Oxytocin receptor: Expression in the trigeminal nociceptive system and potential role in the treatment of headache disorders.
2016; 36 (10): 943-950
National and International Guidelines for Patient Blood Management in Obstetrics: A Qualitative Review.
Anesthesia and analgesia
Our studies investigated the location of oxytocin receptors in the peripheral trigeminal sensory system and determined their role in trigeminal pain.Oxytocin receptor expression and co-localization with calcitonin gene-related peptide was investigated in rat trigeminal ganglion using immunohistochemistry. Enzyme-linked immunosorbent assay was used to determine the effects of facial electrocutaneous stimulation and adjuvant-induced inflammation of the temporomandibular joint on oxytocin receptor expression in the trigeminal ganglion. Finally, the effects of oxytocin on capsaicin-induced calcitonin gene-related peptide release from dural nociceptors were investigated using isolated rat dura mater.Oxytocin receptor immunoreactivity was present in rat trigeminal neurons. The vast majority of oxytocin receptor immunoreactive neurons co-expressed calcitonin gene-related peptide. Both electrocutaneous stimulation and adjuvant-induced inflammation led to a rapid upregulation of oxytocin receptor protein expression in trigeminal ganglion neurons. Oxytocin significantly and dose-dependently decreased capsaicin-induced calcitonin gene-related peptide release from dural nociceptors.Oxytocin receptor expression in calcitonin gene-related peptide containing trigeminal ganglion neurons, and the blockade of calcitonin gene-related peptide release from trigeminal dural afferents suggests that activation of these receptors may provide therapeutic benefit in patients with migraine and other primary headache disorders.
View details for DOI 10.1177/0333102415618615
View details for PubMedID 26590611
Anatomical location of the vocal cords in relation to cervical vertebrae A new predictor of difficult laryngoscopy?
EUROPEAN JOURNAL OF ANAESTHESIOLOGY
2016; 33 (4): 257-262
Delayed emergence after anesthesia
JOURNAL OF CLINICAL ANESTHESIA
2015; 27 (4): 353-360
Postictal agitation after electroconvulsive therapy.
journal of ECT
2014; 30 (3): e27-8
Visualizing Dermal Permeation of Sodium Channel Modulators by Mass Spectrometric Imaging
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
2014; 136 (17): 6401-6405
In developed countries, rates of postpartum hemorrhage (PPH) requiring transfusion have been increasing. As a result, anesthesiologists are being increasingly called upon to assist with the management of patients with severe PPH. First responders, including anesthesiologists, may adopt Patient Blood Management (PBM) recommendations of national societies or other agencies. However, it is unclear whether national and international obstetric societies' PPH guidelines account for contemporary PBM practices. We performed a qualitative review of PBM recommendations published by the following national obstetric societies and international groups: the American College of Obstetricians and Gynecologists; The Royal College of Obstetricians and Gynecologists, United Kingdom; The Royal Australian and New Zealand College of Obstetricians and Gynecologists; The Society of Obstetricians and Gynecologists of Canada; an interdisciplinary group of experts from Austria, Germany, and Switzerland, an international multidisciplinary consensus group, and the French College of Gynaecologists and Obstetricians. We also reviewed a PPH bundle, published by The National Partnership for Maternal Safety. On the basis of our review, we identified important differences in national and international societies' recommendations for transfusion and PBM. In the light of PBM advances in the nonobstetric setting, obstetric societies should determine the applicability of these recommendations in the obstetric setting. Partnerships among medical, obstetric, and anesthetic societies may also help standardize transfusion and PBM guidelines in obstetrics.
View details for PubMedID 27557476
Gene therapy for trigeminal pain in mice
2014; 21 (4): 422-426
Determining permeability of a given compound through human skin is a principal challenge owing to the highly complex nature of dermal tissue. We describe the application of an ambient mass spectrometry imaging method for visualizing skin penetration of sodium channel modulators, including novel synthetic analogs of natural neurotoxic alkaloids, topically applied ex vivo to human skin. Our simple and label-free approach enables successful mapping of the transverse and lateral diffusion of small molecules having different physicochemical properties without the need for extensive sample preparation.
