somatostatin. It is concluded that unmyelinated RVLM presympathetic neurons, presumed to be all C1, innervate splanchnic, renal, and lumbar but not cervical sympathetic outflows, whereas myelinated C1 and non-C1 RVLM neurons innervate all sympathetic outflows examined. These findings suggest that multiple levels of neural control of vasomotor tone exist; myelinated populations may set baseline tone, while unmyelinated neurons may be recruited to provide actions at specific vascular beds in response to distinct stressors.

Asymmetrical changes in lumbar sympathetic nerve activity following stimulation of the sciatic nerve in rat

Noxious stimulation of the leg increases hind limb blood flow (HBF) to the ipsilateral side and decreases to the contralateral in rat. Whether or not this asymmetrical response is due to direct control by sympathetic terminals or mediated by other factors such as local metabolism and hormones remains unclear. The aim of this study was to compare responses in lumbar sympathetic nerve activity, evoked by stimulation of the ipsilateral and contralateral sciatic nerve (SN). We also sought to determine the supraspinal mechanisms involved in the observed responses. In anesthetized and paralyzed rats, intermittent electrical stimulation (1 mA, 0.5 Hz) of the contralateral SN evoked a biphasic sympathoexcitation. Following ipsilateral SN stimulation, the response is preceded by an inhibitory potential with a latency of 50 ms ( N = 26). Both excitatory and inhibitory potentials are abolished following cervical C1 spinal transection ( N = 6) or bilateral microinjections of muscimol ( N = 6) in the rostral ventrolateral medulla (RVLM). This evidence is suggestive that both sympathetic potentials are supraspinally mediated in this nucleus. Blockade of RVLM glutamate receptors by microinjection of kynurenic acid ( N = 4) selectively abolished the excitatory potential elicited by ipsilateral SN stimulation. This study supports the physiological model that activation of hind limb nociceptors evokes a generalized sympathoexcitation, with the exception of the ipsilateral side where there is a withdrawal of sympathetic tone resulting in an increase in HBF.

Pharmacodynamic interaction between pantoprazole and vecuronium at neuromuscular junction

1 The effect of pantoprazole on vecuronium-induced neuromuscular blockade in in vivo has not been clearly defined. In this study, we demonstrate that chronic administration, but not acute administration, of pantoprazole alters the pattern of vecuronium-induced neuromuscular blockade. 2 This study was designed to evaluate the effect of acute and chronic administration of pantoprazole on vecuronium-induced neuromuscular blockade using the rat in vivo sciatic nerve-stimulated gastrocnemius preparation. 3 Vecuronium was administered as a slow intravenous infusion (29.41 μg kg(-1) min(-1)) until the gastrocnemius twitch response to sciatic nerve stimulation was completely abolished. The effect of acute (single dose, i.v.) and chronic administration (per oral for 21 days) of pantoprazole (3.64 mg kg(-1)) on vecuronium-induced blockade was assessed by comparing ED50 values, time required for 50% block, ED95 values, block duration and percentage of recovery with respect to control. 4 Acute administration of pantoprazole had no significant effect on any parameter of vecuronium-induced neuromuscular blockade. Chronic administration of pantoprazole significantly reduced vecuronium ED50 value, time for 50% block, ED95 value and percentage recovery from blockade compared with the control group (P<0.05). Reduction in the duration of vecuronium-induced blockade was not significantly affected by chronic treatment with pantoprazole compared with control. 5 On chronic administration, pantoprazole may produce earlier block, quick relaxation and reduces the recovery of vecuronium without affecting its duration of action.

