Recent Journal Articles: Anesthesiology -- Neurotransmitter.net

Recent Articles in Pain

Tang B, Ji Y, Traub RJ
Estrogen alters spinal NMDA receptor activity via a PKA signaling pathway in a visceral pain model in the rat.
Pain. 2007 Dec 7; .
Pain symptoms in several chronic pain disorders in women, including irritable bowel syndrome, fluctuate with the menstrual cycle suggesting a gonadal hormone component. In female rats, estrogens modulate visceral sensitivity although the underlying mechanism(s) are unknown. In the present study the effects of 17-beta estradiol on N-methyl-d-aspartate (NMDA) receptor signaling of colorectal nociceptive processing in the spinal cord were examined. Estrogen receptor alpha and the NR1 subunit of the NMDA receptor are co-expressed in dorsal horn neurons, supporting a direct action of estradiol on NMDA receptors. Intrathecal administration of the NMDA receptor antagonist d(-)-2-amino-5-phosphonopentanoic acid (APV) dose-dependently attenuated the visceromotor response with greater potency in ovariectomized (OVx) rats compared to OVx with estradiol replacement (E2) rats. Estradiol significantly increased protein expression of NR1 in the lumbosacral spinal cord compared to OVx rats. Colorectal distention significantly increased phosphorylation of NR1ser-897, a PKA phosphorylation site on the NR1 subunit in E2, but not OVx rats. Intrathecal administration of a PKA inhibitor significantly attenuated the visceromotor response, decreased NR1 phosphorylation and increased the potency of APV to attenuate the visceromotor response compared to vehicle-treated E2 rats. These data suggest that estradiol increases spinal processing of visceral nociception by increasing NMDA receptor NR1 subunit expression and increasing site-specific receptor phosphorylation on the NR1 subunit contributing to an increase in NMDA receptor activity. [Abstract]

Zhu H, Yang Y, Zhang H, Han Y, Li Y, Zhang Y, Yin D, He Q, Zhao Z, Blumberg PM, Han J, Wang Y
Interaction between protein kinase D1 and transient receptor potential V1 in primary sensory neurons is involved in heat hypersensitivity.
Pain. 2007 Nov 30;
In previous studies we demonstrated that protein kinase D1 (PKD1/PKCmu) could directly phosphorylate the transient receptor potential V1 (TRPV1) at its N-terminal region and enhance the function of TRPV1 in CHO cells stably transfected with TRPV1. In the current study we assessed the involvement of PKD1 in pain modulation and explored the possible interaction between PKD1 and TRPV1 in rat inflammatory heat hypersensitivity. PKD1 was translocated to cytoplasmic membrane fraction and was trans-phosphorylated only in membrane fraction but not in cytoplasmic fraction of dorsal root ganglia (DRG) at 2 and 6h after Complete Freund's Adjuvant (CFA) treatment. Pre i.t. injection of PKD1 antisense for 4 d or post-i.t. injection for 4 d both alleviated CFA-induced thermal hypersensitivity. Likewise, overexpression of PKD1 in DRG significantly enhanced, while dominant negative PKD1 (DN-PKD1) partly attenuated, heat hypersensitivity. Both PKD1 and TRPV1 were translocated to the cytoplasmic membrane in DRG 6 h after CFA treatment and, at that time, PKD1 interacted with TRPV1 by co-immunoprecipitation in DRG. Electrophysiological measurements indicated that DRG with overexpression of PKD1 were more sensitive to low dose capsaicin than those expressing DN-PKD1. The average magnitude of the peak inward current evoked by capsaicin was greater in the DRG overexpressing PKD1 than in those expressing DN-PKD1. Furthermore, overexpressed PKD1 could up regulate, whereas PKD1 antisense could knock down TRPV1 content in DRG through posttranscriptional regulation manner. We concluded that PKD1 in DRG, through interaction with TRPV1, is involved in developing and maintaining inflammatory heat hypersensitivity. [Abstract]

Miletic G, Miletic V
Loose ligation of the sciatic nerve is associated with TrkB receptor-dependent decreases in KCC2 protein levels in the ipsilateral spinal dorsal horn.
Pain. 2007 Nov 30;
Significant decreases in the protein levels of potassium-chloride co-transporter 2 (KCC2) were detected in the ipsilateral spinal dorsal horn 4h following loose ligation of the sciatic nerve. These decreases were associated with a change in hindlimb weight distribution suggestive of pain behavior. In contrast, no changes in GABA-A receptor subunit alpha-1 levels were detected. The decreases in KCC2 coincided with a significant ipsilateral increase in BDNF protein levels. Both the decreases in KCC2 levels and the early pain behavior were prevented by intrathecal pre-treatment with the BDNF-sequestering TrkB/Fc chimera protein or the tyrosine kinase blocker K252a. The ligation-associated decreases in KCC2 levels were transient. In the ipsilateral spinal dorsal horn of ligated animals exhibiting weight-bearing pain behavior 7 days after the ligation the KCC2 levels were identical to those in control or sham-operated animals. These data suggested that TrkB-dependent reduction in KCC2 protein levels in the spinal dorsal horn was an early consequence of peripheral nerve injury. This decrease in KCC2 may have elicited an early increase in overall dorsal horn neuronal excitability perhaps through a loss of GABA inhibition which is critically dependent on KCC2 activity. The increased neuronal excitability may in turn have caused enhanced and exaggerated communication between primary afferents and dorsal horn neurons to contribute to the early behavioral signs of pain. [Abstract]

Bastuji H, Perchet C, Legrain V, Montes C, Garcia-Larrea L
Laser evoked responses to painful stimulation persist during sleep and predict subsequent arousals.
Pain. 2007 Nov 30;
We studied behavioural responses and 32-channel brain potentials to nociceptive stimuli during all-night sleep in 12 healthy subjects, using sequences of thermal laser pulses delivered over the dorsum of the hand. Laser stimuli less than 20dB over perception threshold had clear awakening properties, in accordance with the intrinsic threatening value of nociceptive signals. Even in cases where nociceptive stimulation did not interrupt sleep, it triggered motor responses in 11% of trials. Only four subjects reported dreams, and on morning questionnaires there was no evidence of incorporation to dreams of nociceptive stimuli. Contrary to previous reports suggesting the absence of cortical nociceptive responses during sleep, we were able to record brain-evoked potentials to laser (LEPs) during all sleep stages. Sleep LEPs were in general attenuated, but their morphology was sleep-stage-dependent: in stage 2, the weakened initial response was often followed by a high-amplitude negative wave with typical features of a K-complex. During paradoxical sleep (PS) LEP morphology was similar to that of waking, but frontal components showed strong attenuation, consistent with the reported frontal metabolic deactivation. A late positive component (450-650ms) was recorded in both stage 2 and PS, the amplitude of which was significantly enhanced in trials that were followed by an arousal. This response appeared functionally related to the P3 wave, which in waking subjects has been associated to conscious perception and memory encoding. [Abstract]