View details for DOI 10.1021/ja501635u
View details for Web of Science ID 000335369200044
View details for PubMedID 24708172
Correction: shaped magnetic field pulses by multi-coil repetitive transcranial magnetic stimulation (rTMS) differentially modulate anterior cingulate cortex responses and pain in volunteers and fibromyalgia patients.
2014; 10: 16-?
The sitting position in neurosurgery: indications, complications and results. a single institution experience of 600 cases
2013; 155 (10): 1887-1893
The aim of this study was to test the efficacy of a single direct injection of viral vector encoding for encephalin to induce a widespread expression of the transgene and potential analgesic effect in trigeminal behavioral pain models in mice. After direct injection of herpes simplex virus type 1 based vectors encoding for human preproenkephalin (SHPE) or the lacZ reporter gene (SHZ.1, control virus) into the trigeminal ganglia in mice, we performed an orofacial formalin test and assessed the cumulative nociceptive behavior at different time points after injection of the viral vectors. We observed an analgesic effect on nociceptive behavior that lasted up to 8 weeks after a single injection of SHPE into the trigeminal ganglia. Control virus-injected animals showed nociceptive behavior similar to naive mice. The analgesic effect of SHPE injection was reversed/attenuated by subcutaneous naloxone injections, a μ-opioid receptor antagonist. SHPE-injected mice also showed normalization in withdrawal latencies upon thermal noxious stimulation of inflamed ears after subdermal complete Freund's adjuvant injection, indicating widespread expression of the transgene. Quantitative immunohistochemistry of trigeminal ganglia showed expression of human preproenkephalin after SHPE injection. Direct injection of viral vectors proved to be useful for exploring the distinct pathophysiology of the trigeminal system and could also be an interesting addition to the pain therapists' armamentarium.
View details for DOI 10.1038/gt.2014.14
View details for Web of Science ID 000333777900010
Sequential bilateral lung isolation with a single bronchial blocker.
A & A case reports
2013; 1 (1): 17-18
The benefit of the sitting position for surgery of the posterior fossa and cervical spine is still a matter of controversy. In our study we analyzed the outcome after sitting position surgery at our institution. We compared the incidence of venous air embolism (VAE) as recognized with different monitoring techniques and the severity of complications.We retrospectively analyzed 600 patients, who underwent surgery for different posterior fossa and cervical spine pathologies, respectively, in the sitting position at our institution from 1995 to 2011. Intraoperative monitoring for VAE included endtidal CO2 level, Doppler ultrasound or intraoperative transesophageal echocardiography (TEE). We defined VAE as a decrease of the endtidal CO2 levels by more than 4 mm Hg, a characteristic sound in the thoracic Doppler, or any sign of air in the TEE.We found an overall incidence of VAE in 19 % of all patients, whereas the rate of severe complications associated with VAE such as a decline of partial oxygen pressure (pO2) or a drop of blood pressure was only 3.3 % in all patients. Only three out of 600 operations had to be terminated because of non-controllable VAE (0.5 %). There was no mortality resulting from VAE in our series. We also found a difference in the incidence of VAE depending on the monitoring technique. The VAE rate as monitored with TEE was 25.6 % whereas the incidence of VAE in patients monitored with Doppler ultrasound was 9.4 %. The rate of a significant VAE was comparable in both methods 4.8 % vs. 1.2 %. All patients were preoperatively screened for persisting foramen ovale (PFO); 24 patients with clinically confirmed PFO were included in this series. There was no case of paradox air embolism.In our series, VAE was detected in 19 % of all patients in the sitting position. However, in only 0.5 % of cases a termination of the surgical procedure became necessary. In all other cases, the cause of air embolism could be found and eliminated during surgery. TEE was found to be the monitoring technique with the highest sensitivity. In our opinion, the sitting position is a safe positioning technique if TEE monitoring is used.
View details for DOI 10.1007/s00701-013-1822-x
View details for Web of Science ID 000324331700012
View details for PubMedID 23925859
Postictal Agitation After Electroconvulsive Therapy Incidence, Severity, and Propofol as a Treatment Option
JOURNAL OF ECT
2013; 29 (3): 189-195
Sequential bilateral lung separation and selective lung collapse can be accomplished with either a double-lumen tube, a single bronchial blocker (BB) that must be repositioned during the operation, or by using 2 BBs, 1 placed in each main bronchus. We provided sequential bilateral lung collapse using a single BB without the need to reposition during surgery.