Interactions between adenosine and K+channel-related pathways in the coupling of somatosensory activation and pial arteriolar dilation

Multiple, perhaps interactive, mechanisms participate in the linkage between increased neural activity and cerebral vasodilation. In the present study, we assessed whether neural activation-related pial arteriolar dilation (PAD) involved interactions among adenosine (Ado) A(2) receptors (A(2)Rs), large-conductance Ca(2+)-operated K(+) (BK(Ca)) channels, and inward rectifier K(+) (K(ir)) channels. In rats with closed cranial windows, we monitored sciatic nerve stimulation (SNS)-induced PAD in the absence or presence of pharmacological blockade of A(2)Rs (ZM-241385), ecto-5'-nucleotidase (α,β-methylene-adenosine diphosphate), BK(Ca) channels (paxilline), and K(ir) channels (BaCl(2)). Individually, these interventions led to 53-66% reductions in SNS-induced PADs. Combined applications of these blockers led to little or no further repression of SNS-induced PADs, suggesting interactions among A(2)Rs and K(+) channels. In the absence of SNS, BaCl(2) blockade of K(ir) channels produced 52-80% reductions in Ado and NS-1619 (BK(Ca) channel activator)-induced PADs. In contrast, paxilline blockade of BK(Ca) channels was without effect on dilations elicited by KCl (K(ir) channel activator) and Ado suffusions, indicating that Ado- and NS-1619-associated PADs involved K(ir) channels. In addition, targeted ablation of the superficial glia limitans was associated with a selective 60-80% loss of NS-1619 responses, suggesting that the BK(Ca) channel participation (and paxilline sensitivity) derived largely from channels within the glia limitans. Additionally, blockade of either PKA or adenylyl cyclase caused markedly attenuated pial arteriolar responses to SNS and, in the absence of SNS, responses to Ado, KCl, and NS-1619. These findings suggested a key, possibly permissive, role for A(2)R-linked cAMP generation and PKA-induced K(+) channel phosphorylation in somatosensory activation-evoked PAD.

Motor-evoked potentials in awake rats are a valid method of assessing hepatic encephalopathy and of studying its pathogenesis

Experimental models of hepatic encephalopathy (HE) are limited by difficulties in objectively monitoring neuronal function. There are few models that examine a well-defined neuronal pathway and lack the confounding effects of anesthetics. Motor-evoked potentials (MEPs) assess the function of the motor tract, which has been shown to be impaired in patients with cirrhosis. MEPs were elicited by cranial stimulation (central) and compound motor action potential by sciatic nerve stimulation (peripheral) in several models of HE in the rat. The experiments were performed using subcutaneous electrodes without anesthetics. Brain water content was assessed by gravimetry, brain metabolites were measured by magnetic resonance spectroscopy, and amino acids in microdialysates from the frontal cortex were analyzed by high-performance liquid chromatography. Abnormalities of MEP were observed in acute liver failure (ALF) induced by hepatic devascularization in relation to the progression of neurological manifestations. Similar disturbances were seen in rats with portocaval anastomosis after the administration of blood or lipopolysaccharide, but were absent in rats with biliary duct ligation. Hypothermia (≤35°C) and mannitol prevented the development of brain edema in acute liver failure, but only hypothermia avoided the decrease in the amplitude of MEP. Disturbances of MEP caused by the administration of blood into the gastrointestinal tract in rats with portocaval anastomosis were associated with an increase in ammonia, glutamine, and glutamate in brain microdialysate. Assessment of MEP in awake rats is a valid method to monitor HE in models of ALF and precipitated HE. This method shows the lack of efficacy of mannitol, a therapy that decreases brain edema, and relates disturbances of the function of the motor tract to ammonia and its metabolites.

Synergetic Analgesia of Propentofylline and Electroacupuncture by Interrupting Spinal Glial Function in Rats

Previous studies indicated that disruption of glial function in the spinal cord enhanced electroacupuncture (EA) analgesia in arthritic rats, suggesting glia is involved in processing EA analgesia. To probe into the potential value for clinical practice, the present study was to investigate the effect of propentofylline, a glia inhibitor, on EA analgesia in rats. Mechanical allodynia induced by tetanic stimulation of sciatic nerve (TSS) was used as a pain model. On day 7 after TSS, EA treatment induced a significant increase in paw withdrawal threshold to mechanical stimulation. Intrathecal or intraperitoneal injection of propentofylline relieved TSS-induced mechanical allodynia. The combination of low dosage of propentofylline and EA produced more potent anti-allodynia than propentofylline or EA alone. Immunohistochemistry exhibited that TSS-induced activation of microglia and astrocytes was inhibited significantly by propentofylline. These results indicate that propentofylline and EA induce synergetic analgesia by interrupting spinal glial function.