Mitchell K, Yang HY, Tessier PA, Muhly WT, Swaim WD, Szalayova I, Keller JM, Mezey E, Iadarola MJ
Localization of S100A8 and S100A9 expressing neutrophils to spinal cord during peripheral tissue inflammation.
Pain. 2007 Dec 4;
Investigation of hyperalgesia at the spinal transcriptome level indicated that carrageenan-induced inflammation of rat hind paws leads to a rapid but sustained increase in S100A8 and S100A9 expression, two genes implicated in the pathology of numerous inflammatory diseases including rheumatoid arthritis and gout. In situ hybridization revealed that the elevation occurred in neutrophils that migrate to the spinal cord vasculature during peripheral inflammation, not in spinal neurons or glial cells. Immunohistochemical analysis suggests, but does not prove, that these neutrophils abundantly release S100A8 and S100A9. Consistent with this, we detected an increase in ICAM and VCAM, both indicators of endothelial activation, a known trigger for secretion of S100A8 and S100A9. Migration of S100A8- and S100A9-expressing neutrophils to spinal cord is selective, since MCP-1- and CD68-expressing leukocytes do not increase in spinal cord vasculature during hind paw inflammation. Examination of many neutrophil granule mediators in spinal cord indicated that they are not regulated to the same degree as S100A8 and S100A9. Neutrophil migration also occurs in the vasculature of brain and pituitary gland during peripheral inflammation. Together, these findings suggest an interaction between a subpopulation of leukocytes and the CNS during peripheral tissue inflammation, as implied by an apparent release and possible diffusion of S100A8 and S100A9 through the endothelial blood-brain barrier. Although the present findings do not establish the neurophysiological or behavioral relevance of these observations to nociceptive processing, the data raise the possibility that selective populations of leukocytes may communicate the presence of disease or tissue damage from the periphery to cells in the central nervous system. [Abstract]

Crombez G, Eccleston C, De Vlieger P, Van Damme S, De Clercq A
Is it better to have controlled and lost than never to have controlled at all? An experimental investigation of control over pain.
Pain. 2007 Dec 4;
Trying to control pain is a common human goal. But little is know about what happens when one loses control over pain. This paper reports an experiment with 74 healthy volunteers, half of whom were given control over a pain stimulus and subsequently lost control, and half of whom never had control over the pain. This study investigates whether having had control and lost it would result in a more unpleasant pain experience, more fear about impending pain, a heightened vigilance to pain, and greater interference on a secondary task. Participants in the experimental group first learned to avoid a painful stimulus by correctly responding to a card sorting task, but later on lost control over the painful stimulus. In the yoked comparison group, participants had no control over the painful stimulus from the beginning. Results indicated that losing control over pain and, relatedly, attempting to control uncontrollable pain have significant costs such as a higher fear of the impending pain stimulus and retarded performance on a secondary task. When attempts to avoid pain are blocked, individuals persist in their avoidance attempts, try harder, and narrow their focus of attention upon the problem to be solved. These findings are discussed within the context of a dual process model of coping with uncontrollable adverse events [Brandtst�dter J, Renner G. Tenacious goal pursuit and flexible goal adjustment: explication and age-related analysis of assimilative and accommodative strategies of coping. Psychol Aging 1990;5:58-67] and possible mechanisms for perseverance with ineffective solutions. [Abstract]

Crombez G, Eccleston C, Van Hamme G, De Vlieger P
Attempting to solve the problem of pain: A questionnaire study in acute and chronic pain patients.
Pain. 2007 Dec 4;
When faced with the problem of pain one can attempt a solution aimed at relief (assimilation) or a solution aimed at acceptance (accommodation). Using this dual process model of adaptation to pain, this study compares acute and chronic pain patients on their approach to problem solving. Three hundred and sixty-four patients were recruited from clinical settings, 303 with chronic pain and 61 with acute pain, and completed a range of measures of both affect and pain-related behavior, including the Pain Solutions Questionnaire. The effects of overall duration of pain were also investigated. Chronic pain patients reported greater disability and catastrophic thinking about pain than acute pain patients, and assimilative coping was associated with greater disability, greater attention to pain, and more catastrophic thinking about pain, beyond the effects of demographic variables and pain severity. Pain duration did not moderate these associations. Only in the case of catastrophic thinking about pain was it found that the effects of assimilative coping were moderated by pain duration. For chronic pain patients, catastrophic thinking about pain was greater when assimilative coping was higher. These results are discussed within the context of a goal directed motivational model of adaptation to chronic pain. [Abstract]

Buchgreitz L, Lyngberg AC, Bendtsen L, Jensen R
Increased pain sensitivity is not a risk factor but a consequence of frequent headache: A population-based follow-up study.
Pain. 2007 Nov 29;
Altered pain sensitivity is believed to play an important role for chronification of headache. It has however mainly been evaluated in highly selected patients from headache clinics and never in longitudinal studies. The present study is a 12-year follow-up of a population-based study of primary headache disorders and pain perception, combining a diagnostic headache interview with examination of muscle tenderness and measurement of pressure pain thresholds in 1000 subjects drawn randomly from the general population in Denmark. The aim of the study was to explore the cause-effect relationship between the increased pain sensitivity and the development of headache. The pressure pain thresholds were normal at baseline but had decreased at follow-up in subjects who developed chronic tension-type headache over the 12-year period (p=0.025). In subjects who developed frequent episodic tension-type headache the tenderness was normal at baseline but had increased at follow-up (p<0.01) while the pain thresholds were normal both at baseline and at follow-up. The findings demonstrate that increased pain sensitivity is a consequence of frequent tension-type headache, not a risk factor, and support that central sensitization plays an important role for the chronification of tension-type headache. [Abstract]

Gureje O
Treating chronic pain in the context of comorbid depression.
Pain. 2007 Dec 4; [Abstract]

Moseley GL, Zalucki NM, Wiech K
Tactile discrimination, but not tactile stimulation alone, reduces chronic limb pain.
Pain. 2007 Dec 1;
Chronic pain is often associated with reduced tactile acuity. A relationship exists between pain intensity, tactile acuity and cortical reorganisation. When pain resolves, tactile function improves and cortical organisation normalises. Tactile acuity can be improved in healthy controls when tactile stimulation is associated with a behavioural objective. We hypothesised that, in patients with chronic limb pain and decreased tactile acuity, discriminating between tactile stimuli would decrease pain and increase tactile acuity, but tactile stimulation alone would not. Thirteen patients with complex regional pain syndrome (CRPS) of one limb underwent a waiting period and then approximately 2 weeks of tactile stimulation under two conditions: stimulation alone or discrimination between stimuli according to their diameter and location. There was no change in pain (100mm VAS) or two-point discrimination (TPD) during a no-treatment waiting period, nor during the stimulation phase (p>0.32 for both). Pain and TPD were lower after the discrimination phase [mean (95% CI) effect size for pain VAS=27mm (14-40mm) and for TPD=5.7mm (2.9-8.5mm), p<0.015 for both]. These gains were maintained at three-month follow-up. We conclude that tactile stimulation can decrease pain and increase tactile acuity when patients are required to discriminate between the type and location of tactile stimuli. [Abstract]

Rainville P
Hypnosis and the analgesic effect of suggestions.
Pain. 2007 Nov 21; [Abstract]