View details for DOI 10.1097/ACC.0b013e318291d364
View details for PubMedID 25611606
Anaesthesia and orphan disease: traumatic cardiac arrest in a patient with osteogenesis imperfecta
EUROPEAN JOURNAL OF ANAESTHESIOLOGY
2013; 30 (8): 509-511
Shaped magnetic field pulses by multi-coil repetitive transcranial magnetic stimulation (rTMS) differentially modulate anterior cingulate cortex responses and pain in volunteers and fibromyalgia patients
High-dose remifentanil prevents development of thermal hyperalgesia in a neuropathic pain model
BRITISH JOURNAL OF ANAESTHESIA
2013; 110 (2): 287-292
Postictal agitation (PIA) after electroconvulsive therapy (ECT) is a major medical problem. This observational study investigated the incidence and severity of PIA and evaluated propofol as a treatment option in a patient population.The study included 14 patients that underwent a series of ECTs performed either with or without an approximately 0.5-mg/kg propofol bolus after the end of an electroencephalography (EEG) seizure. Among other values, we documented PIA incidence and severity as rated by a simple score; orientation to person, time, place, and situation; transfer times to the postanesthesia care (PACU) and inpatient unit; nurses' and patients' rating of recovery period, and others and tested for significant differences.Five minutes after the end of ECT, the patients showed moderate to severe PIA in 8 of 37 ECT sessions. Incidence was significantly lower when patients had received propofol (3/37). Transfer time to the PACU was longer, but transfer time to the inpatient unit was shorter after administration of propofol. The recovery period was rated significantly better after propofol administration by nurses and patients.A single bolus of propofol administered after the end of the seizure reduced the incidence of post-ECT PIA. The PACU staff and patients rated the emergence period significantly better when propofol was administered.
View details for DOI 10.1097/YCT.0b013e3182887b5b
View details for Web of Science ID 000330362100017
View details for PubMedID 23792779
Advantages of the Sitting Position in a Case of Severe COPD
JOURNAL OF NEUROSURGICAL ANESTHESIOLOGY
2013; 25 (1): 93-94
The Orofacial Formalin Test in Mice Revisited-Effects of Formalin Concentration, Age, Morphine and Analysis Method
JOURNAL OF PAIN
2011; 12 (6): 633-639
Intraoperative nerve lesions can lead to chronic postoperative pain. There are conflicting data as to whether or not anaesthetics administered intraoperatively are beneficial. We investigated if remifentanil administered at the time of nerve injury was able to attenuate neuropathic hypersensitivity.Rats were anaesthetized with isoflurane, endotracheally intubated, and a tail vein catheter was inserted. Rats received an i.v. infusion of either saline or low- or high-dose remifentanil (2 or 20 μg kg(-1) min(-1), respectively) for 20 min. During this time, rats received a spinal nerve L5 transection to induce neuropathic pain or a sham procedure. Behavioural tests to assess mechanical and cold allodynia and heat hyperalgesia were performed on postoperative days 1, 3, 7, 14, 21, and 28.Sham-operated animals exhibited no hypersensitivity regardless of the intraoperative remifentanil dose. In rats which received spinal nerve L5 transection, mechanical and cold allodynia developed with no significant differences between treatment groups. However, thermal hyperalgesia was reduced in rats given high-dose remifentanil: mean (standard deviation) area under the curve 426 (53) compared with 363 (34) and 342 (24) in saline or low-dose remifentanil treated rats, respectively (P<0.05).High-dose remifentanil administered at the time of transection of the spinal nerve at L5 prevents subsequent thermal hyperalgesia.
View details for DOI 10.1093/bja/aes360
View details for Web of Science ID 000313826500018
Selective nociceptor activation in volunteers by infrared diode laser
The orofacial formalin test is established in rats and was recently transferred to mice. The aim of this study was to determine the ideal formalin concentration for testing analgesic drugs, to examine alternatives for the assessment of nociceptive and non-nociceptive behavior as well as the effects of morphine and age on formalin-induced nociception. Formalin (.5, 1, 2.5, 5, 7.5, 10, and 15%) was injected into the vibrissa of mice. The cumulative nociceptive behavior was measured as well as nociceptive and non-nociceptive behavior based on a score that was recorded over a 5-second observation period once per minute. We also examined the effects of morphine on the nociceptive response induced by 2.5% formalin. Age-dependent differences were tested in the third part of the experiment. NONMEM was used to model the pharmacodynamic effects of formalin and morphine. Injection of formalin lead to a concentration-dependent increase in cumulative nociceptive behavior ratings as well as the specific nociceptive behavior 3 of scratching injection site with hindpaw (score 3). The formalin concentrations that lead to 50% of the maximum effect were 2.6 and 3.3%, respectively, for the continuous rating method and the scoring method. Morphine dose dependently suppressed the nociceptive behavior and the number of score 3 ratings of the nociceptive behavior. Age differences in behavior could not be detected by either analytic method.To improve the existing behavioral nociceptive assay for pain processed by the trigeminal system, we determined an ideal formalin concentration for the orofacial formalin test in mice, evaluated alternative timesaving analysis approaches, and investigated effects of morphine and age on formalin-induced nociception.
View details for DOI 10.1016/j.jpain.2010.11.009
View details for Web of Science ID 000291959100003
View details for PubMedID 21481645
Trigeminal antihyperalgesic effect of intranasal carbon dioxide
2010; 87 (1-2): 36-41
Two main classes of peripheral sensory neurons contribute to thermal pain sensitivity: the unmyelinated C fibers and thinly myelinated A? fibers. These two fiber types may differentially underlie different clinical pain states and distinctions in the efficacy of analgesic treatments. Methods of differentially testing C and A? thermal pain are widely used in animal experimentation, but these methods are not optimal for human volunteer and patient use. Thus, this project aimed to provide psychophysical and electrophysiological evidence that whether different protocols of infrared diode laser stimulation, which allows for direct activation of nociceptive terminals deep in the skin, could differentially activate A? or C fiber thermonociceptors in volunteers.Short (60 ms), high intensity laser pulses (SP) evoked monomodal "pricking" pain which was not enhanced by topical capsaicin, whereas longer, lower power pulses (LP) evoked monomodal "burning" pain which was enhanced by topical capsaicin. SP also produced cortical evoked EEG potentials consistent with A? mediation, the amplitude of which was directly correlated with pain intensity but was not affected by topical capsaicin. LP also produced a distinct evoked potential pattern the amplitude of which was also correlated with pain intensity, which was enhanced by topical capsaicin, and the latency of which could be used to estimate the conduction velocity of the mediating nociceptive fibers.Psychophysical and electrophysiological data were consistent with the ability of short high intensity infrared laser pulses to selectively produce A? mediated pain and of longer pulses to selectively produce C fiber mediated thermal pain. Thus, the use of these or similar protocols may be useful in developing and testing novel therapeutics based on the differential molecular mechanisms underlying activation of the two fiber types (e.g., TRPV1, TRPV2, etc). In addition, these protocol may be useful in determining the fiber mediation of different clinical pain types which may, in turn be useful in treatment choice.
View details for DOI 10.1186/1744-8069-7-18
View details for Web of Science ID 000289115700001
View details for PubMedID 21426575
Long-term treatment of neuropathic pain with a 5% lidocaine medicated plaster
EUROPEAN JOURNAL OF ANAESTHESIOLOGY
2010; 27 (2): 169-173
Clinical studies demonstrate attenuation of trigeminal-related pain states such as migraine by intranasal CO(2) application. This study investigated the underlying mechanisms of this observation and its potential use to reverse trigeminal pain and hypersensitivity.We used a behavioral rat model of capsaicin-induced trigeminal thermal hyperalgesia, intranasal CO2 application and several pharmacologic agents such as carbonic anhydrase, acid-sensing ion channels (ASICs), and TRPV1 blocker as well as acidic buffer solutions to investigate and mimic the underlying mechanism.Intranasal CO(2) application produced a robust dose-dependent antihyperalgesic effect in rats that lasted at least one hour. Blockade of nasal carbonic anhydrase with a dorzolamide solution (Trusopt ophthalmic solution) showed only a non-significant decrease of the antihyperalgesic effect of intranasal CO(2) application. Pharmacologic blockade of ASICs or TRPV(1) receptor significantly attenuated the antihyperalgesic effect of CO(2) application. The effect of intranasal CO(2) application could be mimicked by application of pH 4, but not pH 5, buffer solution to the nasal mucosa. As with CO(2) application, the antihyperalgesic effect of intranasal pH 4 buffer was blocked by nasal application of antagonists to ASICs and TRPV(1) receptors.Our results indicate that intranasal CO(2) application results in a subsequent attenuation of trigeminal nociception, mediated by protonic activation of TRPV(1) and ASIC channels. A potential central mechanism for this attenuation is discussed. The antihyperalgesic effects of intranasal CO(2) application might be useful for the treatment of trigeminal pain states.