Nieto FR, Entrena JM, Cend�n CM, Pozo ED, Vela JM, Baeyens JM
Tetrodotoxin inhibits the development and expression of neuropathic pain induced by paclitaxel in mice.
Pain. 2007 Nov 21;
We evaluated the effect of low doses of systemically administered tetrodotoxin (TTX) on the development and expression of neuropathic pain induced by paclitaxel in mice. Treatment with paclitaxel (2mg/kg, i.p., once daily during 5 days) produced long-lasting (2-4 weeks) heat hyperalgesia (plantar test), mechanical allodynia (electronic Von Frey test) and cold allodynia (acetone drop method), with maximum effects observed on days 7, 10 and 10-14, respectively. Acute subcutaneous treatment with 1 or 3mug/kg of TTX reduced the expression of mechanical allodynia, whereas higher doses (3 or 6mug/kg) were required to reduce the expression of cold allodynia and heat hyperalgesia. In contrast, TTX (3 or 6mug/kg, s.c.) did not affect the response to the same thermal and mechanical stimuli in control animals, which indicates that the antihyperalgesic and antiallodynic effects of TTX were not due to unspecific inhibition of the perception of these stimuli. Administration of TTX (6mug/kg, s.c.) 30min before each of the 5 doses of paclitaxel did not modify the development of heat hyperalgesia produced by the antineoplastic, but abolished the development of mechanical and cold allodynia. Coadministration of a lower dose of TTX (3mug/kg) also prevented the development of mechanical allodynia. No signs of TTX-induced toxicity or motor incoordination were observed. These data suggest that low doses of TTX can be useful to prevent and treat paclitaxel-induced neuropathic pain, and that TTX-sensitive subtypes of sodium channels play a role in the pathogenesis of chemotherapy-induced neuropathic pain. [Abstract]

McIntyre D, Kavussanu M, Ring C
Effects of arterial and cardiopulmonary baroreceptor activation on the upper limb nociceptive flexion reflex and electrocutaneous pain in humans.
Pain. 2007 Nov 21;
Attenuation of the lower limb nociceptive flexion reflex (NFR) during the cardiac cycle has been attributed to inhibition of sensorimotor function by arterial baroreceptor activation. It has been proposed that cardiopulmonary baroreceptors might have similar inhibitory effects. This study examined the effects of arterial and cardiopulmonary baroreceptor stimulation on nociceptive responding in the upper limb by delivering electrocutaneous stimuli to the ulnar nerve at 0, 150, 300, 450, or 600ms after the R-wave of the electrocardiogram while participants lay supine with their legs raised or lowered. Nociceptive responding varied in a quadratic manner with phase of the cardiac cycle; responses were lowest at R+450ms. Nociceptive responding and pain ratings did not differ between postures suggesting no cardiopulmonary effects. This phasic modulation of the upper limb withdrawal response provides further support for arterial baroreceptor-mediated inhibition of nociceptive transmission. [Abstract]

Versloot J, Veerkamp JS, Hoogstraten J
Children's self-reported pain at the dentist.
Pain. 2007 Nov 20;
The aim of the present study is to get an insight into the pain report of children over two sequential dental visits. Furthermore, it was studied whether age, previous dental experience, level of dental anxiety and injection site were of influence on the self-reported pain of children during the first and second treatment session. One hundred and forty-seven children (4-11 years old) were included in the study. After receiving a local anesthesia injection prior to their dental treatment, they were asked how much pain they had felt. The level of dental anxiety was measured once by the parental version of the Dental Subscale of the Children's Fear Survey Schedule. Young children with a low level of dental anxiety show a sensitized reaction trend for self-reported pain over two sequential dental visits. Young children with a high level of dental anxiety reported the most pain on the first treatment session. For the older children, the children having previous dental experience gave the highest pain ratings on the first treatment session. Furthermore, for both young and older children the amount of pain reported for the second injection was best predicted by the amount of pain reported for the first injection, whereby higher scores the first time predict higher scores the second time. In conclusion, the memory of previous experience with dentistry and earlier treatment sessions seems of great influence on the behaviour and the experience of children during subsequent treatment sessions. [Abstract]

Jordan A, Eccleston C, McCracken LM, Connell H, Clinch J
The Bath Adolescent Pain - Parental Impact Questionnaire (BAP-PIQ): Development and preliminary psychometric evaluation of an instrument to assess the impact of parenting an adolescent with chronic pain.
Pain. 2007 Nov 20;
When an adolescent has chronic pain many aspects of a parent's life can be affected, including their emotional and social functioning. The assessment of this multidimensional parental impact is an essential, yet often neglected, clinical task. This study reports on the development and psychometric evaluation of the Bath Adolescent Pain - Parental Impact Questionnaire (BAP-PIQ), an assessment tool comprising multiple scales thought to be relevant for better understanding changes in functioning and behavior associated with parenting an adolescent with chronic pain. A sample of 194 parents of adolescents with chronic pain, recruited from three UK clinics, completed the 94 item draft inventory. Frequency and item correlation analyses resulted in a final inventory of 62 items. Internal consistency of all eight scales was established based on Cronbach's alpha. Convergent validity was undertaken by comparison of individual scales with existing validated measures of parental stress, mood, parenting behavior, marital adjustment, and general functioning. The temporal reliability of each scale was established using a sub-sample of 46 participants over a 14-day period. Psychometric evaluation suggests that the inventory yields a reliable and valid assessment of the multiple impacts of parenting an adolescent with chronic pain. The BAP-PIQ may offer a comprehensive assessment of these impacts in both a research and a clinical setting. Further study of the validity of BAP-PIQ scales and their ability to detect clinically meaningful change would be of use. Additional data from samples comprising fathers of adolescents with chronic pain and parents of adolescents with non-musculoskeletal pain would be of benefit. [Abstract]

Linton SJ, McCracken LM, Vlaeyen JW
Reassurance: Help or hinder in the treatment of pain.
Pain. 2007 Nov 20; [Abstract]

Jensen MP, Mardekian J, Lakshminarayanan M, Boye ME
Validity of 24-h recall ratings of pain severity: Biasing effects of "Peak" and "End" pain.
Pain. 2007 Nov 20;
Despite the frequent use of pain recall ratings in clinical research, there remains doubt about the ability of individuals to accurately recall their pain. In particular, previous research indicates the possibility that the most pain experienced during a recall period and the most recent pain experienced (known as peak and end effects, respectively) might bias recall ratings. The current study used data from a published clinical trial to determine the relative validity of a 24-h recall rating of average post-operative pain and the nature and extent of any biasing influence of peak and end effects on nine separate 24-h recall ratings. The results supported a statistically significant but small biasing influence of both peak and end pain. Also, the influence of peak pain was stronger than that of end pain. However, the biasing impact of both peak and end pain together was very small, suggesting that 24-h recall ratings are adequately valid indicants of average pain for patients participating in post-surgery clinical pain trials. [Abstract]

Edwards L, Inui K, Ring C, Wang X, Kakigi R
Pain-related evoked potentials are modulated across the cardiac cycle.
Pain. 2007 Nov 20;
Evidence suggests that the arterial baroreceptors modulate pain. To examine whether cortical processing of nociception is modulated by natural variations in arterial baroreceptor stimulation during the cardiac cycle, peak-to-peak amplitudes of the N2-P2 pain-related potential and pain ratings were recorded in response to noxious laser stimulation at different times during the cardiac cycle in 10 healthy males. Significant variations in the N2-P2 amplitudes occurred across the cardiac cycle, with smaller amplitudes midcycle, indicating that cortical processing of nociception was attenuated during systole compared to diastole. Pain ratings did not vary across the cardiac cycle. These data support the hypothesis that arterial baroreceptors modulate the processing of nociception during each cardiac cycle. [Abstract]