View details for DOI 10.1016/j.lfs.2010.05.013
View details for Web of Science ID 000279499000005
View details for PubMedID 20561904
Opioid-induced hyperalgesia or opioid-withdrawal hyperalgesia?
EUROPEAN JOURNAL OF ANAESTHESIOLOGY
2007; 24 (9): 811-812
Antihyperalgesic effect of a recombinant herpes virus encoding antisense for calcitonin gene-related peptide
2007; 106 (6): 1196-1203
The 5% lidocaine medicated plaster is a topical treatment for peripheral neuropathic pain symptoms (e.g. burning, shooting and stabbing pain) and is registered for the treatment of postherpetic neuralgia. This study examined the efficacy and tolerability of long-term treatment with the 5% lidocaine medicated plaster in patients with localized neuropathic pain conditions.Twenty patients with localized neuropathic pain [postoperative neuropathic pain (n = 14); complex regional pain syndrome (n = 2); and postherpetic neuralgia (n = 4)], who had been successfully treated with 5% lidocaine medicated plaster, were followed up by telephone interview after 3 and 5 years. Questions were related to the efficacy, development of tolerance, tolerability, wear time and comfort of the plaster.At 3 years, 10 out of 20 (50%) initial responders were still using the plasters with no decline in analgesic efficacy. After 5 years, eight of the original 20 responders (40%) maintained treatment and continued to experience effective pain relief. The 12 responders who discontinued treatment did so because they no longer required analgesic therapy (n = 4); their health insurer refused to fund treatment (n = 2); they were lost to follow-up (n = 1); or had died from an illness unrelated to plaster treatment (n = 5). No patient discontinued because of inadequate analgesia or intolerable side effects. Reversible erythema occurred in two patients wearing the plaster for more than 16 h. There were no systemic side effects.The 5% lidocaine medicated plaster provides sustained pain relief over long-term treatment in patients with neuropathic pain of various causes and is well tolerated.
View details for DOI 10.1097/EJA.0b013e328330e989
View details for Web of Science ID 000274176900007
View details for PubMedID 20010108
Development of acute tolerance to the EEG effect of propofol in rats
BRITISH JOURNAL OF ANAESTHESIA
2005; 95 (3): 367-371
Calcitonin gene-related peptide (CGRP) is contained in and released by small-diameter, nociceptive primary afferent sensory neurons. Upon spinal release, one of the effects of CGRP seems to be to sensitize dorsal horn neurons to subsequent input from nociceptive afferents and, consequently, to induce a behavioral hyperalgesia. Therefore, attenuating evoked release of CGRP from central terminals of nociceptors should have an antihyperalgesic effect.The authors applied a recombinant herpes vector, encoding an antisense sequence to the whole CGRP gene, to the dorsal surface of the hind paw of mice to knock down expression of the peptide selectively in primary afferents innervating this tissue.Herpes virus-based vector encoding an antisense sequence for the whole CGRP clearly reduced CGRP immunoreactivity in the infected spinal dorsal horn levels as well as in cultured dorsal root ganglia neurons. Selective knockdown of CGRP in primary afferents significantly attenuated the thermal, C-fiber hyperalgesia normally observed after topical application of capsaicin. The effect of viral vector-mediated knockdown of CGRP was comparable to the effect of intrathecal application of the CGRP antagonist CGRP8-37, but lasted for 14 weeks after one single application.Viral vector-mediated knockdown of CGRP in primary afferent neurons provides a promising tool for treatment of chronic pain states as well as for studies investigating the pathophysiology underlying these conditions.
View details for Web of Science ID 000246797500019
View details for PubMedID 17525595
Differential activation of trigeminal C or A delta nociceptors by infrared diode laser in rats: Behavioral evidence
2005; 1037 (1-2): 148-156
A previous study in rats with propofol suggested the development of acute tolerance to the EEG effect. The aim of this study was to evaluate acute tolerance by means of EEG-controlled closed-loop anaesthesia as this approach allows precise determination of drug requirement to maintain a defined drug effect.Ten male Sprague-Dawley rats [weight 402 (40) g, mean (SD)] were included in the study. The EEG was recorded with occipito-occipital needle electrodes and a modified median frequency (mMEF) of the EEG power spectrum was used as a pharmacodynamic control parameter. The propofol infusion rate was controlled by a model-based adaptive algorithm to maintain a set point of mMEF=3 (0.5) Hz for 90 min. The performance of the closed-loop system was characterized by the prediction error PE=(mMEF-set point)/set point. Plasma propofol concentrations were determined from arterial samples by HPLC.The chosen set point was successfully maintained in all rats. The median (SE) and absolute median values of PE were -5.0 (0.3) and 11.3 (0.2)% respectively. Propofol concentration increased significantly from 2.9 (2.2) microg ml(-1) at the beginning to 5.8 (3.8) microg ml(-1) at 90 min [mean (SD), P<0.05]. The cumulative dose increased linearly, with a mean infusion rate of 0.60 (0.16) mg kg(-1) min(-1). The minimum value of the mean arterial pressure during closed-loop administration of propofol was 130 (24) mm Hg, compared with a baseline value of 141 (12) mm Hg.The increase in propofol concentration at constant EEG effect indicates development of acute tolerance to the hypnotic effect of propofol.
View details for DOI 10.1093/bja/aei179
View details for Web of Science ID 000231701600016
View details for PubMedID 15980043
Decrease in inflammatory hyperalgesia by herpes vector-mediated knockdown of Na(v)1.7 sodium channels in primary afferents
HUMAN GENE THERAPY
2005; 16 (2): 271-277
Radiant heat is often used for studying thermal nociception, although inherent characteristics such as the broad spectrum of applied wavelengths of typical light sources limit control over and repeatability of stimuli. To overcome these problems, we used a diode infrared laser-based stimulator (wavelength: 980 nm) for selectively stimulating trigeminal Adelta or C thermonociceptors in rats. To provide indirect evidence for nociceptor-selective stimulation, we tested the effects of capsaicin, dimethylsulfoxide (DMSO), and morphine on withdrawal latencies for long pulses with a low current (hypothesized to selectively stimulate C nociceptors) and for threshold currents of short pulses with high current (hypothesized to selectively stimulate Adelta nociceptors) in lightly anesthetized rats. Nonmem analysis was used to perform pharmacodynamic modeling. The measured baseline withdrawal latency for long pulses was 12.5 +/- 0.3 s which was changed significantly to 6.7 +/- 0.4 s after applying topical capsaicin which selectively sensitizes C nociceptors and to 16.5 +/- 1.3 s after 1.0 mg/kg morphine which preferentially attenuates C fiber nociception. Topical DMSO which appears to selectively sensitize Adelta afferents did not significantly alter withdrawal latencies to the long pulses. Fitted threshold currents for short pulses after DMSO were however significantly lower (974 +/- 53 mA vs. 1113 +/- 12 mA for baseline) indicating Adelta sensitization. Capsaicin and morphine did not significantly change threshold currents. Best Nonmem fits for the long pulse were obtained using a model assuming no DMSO effect, but a different inter-individual variability after applying this substance. For the short pulse, a model assuming no capsaicin or morphine effect, but again allowing different inter-individual variabilities after applying these drugs, best described the data. We conclude that different settings of the stimulator used in this study were capable of selectively activating trigeminal Adelta or C thermonociceptors.