Sabsovich I, Guo TZ, Wei T, Zhao R, Li X, Clark DJ, Geis C, Sommer C, Kingery WS
TNF signaling contributes to the development of nociceptive sensitization in a tibia fracture model of complex regional pain syndrome type I.
Pain. 2007 Nov 20;
Tibia fracture in rats initiates a cascade of nociceptive, vascular, and bone changes resembling complex regional pain syndrome type I (CRPS I). Previous studies suggest that the pathogenesis of these changes is attributable to an exaggerated regional inflammatory response to injury. We postulated that the pro-inflammatory cytokine tumor necrosis factor alpha (TNF) might mediate the development of CRPS-like changes after fracture. RT-PCR and EIA assays were used to evaluate changes in TNF expression and content in skin, nerve, and bone after fracture. Bilateral hindpaw thickness, temperature, and nociceptive thresholds were determined, and bone microarchitecture was measured using microcomputed tomography. Lumbar spinal cord Fos immunostaining was performed for quantification of Fos positive neurons. After baseline testing, the distal tibia was fractured and the hindlimb casted for 4 weeks. The rats were subcutaneously injected either with a soluble TNF receptor type 1 (sTNF-R1, 5mg/kg/d) or saline every 3 days over 28 days and then were retested at 4 weeks post-fracture. Tibia fracture chronically upregulated TNF expression and protein levels in the hindpaw skin and sciatic nerve. After fracture the rats developed hindpaw mechanical allodynia and unweighting, which were reversed by sTNF-R1 treatment. Consistent with the behavioral data, spinal Fos increased after fracture and this effect was inhibited by sTNF-R1 treatment. Collectively, these data suggest that facilitated TNF signaling in the hindlimb is an important mediator of chronic regional nociceptive sensitization after fracture, but does not contribute to the hindlimb warmth, edema, and bone loss observed in this CRPS I model. [Abstract]

De Pascalis V, Cacace I, Massicolle F
Focused analgesia in waking and hypnosis: Effects on pain, memory, and somatosensory event-related potentials.
Pain. 2007 Nov 17;
Somatosensory event-related potentials (SERPs) to painful electric standard stimuli under an odd-ball paradigm were analyzed in 12 high hypnotizable (HH), 12 medium hypnotizable (MH), and 12 low hypnotizable (LH) subjects during waking, hypnosis, and a cued eyes-open posthypnotic condition. In each of these conditions subjects were suggested to produce an obstructive imagery of stimulus perception as a treatment for pain reduction. A No-Analgesia treatment served as a control in waking and hypnosis conditions. The subjects were required to count the number of delivered target stimuli. HH subjects experienced significant pain and distress reductions during posthypnotic analgesia as compared to hypnotic analgesia and between these two analgesic conditions as compared to the two control conditions. Outside of hypnosis, these subjects remembered less pain and distress levels than they reported during hypnotic and posthypnotic analgesia treatments. In contrast, for waking-analgesia treatment, HH subjects remembered similar pain and distress levels to those they reported concurrently with the stimulation. HH subjects, during hypnotic and posthypnotic analgesia treatments, detected a smaller number of target stimuli and displayed a significant amplitude reduction of the midline frontal and central N140 and P200 SERP components. No significant SERP differences were observed for these subjects between treatments in waking condition and between hypnotic and posthypnotic analgesic treatments. For the MH and LH subjects no significant N140 and P200 amplitude changes were observed among analgesic conditions as compared to control conditions. These amplitude findings are seen as indicating that hypnotic analgesia can affect earlier and later stages of stimulus processing. [Abstract]

Sikes RW, Vogt LJ, Vogt BA
Distribution and properties of visceral nociceptive neurons in rabbit cingulate cortex.
Pain. 2007 Nov 15;
Human imaging localizes most visceral nociceptive responses to anterior cingulate cortex (ACC), however, imaging in conscious subjects cannot completely control anticipatory and reflexive activity or resolve neuron activity. This study overcame these shortcomings by recording individual neuron responses in 12 anesthetized and paralyzed rabbits to define the visceronociceptive response pattern by region and layer. Balloon distension was applied to the colon at innocuous (15mmHg) or noxious (60mmHg) intensities, and innocuous and noxious mechanical, thermal and electrical stimuli were applied to the skin. Simultaneous recording from multiple regions assured differences were not due to anesthesia and neuron responses were resolved by spike sorting using principal components analysis. Of the total 346 neurons, 48% were nociceptive; responding to noxious levels of visceral or cutaneous stimulation, or both. Visceronociceptive neurons were most frequent in ACC (39%) and midcingulate cortex (MCC, 36%) and infrequent in retrosplenial cortex (RSC, 12%). In contrast, cutaneous nociceptive units were higher in MCC (MCC, 43%; ACC, 32%; RSC, 23%). Visceral-specific neurons were proportionately more frequent in ACC (37%), while cutaneous-specific units predominated in RSC (62.5%). Visceral nociceptive response durations were longer than those for cutaneous responses. Postmortem analysis of electrode tracks confirmed regional designations, and laminar analysis found inhibitory responses mainly in superficial layers and excitatory in deep layers. Thus, cingulate visceral nociception extends beyond ACC, this is the first report of nociceptive activity in RSC including nociceptive cutaneous responses, and these regional differences require a new model of cingulate nociceptive processing. [Abstract]

G�ndel H, Valet M, Sorg C, Huber D, Zimmer C, Sprenger T, T�lle TR
Altered cerebral response to noxious heat stimulation in patients with somatoform pain disorder.
Pain. 2007 Nov 15;
Idiopathic chronic pain conditions with a mismatch between anatomical abnormalities and symptoms can be categorized as somatoform pain disorder according to the DSM-IV criteria. A dysfunction of pain processing circuits has been suggested as one underlying pathophysiological factor. There is accumulating evidence for a crucial role of affect regulating brain structures such as the medial frontal cortex in this context. We investigated the cerebral processing of noxious heat stimuli as objective marker for pain sensation in 12 right handed women with somatoform pain disorder fulfilling DSM-IV criteria and 13 age-matched healthy volunteers using functional MRI. The average ratings for experimentally induced pain were not significantly different between controls and patients concerning pain intensity and pain unpleasantness. Comparing patients with controls a pain related hypoactive state of the ventromedial prefrontal/orbitofrontal cortex (BA 10/11) and a hyperactive state of the parahippocampal gyrus, amygdala and anterior insula were found in the patient group. Our findings of an altered cerebral processing of experimentally induced pain in patients with somatoform pain disorder support the hypothesis of dysfunctional pain processing, especially in affect regulating regions. [Abstract]

Kroenke K, Shen J, Oxman TE, Williams JW, Dietrich AJ
Impact of pain on the outcomes of depression treatment: Results from the RESPECT trial.
Pain. 2007 Nov 15;
Objective: Pain is prevalent in patients with depression. The purpose of this study was to determine the impact of pain on depression treatment outcomes. Methods: Data was analyzed from a randomized controlled trial comparing a collaborative care intervention to usual care for the treatment of depression in 60 primary care practices. A total of 405 patients with either current major depressive disorder or dysthymia were enrolled, and assessed at baseline, 3, and 6months. Main measures included the 20-item Hopkins Symptom Check List (HSCL-20) depression score, and the SF-36 pain interference score. Results: Pain severe enough to produce at least moderate interference with daily activities was present in 42% of depressed patients at baseline. Pain outcomes did not differ between intervention and control groups but improved similarly in both over time. However, pain was still at least moderately severe in 32% of patients at 6months. Both baseline pain and the amount of pain improvement over time were associated with depression remission and response rates. In a multivariate model controlling for age, gender, and medical co-morbidity, depression severity increased with higher pain interference and decreased with the passage of time (p<.0001 for both). There was also a significant pain by time by treatment group interaction (p=.027). The beneficial effects of collaborative care on depression outcome persisted (p=.049) even after controlling for pain interference, time, covariates, and interaction effects. Conclusions: Pain has a strong negative impact on the response of depression to treatment. Recognizing and optimizing the management of comorbid pain that commonly coexists with depression may be important in enhancing depression response and remission rates. [Abstract]

Gottschling S, Meyer S, Gribova I, Distler L, Berrang J, Gortner L, Graf N, Shamdeen MG
Laser acupuncture in children with headache: A double-blind, randomized, bicenter, placebo-controlled trial.
Pain. 2007 Nov 15;
To investigate whether laser acupuncture is efficacious in children with headache and if active laser treatment is superior to placebo laser treatment in a prospective, randomized, double-blind, placebo-controlled trial of low level laser acupuncture in 43 children (mean age (SD) 12.3 (+/-2.6) years) with headache (either migraine (22 patients) or tension type headache (21 patients)). Patients were randomized to receive a course of 4 treatments over 4 weeks with either active or placebo laser. The treatment was highly individualised based on criteria of Traditional Chinese medicine (TCM). The primary outcome measure was a difference in numbers of headache days between baseline and the 4 months after randomization. Secondary outcome measures included a change in headache severity using a 10cm Visual Analogue Scale (VAS) for pain and a change in monthly hours with headache. Measurements were taken during 4 weeks before randomization (baseline), at weeks 1-4, 5-8, 9-12 and 13-16 from baseline. The mean number of headaches per month decreased significantly by 6.4 days in the treated group (p<0.001) and by 1.0 days in the placebo group (p=0.22). Secondary outcome measures headache severity and monthly hours with headache decreased as well significantly at all time points compared to baseline (p<0.001) and were as well significantly lower than those of the placebo group at all time points (p<0.001). We conclude that laser acupuncture can provide a significant benefit for children with headache with active laser treatment being clearly more effective than placebo laser treatment. [Abstract]

Williams AC, Amris K
Pain from torture.
Pain. 2007 Dec 15;133(1-3): [Abstract]

Nurmikko TJ, Serpell MG, Hoggart B, Toomey PJ, Morlion BJ, Haines D
Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial.
Pain. 2007 Dec 15;133(1-3):
Cannabinoids are known to have analgesic properties. We evaluated the effect of oro-mucosal sativex, (THC: CBD), an endocannabinoid system modulator, on pain and allodynia, in 125 patients with neuropathic pain of peripheral origin in a five-week, randomised, double-blind, placebo-controlled, parallel design trial. Patients remained on their existing stable analgesia. A self-titrating regimen was used to optimise drug administration. Sixty-three patients were randomised to receive sativex and 62 placebo. The mean reduction in pain intensity scores (primary outcome measure) was greater in patients receiving sativex than placebo (mean adjusted scores -1.48 points vs. -0.52 points on a 0-10 Numerical Rating Scale (p=0.004; 95% CI: -1.59, -0.32). Improvements in Neuropathic Pain Scale composite score (p=0.007), sleep NRS (p=0.001), dynamic allodynia (p=0.042), punctate allodynia (p=0.021), Pain Disability Index (p=0.003) and Patient's Global Impression of Change (p<0.001) were similarly greater on sativex vs. placebo. Sedative and gastrointestinal side effects were reported more commonly by patients on active medication. Of all participants, 18% on sativex and 3% on placebo withdrew during the study. An open-label extension study showed that the initial pain relief was maintained without dose escalation or toxicity for 52 weeks. [Abstract]

Coste J, Voisin DL, Miraucourt LS, Dallel R, Luccarini P
Dorsal horn NK1-expressing neurons control windup of downstream trigeminal nociceptive neurons.
Pain. 2007 Oct 29;
Windup is a progressive, frequency-dependent increase in the excitability of trigeminal and spinal dorsal horn wide dynamic range (WDR) nociceptive neurons to repetitive stimulation of primary afferent nociceptive C-fibers. Superficial dorsal horn neurokinin 1 receptor (NK1R)-expressing neurons were recently shown to regulate sensitization of WDR nociceptive neurons through activation of a defined spino-bulbo-spinal loop. However, the windup of WDR nociceptive neurons was not regulated through this loop. In the present study, we sought to identify the alternative circuit activated by dorsal horn NK1Rs that mediates WDR neuron windup. As a model we used the rat spinal trigeminal nucleus, in which the subnucleus oralis (Sp5O) contains a pool of WDR neurons that receive their nociceptive C-input indirectly via interneurons located in the medullary dorsal horn (MDH). First, we found that intravenous injection of NK1R antagonists (SR140333 and RP67580) produced a reversible inhibition of Sp5O WDR neuron windup. Second, we anatomically identified in the MDH lamina III a subpopulation of NK1R-expressing local interneurons that relay nociceptive information from the MDH to downstream Sp5O neurons. Third, using microinjections of NK1R antagonists during in vivo electrophysiological recordings from Sp5O WDR neurons, we showed that WDR neuron windup depends on activation of NK1Rs located in the MDH laminae I-III. We conclude that, in contrast to central sensitization that is controlled by a spino-bulbo-spinal loop, Sp5O WDR neuron windup is regulated through a local circuit activated by MDH lamina III NK1Rs. [Abstract]

Petersen KL, Meadoff T, Press S, Peters MM, Lecomte MD, Rowbotham MC
Changes in morphine analgesia and side effects during daily subcutaneous administration in healthy volunteers.
Pain. 2007 Oct 29;
Tolerance to the anti-nociceptive effects of opioids develops rapidly in animals. In contrast, humans with chronic pain show little or no loss of pain relief in prospective opioid trials of 4-8 weeks duration. Employing the Brief Thermal Sensitization model to induce transient cutaneous secondary hyperalgesia, we tested the hypothesis that opioid analgesic tolerance would develop rapidly. In this outpatient randomized placebo-controlled study, subjects in the MMMMP group received two injections of subcutaneous morphine 6mg (150min apart) on Monday-Thursday (total 48mg over 4 days) and matching saline placebo on Friday. Subjects in the PPPPM group received placebo on Monday-Thursday and morphine (total 12mg) on Friday. Sixty-one healthy volunteers were enrolled; morphine side effects accounted for all nine non-completions. Compared to the first placebo day, the reduction in the area of secondary hyperalgesia on the first morphine day was significant and robust in both groups. Morphine suppression of the painfulness of skin heating and elevation of the heat pain detection threshold were also significant. During 4 days of twice-daily injections, the decline in anti-hyperalgesic effects of morphine did not reach statistical significance (p=0.06) compared to placebo. Morphine side effects did not correlate with anti-hyperalgesic effects and withdrawal symptoms did not emerge. As 4 days is the threshold for demonstrating analgesic tolerance to twice-daily morphine in animal models, a longer period of opioid exposure in healthy volunteers might be needed to detect analgesic tolerance. [Abstract]