View details for DOI 10.1016/j.brainres.2005.01.019
View details for Web of Science ID 000228251400018
View details for PubMedID 15777763
Ameroid rings for gradual chronic constriction of the sciatic nerve in rats: contribution of different nerves to neuropathic pain
BRAIN RESEARCH BULLETIN
2004; 64 (2): 127-132
Induction of peripheral inflammation increases the expression of the Nav1.7 sodium channel in sensory neurons, potentially increasing their excitability. Peripheral inflammation also produces hyperalgesia in humans and an increase in nociceptive responsiveness in animals. To test the relationship between these two phenomena we applied a recombinant herpes simplex-based vector to the hindpaw skin of mice, which encoded both green fluorescent protein (GFP) as well as an antisense sequence to the Nav1.7 gene. The hindpaw was subsequently injected with complete Freund's adjuvant to induce robust inflammation. Application of the vector, but not a control vector encoding only GFP, prevented an increase in Nav1.7 expression in GFP-positive neurons and prevented development of hyperalgesia in both C and Adelta thermonociceptive tests. These results provide clear evidence of the involvement of an increased expression of the Nav1.7 channel in nociceptive neurons in the development of inflammatory hyperalgesia.
View details for Web of Science ID 000227543900012
View details for PubMedID 15761266
EEG-controlled closed-loop dosing of propofol in rats
BRITISH JOURNAL OF ANAESTHESIA
2004; 92 (4): 564-569
Mononeuropathy was induced by placing an ameroid ring around the sciatic nerve and was compared with chronic constriction injury (CCI) of the sciatic nerve [Pain 33 (1988) 87] in rats. Mechanical allodynia was assessed and the role of sciatic and saphenous afferents (Adelta and C) in thermal hyperalgesia investigated. A shorter duration of mechanical allodynia in ameroid rats as compared to CCI rats was observed. Thermal hyperalgesia was observed in the saphenous innervated skin of the hindpaw for Adelta and C nociceptors in ameroid and for Adelta nociceptors only in CCI rats, respectively. The sciatic innervated skin showed a thermal hypoalgesia with a fast onset for Adelta afferents and a slower onset for C afferents in CCI and ameroid rats. The duration of both thermal hypo- and hyperalgesia was longer in ameroid rats. We conclude that ameroid rings are a useful tool for the investigation of long-duration hyperalgesic effects of nerve injury, as the effects were more stable and seen for a longer time (>8 weeks) as compared to the CCI model. The uninjured saphenous afferents, in particular C fibers, mediate thermal hyperalgesia after chronic constriction of the sciatic nerve using an ameroid ring.
View details for DOI 10.1016/j.brainresbull.2004.05.006
View details for Web of Science ID 000224035600004
View details for PubMedID 15342099
Pharmacokinetics and pharmacodynamics of the new propofol prodrug GPI 15715 in rats (Retracted article. See vol. 20, pg. 182, 2003)
EUROPEAN JOURNAL OF ANAESTHESIOLOGY
2003; 20 (3): 182-190
Based on previous pharmacokinetic and pharmacodynamic studies, we have developed an EEG-controlled closed-loop system for the i.v. hypnotic agent propofol in rats.Seven adult male Sprague-Dawley rats (weight 423-584 g) were included in the study. EEG was recorded with occipito-occipital needle electrodes and the EEG power spectrum was estimated. The median frequency (MEF) was extracted from the power spectrum and was modified MEF (mMEF) to account for the occurrence of spikes and burst suppression patterns in the EEG. Propofol infusion was controlled by a model-based adaptive control algorithm to maintain a set point of mMEF=3.0 (sd 0.5) Hz. The performance of the feedback system was characterized by the median performance error MDPE=median[(mMEF-set point)/set point] and the median absolute performance error (MDAPE). The effective therapeutic infusion (ETI) to maintain the set point was determined from the resulting infusion rates.In all rats a feedback period of 90 min could be performed. Mean MDPE was 1.2 (se 0.4)% and MDAPE was 13.9 (0.3)%. The ETI was 0.73 (sd 0.20) mg kg(-1) min(-1). Mean arterial pressure before propofol infusion was 148 (14) mm Hg, with the lowest value during closed-loop infusion being 110 (20) mm Hg.The feedback system presented here may be a useful tool not only for automatic drug control to maintain a defined hypnotic effect but may also be a powerful device in pharmacological studies such as the determination of dose requirements or the assessment of drug-drug interactions.