Sutherland R, Morley S
Self-pain enmeshment: Future possible selves, sociotropy, autonomy and adjustment to chronic pain.
Pain. 2007 Oct 29;
The aims of this study were to replicate and extend previous observations on the relationship between enmeshment of the self and pain and measures of adjustment [Morley et al., Possible selves in chronic pain: self-pain enmeshment, adjustment and acceptance, Pain 2005;115:84-94], and to test the hypothesis that individual variation in motivational preferences interacts with enmeshment. 82 chronic pain patients completed standardized self-report measures of depression, anxiety, acceptance and the possible selves interview which generated measures of their hoped-for (own and other perspectives) and feared-for selves. They made judgments about the conditionality of each self on the continuing presence of pain as a measure of self-pain enmeshment. A series of hierarchical regression analyses, that adjusted for demographics, pain characteristics and disability, confirmed the relationship between self enmeshment and depression and acceptance. When anxiety was considered, there was no main effect for any of the self aspects but there were specific interactions between the hoped-for (own) and (other) selves and two motivational preferences - autonomy and sociotropy. [Abstract]

Aasvang EK, Brandsborg B, Christensen B, Jensen TS, Kehlet H
Neurophysiological characterization of postherniotomy pain.
Pain. 2007 Oct 30;
Inguinal herniotomy is one of the most frequent surgical procedures and chronic pain affecting everyday activities is reported in approximately 10% of patients. However, the neurophysiological changes and underlying pathophysiological mechanisms of postherniotomy pain are not known in detail, thereby precluding advances in treatment strategies and prophylaxis. Therefore, we examined forty-six patients reporting moderate to severe postherniotomy pain affecting daily activities for more than a year postoperatively, and compared them with a control group of patients without pain 1yr postoperatively. A quantitative sensory testing protocol was used, assessing sensory dysfunction type, location and severity. We assessed the protocol test-retest variability using data from healthy control subjects. All patients (pain and pain-free) had signs of nerve damage, seen as sensory dysfunction. Detection thresholds for tactile and warmth stimulation were significantly increased while cold detection and pressure pain detection thresholds were significantly decreased in pain patients compared to controls. Repetitive punctuate and brush stimulation resulted in significantly more frequent and intense pain on the painful side than on the unaffected side in pain patients, and was not observed in controls. Our findings showed large and small fiber dysfunction in both pain and pain-free patients but more profound in pain patients and with signs of central sensitization (abnormal temporal summation). The specific finding of reduced pain detection threshold over the external inguinal annulus is consistent with damage to the cutaneous innervation territory of nervous structures in the inguinal region. The correspondence between pain location and sensory disturbance suggests that the pain is neuropathic in nature. Whether the underlying pathophysiological mechanisms are related to direct intraoperative nerve injury or nerve injury due to an inflammatory mesh response remains to be determined. [Abstract]

Recent Articles in Anesthesiology

Instructions for Obtaining Journal CME Credit.
Anesthesiology. 2007 Dec;107(6):1045-1046. [Abstract]

Nominations Sought for: Award for Excellence in Research.
Anesthesiology. 2007 Dec;107(6):1044. [Abstract]

Petterson MT
Misleading Behavior of Masimo Pulse Oximeter Tone during Profound Bradycardia.
Anesthesiology. 2007 Dec;107(6):1039-1040. [Abstract]

St Jean B
Potential Hazard Associated with a Laryngoscope Blade.
Anesthesiology. 2007 Dec;107(6):1038. [Abstract]

Forde RE, DeBros FM, Guimaraes EL, Sandberg WS
Misleading behavior of Masimo pulse oximeter tone during profound bradycardia.
Anesthesiology. 2007 Dec;107(6):1038-9; discussion 1039-40. [Abstract]

Luginbuehl I, Matthews K
Potential hazard associated with a laryngoscope blade.
Anesthesiology. 2007 Dec;107(6):1037-8; discussion 1038. [Abstract]

Altose MD, Le�n-Ruiz E
Etomidate Unlikely to Have Induced Pacemaker-mediated Tachycardia.
Anesthesiology. 2007 Dec;107(6):1037. [Abstract]

Rozner MA
Etomidate unlikely to have induced pacemaker-mediated tachycardia.
Anesthesiology. 2007 Dec;107(6):1036; author reply 1037. [Abstract]

Scott DA, Cameron CM, Davies MJ, McDonald WM
Epidural Complications across the Globe.
Anesthesiology. 2007 Dec;107(6):1035. [Abstract]

McCabe SE, Christie IW
Epidural complications across the globe.
Anesthesiology. 2007 Dec;107(6):1034-5; author reply 1035. [Abstract]

Heitmiller E, Martinez E, Pronovost PJ
Medication Error: A Leading Cause of Anesthesia-related Morbidity and Mortality.
Anesthesiology. 2007 Dec;107(6):1034. [Abstract]

Hove LD, Steinmetz J
Medication Error: A Leading Cause of Anesthesia-related Morbidity and Mortality.
Anesthesiology. 2007 Dec;107(6):1034. [Abstract]

Meyer R, Orser BA, Byrick R
Medication error: a leading cause of anesthesia-related morbidity and mortality.
Anesthesiology. 2007 Dec;107(6):1033; author reply 1034. [Abstract]

Augoustides JG
Perioperative central venous cannulation: it is time for action.
Anesthesiology. 2007 Dec;107(6):1032-3; author reply 1034. [Abstract]

Gupta DK, Manyam SC, Johnson KB, Egan TD
Can 1% Sevoflurane with 5 ng/ml Remifentanil Prevent Implicit Memory?
Anesthesiology. 2007 Dec;107(6):1031. [Abstract]

Richman JM
Does combined epidural-general anesthesia increase risk over either technique used alone?
Anesthesiology. 2007 Dec;107(6):1031-2; author reply 1034. [Abstract]

Hagihira S, Takashina M, Mori T, Mashimo T
Can 1% sevoflurane with 5 ng/ml remifentanil prevent implicit memory?
Anesthesiology. 2007 Dec;107(6):1030; author reply 1031. [Abstract]

Preece A
Clarifying equipment specifications and performance characteristics.
Anesthesiology. 2007 Dec;107(6):1029; author reply 1029-30. [Abstract]

Jaber S, Tassaux D, Sebbane M, Pouzeratte Y, Battasti A, Capdevila X, Eledjam JJ, Jolliet P
Clarifying Equipment Specifications and Performance Characteristics.
Anesthesiology. 2007 Dec;107(6):1029-1030. [Abstract]

Lavi R, Lavi S, Daghini E, Lerman LO
New frontiers in the evaluation of cardiac patients for noncardiac surgery.
Anesthesiology. 2007 Dec;107(6):1018-28. [Abstract]

Rittner HL, Lux C, Labuz D, Mousa SA, Sch�fer M, Stein C, Brack A
Neurokinin-1 receptor antagonists inhibit the recruitment of opioid-containing leukocytes and impair peripheral antinociception.
Anesthesiology. 2007 Dec;107(6):1009-17.
BACKGROUND: Neurokinins (e.g., substance P) contribute to pain transmission in the central nervous system, peripheral neurogenic inflammation, and leukocyte recruitment in inflammation. Leukocyte recruitment involves (1) up-regulation of adhesion molecule expression through neurokinin-1 (NK1) receptors on endothelial cells, (2) augmented chemokine production, or (3) chemotaxis through NK1 receptors on leukocytes. In inflammation, leukocytes can trigger endogenous antinociception through release of opioid peptides and activation of opioid receptors on peripheral sensory neurons. The authors hypothesized that NK1 receptor antagonists impair recruitment of opioid-containing leukocytes and stress-induced antinociception. METHODS: Rats were treated intraperitoneally and intrathecally with peripherally restricted (SR140333) or blood-brain barrier-penetrating (L-733,060) NK1 receptor antagonists and were evaluated for paw pressure thresholds, numbers of infiltrating opioid-containing leukocytes and leukocyte subpopulations, expression of adhesion molecules, NK1 receptors, and chemokines 24-48 h after complete Freund adjuvant-induced hind paw inflammation. RESULTS: Systemic and peripherally selective, but not intrathecal, NK1 receptor blockade reduced stress-induced antinociception (control: 177 +/- 9 g, L-733,060: 117 +/- 8 g, and control: 166 +/- 30 g, SR140333: 89 +/- 3 g; both P < 0.05, t test) without affecting baseline hyperalgesia. In parallel, local recruitment of opioid-containing leukocytes was decreased (L-733,060 and SR140333: 56.0 +/- 4.3 and 59.1 +/- 7.9% of control; both P < 0.05, t test). NK1 receptors were expressed on peripheral neurons, infiltrating leukocytes and endothelial cells. Peripheral NK1 receptor blockade did not alter endothelial expression of intercellular adhesion molecule-1 or local chemokine and cytokine production, but decreased polymorphonuclear cell and macrophage recruitment. CONCLUSIONS: Endogenous inhibition of inflammatory pain is dependent on NK1 receptor-mediated recruitment of opioid-containing leukocytes. [Abstract]

White RL, Cohen SP
Return-to-duty rates among coalition forces treated in a forward-deployed pain treatment center: a prospective observational study.
Anesthesiology. 2007 Dec;107(6):1003-8.
BACKGROUND: Non-battle-related injuries and the recurrence of chronic pain are major causes of medical evacuation in wartime. Because a pain medicine specialist may or may not be assigned to a forward-deployed medical unit, the treatment of pain from non-battle-related injuries in war zones is a serendipitous endeavor. Previous studies have demonstrated that the return-to-unit rate for soldiers evacuated to a tertiary care facility for pain management is abysmally low. METHODS: This is a prospective, observational study measuring return-to-duty rates in the first forward-deployed pain treatment center. RESULTS: Over a 6-month period, 132 patients were treated, the large majority (n = 113) of whom were coalition forces. In descending order, the four most common diagnoses among coalition forces were lumbar radiculopathy (n = 63), thoracic pain (n = 13), cervical radiculopathy (n = 8), and groin pain (n = 8). Epidural steroid injections (n = 125) were by far the most frequently performed procedure, followed by trigger point injections (n = 21), lumbar facet blocks (n = 16), and groin blocks (n = 9). Nonsteroidal antiinflammatory drugs were prescribed to 70% of patients, and 24% were referred to physical therapy. The return-to-duty rate for coalition forces was 94.7%. The primary complaint of all 7 patients who required medical evacuation outside the theaters of operation was groin pain. CONCLUSIONS: These results demonstrate the feasibility of obtaining high return-to-duty rates when aggressive pain management strategies are used in forward-deployed areas. [Abstract]

Yasui Y, Masaki E, Kato F
Sevoflurane directly excites locus coeruleus neurons of rats.
Anesthesiology. 2007 Dec;107(6):992-1002.
BACKGROUND: Sevoflurane, an anesthetic showing high incidence of emergence agitation in human patients, especially in children, increases noradrenaline release in the preoptic area in the rat brain. The clinically observed frequency of emergence agitation with sevoflurane is significantly reduced by drugs activating alpha2 adrenoceptors. The locus coeruleus (LC) is a source nucleus of widely spreading noradrenergic projections in the central nervous system and is also known as one of the principal targets of some alpha2-adrenoceptor agonists, such as dexmedetomidine. The authors analyzed the effects of sevoflurane and other anesthetics on the membrane current of the LC neurons to study the mechanism of the paradoxical "excitatory" effects of the anesthetics. METHODS: Effects of volatile and nonvolatile anesthetics on the membrane potential and currents of LC neurons in pontine slices of the rat were evaluated. Action potential-dependent transmission was suppressed with tetrodotoxin. RESULTS: Sevoflurane at 5% (measured concentration in the recording chamber, 0.5 mm) induced an early-phase inward current in most of LC neurons in a robust manner, which significantly increased the firing frequency in the absence of tetrodotoxin under current clamp recording. Preadministration of dexmedetomidine (1-3 nm) occluded this increase in firing frequency with sevoflurane. This inward current was inhibited by a gap junction inhibitor carbenoxolone and was not observed with nonvolatile general anesthetics and in non-LC neurons examined. CONCLUSIONS: The excitatory current activated by sevoflurane in LC neurons, likely to be mediated by gap junction-related mechanisms, might be one of the potential cellular mechanisms underlying paradoxical excitatory effect of sevoflurane. [Abstract]

Hudetz AG, Imas OA
Burst activation of the cerebral cortex by flash stimuli during isoflurane anesthesia in rats.
Anesthesiology. 2007 Dec;107(6):983-91.
BACKGROUND: The degree of suppression of sensory functions during general anesthesia is controversial. Here, the authors investigated whether discrete flash stimuli induced cortical field potential responses at an isoflurane concentration producing burst suppression and compared the spatiotemporal properties and frequency spectra of flash-induced burst responses with those occurring spontaneously. METHODS: Rats were equipped with multiple epidural and intracortical electrodes to record cortical field potentials in the right hemisphere at several locations along the anterior-posterior axis. At isoflurane concentrations of 1.1, 1.4, and 1.8%, discrete light flashes were delivered to the left eye while cortical field potentials were continuously recorded. RESULTS: Isoflurane at 1.4-1.8% produced burst suppression. Each flash produced a visual evoked potential in the primary visual cortex followed by secondary bursting activity in more anterior regions. The average latency and duration of these bursts were 220 and 810 ms, respectively. The spontaneous and flash-induced bursts were similar in frequency, duration, and spatial distribution. They had maximum power in the frontal (primary motor) cortex with a dominant frequency of 10 Hz. CONCLUSIONS: The results suggest that discrete flash stimuli activate the motor regions of the cerebral cortex during isoflurane anesthesia and that these activations are analogous with those that occur spontaneously during burst suppression. Electrocortical suppression of the cortex during anesthesia does not prevent its response to visual stimuli. [Abstract]