View details for DOI 10.1093/bja/aeh102
View details for Web of Science ID 000220180400019
View details for PubMedID 14977798
Propofol in rats: testing for nonlinear pharmacokinetics and modelling acute tolerance to EEG effects
EUROPEAN JOURNAL OF ANAESTHESIOLOGY
2002; 19 (3): 177-188
We studied the pharmacokinetics and pharmacodynamics of GPI 15715 (Aquavan injection), a new water-soluble prodrug metabolized to propofol by hydrolysis.Nine adult male Sprague-Dawley rats (398 +/- 31 g) received a bolus dose of 40 mg GPI 15715. The plasma concentrations of GPI 15715 and propofol were determined from arterial blood samples, and the pharmacokinetics of both compounds were investigated using compartment models whereby the elimination from the central compartment of GPI 15715 was used as drug input for the central compartment of propofol. Pharmacodynamics were assessed using the median frequency of the EEG power spectrum.A maximum propofol concentration of 7.1 +/- 1.7 microg mL(-1) was reached 3.7 +/- 0.2 min after bolus administration. Pharmacokinetics were best described by two-compartment models. GPI 15715 showed a short half-life (2.9 +/- 0.2 and 23.9 +/- 9.9 min), an elimination rate constant of 0.18 +/- 0.01 min(-1) and a central volume of distribution of 0.25 +/- 0.02 L kg(-1). For propofol, the half-life was 1.9 +/- 0.1 and 45 +/- 7 min, the elimination rate constant was 0.15 +/- 0.02 min(-1) and the central volume of distribution was 2.3 +/- 0.6 L kg(-1). The maximum effect on the electroencephalogram (EEG)--EEG suppression for >4 s--occurred 6.5 +/- 1.2 min after bolus administration and baseline values of the EEG median frequency were regained 30 min later. The EEG effect could be described by a sigmoid Emax model including an effect compartment (E0 = 16.9 +/- 7.9 Hz, EC50 = 2.6 +/- 0.8 microg mL(-1), ke0 = 0.35 +/- 0.04 min(-1)).Compared with known propofol formulations, propofol from GPI 15715 showed a longer half-life, an increased volume of distribution, a delayed onset, a sustained duration of action and a greater potency with respect to concentration.
View details for Web of Science ID 000181685500002
View details for PubMedID 12650488
Pharmacokinetics of propofol in rats have usually been described using linear models. Furthermore, there are only a few investigations for a pharmacodynamic model of the electroencephalographic effects of propofol in rats. We investigated pharmacokinetics and pharmacodynamics of propofol in rats with special regard to linearity in pharmacokinetics and development of tolerance.Twelve adult male Sprague-Dawley rats received propofol in three successive infusion periods of 30 min each with infusion rates of 0.5, 1 and 0.5 mg kg(-1) min(-1). Propofol plasma concentrations were determined from arterial blood samples. Pharmacokinetics were tested for linearity using the ratio of the concentrations at the end of the first and second infusion interval as a model independent criterion. Several linear and nonlinear models were investigated with population pharmacokinetic analysis. Pharmacodynamics were analysed using the median frequency of the electroencephalographic power spectrum as a quantitative measure of the hypnotic effect.Pharmacokinetics were found to be nonlinear and were best described by a two-compartment model with Michaelis-Menten elimination (Vm = 2.17 microg mL(-1) min(-1), Km = 2.65 microg mL(-1), k12 = 0.30 min(-1), k21 0.063 min(-1), Vc = 0.13 L). Acute tolerance to the electroencephalographic effect of propofol was observed. The hypnotic effect was best described by a sigmoid Emax model (E0 = 17.8 Hz, Emax = 17.7 Hz, EC50 = 4.1 microg mL(-1), gamma = 2.3, ke0 = 0.36 min(-1)) with competitive antagonism of propofol and a hypothetical drug in an additional tolerance compartment.For the applied infusion scheme, propofol pharmacokinetics in rats were nonlinear and a development of tolerance to the electroencephalographic effect of propofol was observed during an infusion time of 90 min.
View details for Web of Science ID 000174709600005
View details for PubMedID 12071237