Metz LB, Dasgupta N, Liu C, Hunt SJ, Crowder CM
An evolutionarily conserved presynaptic protein is required for isoflurane sensitivity in Caenorhabditis elegans.
Anesthesiology. 2007 Dec;107(6):971-82.
BACKGROUND: Volatile general anesthetics inhibit neurotransmitter release by an unknown mechanism. A mutation in the presynaptic soluble NSF attachment protein receptor (SNARE) protein syntaxin 1A was previously shown to antagonize the anesthetic isoflurane in Caenorhabditis elegans. The mechanism underlying this antagonism may identify presynaptic anesthetic targets relevant to human anesthesia. METHODS: Sensitivity to isoflurane concentrations in the human clinical range was measured in locomotion assays on adult C. elegans. Sensitivity to the acetylcholinesterase inhibitor aldicarb was used as an assay for the global level of C. elegans neurotransmitter release. Comparisons of isoflurane sensitivity (measured by the EC50) were made by simultaneous curve fitting and F test as described by Waud. RESULTS: Expression of a truncated syntaxin fragment (residues 1-106) antagonized isoflurane sensitivity in C. elegans. This portion of syntaxin interacts with the presynaptic protein UNC-13, suggesting the hypothesis that truncated syntaxin binds to UNC-13 and antagonizes an inhibitory effect of isoflurane on UNC-13 function. Consistent with this hypothesis, overexpression of UNC-13 suppressed the isoflurane resistance of the truncated syntaxins, and unc-13 loss-of-function mutants were highly isoflurane resistant. Normal anesthetic sensitivity was restored by full-length UNC-13, by a shortened form of UNC-13 lacking a C2 domain, but not by a membrane-targeted UNC-13 that might bypass isoflurane inhibition of membrane translocation of UNC-13. Isoflurane was found to inhibit synaptic localization of UNC-13. CONCLUSIONS: These data show that UNC-13, an evolutionarily conserved protein that promotes neurotransmitter release, is necessary for isoflurane sensitivity in C. elegans and suggest that its vertebrate homologs may be a component of the general anesthetic mechanism. [Abstract]

Zhao P, Peng L, Li L, Xu X, Zuo Z
Isoflurane preconditioning improves long-term neurologic outcome after hypoxic-ischemic brain injury in neonatal rats.
Anesthesiology. 2007 Dec;107(6):963-70.
BACKGROUND: Preconditioning the brain with relatively safe drugs seems to be a viable option to reduce ischemic brain injury. The authors and others have shown that the volatile anesthetic isoflurane can precondition the brain against ischemia. Here, the authors determine whether isoflurane preconditioning improves long-term neurologic outcome after brain ischemia. METHODS: Six-day-old rats were exposed to 1.5% isoflurane for 30 min at 24 h before the brain hypoxia-ischemia that was induced by left common carotid arterial ligation and then exposure to 8% oxygen for 2 h. The neuropathology, motor coordination, and learning and memory functions were assayed 1 month after the brain ischemia. Western analysis was performed to quantify the expression of the heat shock protein 70, Bcl-2, and survivin 24 h after isoflurane exposure. RESULTS: The mortality was 45% after brain hypoxia-ischemia. Isoflurane preconditioning did not affect this mortality. However, isoflurane preconditioning attenuated ischemia-induced loss of neurons and brain tissues, such as cerebral cortex and hippocampus in the survivors. Isoflurane also improved the motor coordination of rats at 1 month after ischemia. The learning and memory functions as measured by performance of Y-maze and social recognition tasks in the survivors were not affected by the brain hypoxia-ischemia or isoflurane preconditioning. The expression of Bcl-2, a well-known antiapoptotic protein, in the hippocampus is increased after isoflurane exposure. This increase was reduced by the inhibitors of inducible nitric oxide synthase. Inducible nitric oxide synthase inhibition also abolished isoflurane preconditioning-induced neuroprotection. CONCLUSIONS: Isoflurane preconditioning improved the long-term neurologic outcome after brain ischemia. Inducible nitric oxide synthase may be involved in this neuroprotection. [Abstract]

Heerdt PM, Lane P, Pan BY, Schaefer U, Crabtree M, Hong R, Singer AA, Levi R, Park BJ
Nitrosative stress and myocardial sarcoplasmic endoreticular calcium adenosine triphosphatase subtype 2a activity after lung resection in swine.
Anesthesiology. 2007 Dec;107(6):954-62.
BACKGROUND: Chronic, disease-associated oxidative stress induces myocardial peroxynitrite formation that may lead to nitrosative inhibition of the calcium cycling protein sarcoplasmic endoreticular calcium adenosine triphosphatase subtype 2a (SERCA2a). The current study was designed to test the hypothesis that the acute oxidative stress associated with lung resection also induces myocardial nitrosative stress and alters SERCA2a activity. METHODS: Ventricular myocardium from 16 swine was studied; 11 animals had undergone left upper lobectomy (n = 7) or sham thoracotomy (n = 4) 3 days before harvest, and 5 were nonoperated controls. Tissue peroxynitrite was assessed by measurement of 3-nitrotyrosine incorporation into proteins. SERCA2a activity was determined from indo-1 uptake by isolated sarcoplasmic reticular membranes. Expression of SERCA2a and its regulatory protein phospholamban were determined by Western blotting, as was the phospholamban phosphorylation state (when dephosporylated, phospholamban inhibits SERCA2a). Mechanical significance of changes in SERCA2a activity was assessed from the force-frequency relation of isometric myocardial trabeculae. RESULTS: Relative to both the control and sham groups, lobectomy animals exhibited a greater than twofold higher myocardial 3-nitrotyrosine incorporation and an approximately 50% lower SERCA2a activity, but no difference in SERCA2a or phospholamban expression or phospholamban phosphorylation. Concomitantly, whereas the trabecular force-frequency relation of control animals was positive, that of lobectomy animals was negative, consistent with impaired calcium cycling. CONCLUSIONS: These data indicate that oxidative/nitrosative stress associated with lung resection influences SERCA2a activity independent of any influence on protein expression or phospholamban phosphorylation. The findings link an acute event with a subcellular process primarily described for chronic illness and suggest a biochemical basis for perioperative changes in myocardial mechanical reserve. [Abstract]

Breschan C, Platzer M, Jost R, Schaumberger F, Stettner H, Likar R
Comparison of catheter-related infection and tip colonization between internal jugular and subclavian central venous catheters in surgical neonates.
Anesthesiology. 2007 Dec;107(6):946-53.
BACKGROUND: The primary aim of this study was to compare catheter-associated infections and tip contaminations between percutaneously placed central venous catheters in the internal jugular and subclavian veins in surgical neonates undergoing major noncardiac surgery. METHODS: The prospectively computerized protocols of 295 procedures were analyzed retrospectively. RESULTS: One hundred twenty-nine internal jugular venous (group I) and 107 subclavian venous catheters (group S) were included. The median postconceptual age was 37 weeks in group I and 38 in group S. The weight ranged from 580 g to 4.5 kg in group I and from 820 g to 4.5 kg in group S at the time of insertion. Significantly more catheter-associated infections were observed in group I (15.5 vs. 4.7%; chi-square analysis: P < 0.01). The internal jugular venous catheters were also associated with a significantly increased probability of an earlier onset of a catheter-associated infection compared with the subclavian venous catheters (log rank test: P < 0.01; Cox model: P < 0.01). This probability was only slightly increased by a lower weight (Cox model: P = 0.075), and it was not increased by a lower age (Cox model: P = 0.93). Significantly more catheter tips were contaminated by pathogens in