Nociceptive System Research Articles

Can aberrant spinal nociception be a marker of chronicity of pain in fibromyalgia syndrome?

Pain sensitivity is a recognized feature of fibromyalgia syndrome (FMS) but the contribution of spinal nociceptive circuitry to this phenomenon is unknown. Therefore, the objectives were to study the changes in spinal nociception i.e. nociceptive flexion reflex (NFR) in patients with FMS and to investigate correlation if any, between NFR threshold, pain duration and tender points in FMS. One hundred and three patients with FMS and 74 healthy volunteers participated in the study. To record NFR, sural nerve was stimulated in the retro malleolar region and the reflex response was recorded from the short head of biceps femoris muscle. NFR was elicited at significantly lower [21.0(18.0–25.0)V] thresholds in FMS group when compared to healthy subjects [30.0(24.75–35.0)V; p = 0.001] indicating hyperalgesic response to electrocutaneous stimulation in FMS patients. The latency and other parameters of NFR were comparable in both the groups. No significant correlation was found among NFR threshold and pain duration or tender points. On the basis of results of present study, it may be concluded that the functional deficit of the spinal nociceptive system can contribute to hyperalgesia in FMS. This is first study that correlates a marker of central hyper-excitability (NFR threshold) with clinical symptoms (pain duration and tender points) of FMS.

Integration of bilateral nociceptive inputs tunes spinal and cerebral responses

Together with the nociceptive system, pain protects the body from tissue damage. For instance, when the RIII-reflex is evoked by sural nerve stimulation, nociceptive inputs activate flexor muscles and inhibit extensor muscles of the affected lower limb while producing the opposite effects on the contralateral muscles. But how do the spinal cord and brain integrate concurrent sensorimotor information originating from both limbs? This is critical for evoking coordinated responses to nociceptive stimuli, but has been overlooked. Here we show that the spinal cord integrates spinal inhibitory and descending facilitatory inputs during concurrent bilateral foot stimulation, resulting in facilitation of the RIII-reflex and bilateral flexion. In these conditions, high-gamma oscillation power was also increased in the dorsolateral prefrontal, anterior cingulate and sensorimotor cortex, in accordance with the involvement of these regions in cognitive, motor and pain regulation. We propose that the brain and spinal cord can fine-tune nociceptive and pain responses when nociceptive inputs arise from both lower limbs concurrently, in order to allow adaptable behavioural responses.

Some Physiological Mechanisms Functioning in Models of Pain-Related Processes

Psychophysiological sensing of pain is formed due to the activity of a number of neuronal mechanisms. Among the pain-related processes, nociception per se, peripheral sensitization, synaptic plasticity, central sensitization, forming of abnormal excitability, structural reorganization in the respective neuronal networks, modulation of recurrent suppression, and a few other phenomena/processes can be mentioned. Nociception includes the processes of transduction, transmission, spreading, and perception of the pain signals. Transduction of the pain influences is a process of transformation of excessively strong and/or (sometimes) long-lasting mechanical, thermal, or chemical stimuli in electrical spike activity generated in peripheral processes of primary nociceptive sensory neurons. This process is mediated by specific receptor-channel complexes that are expressed exclusively in the nociceptive units; it also includes synaptic transmission to secondary and higher-order neurons of the nociception system and modulation of this transmission in neuron-to-neuron synapses in the nociception ascending pathways. The abnormal excitability, structural reorganization, and modulation of recurrent suppression are especially typical of neuropathic pain. Central sensitization is a phenomenon typical of inflammation-related pain, neuropathic pain, and “functional” pain. Different mechanisms responsible for the formation of pain can be targets for analgesic agents; naturally, elucidation of the mechanisms of antinociceptive effects is critically important. Some aspects of the nociception and antinociception events can, in many cases, be examined only in model experiments on animals. In this review, we describe the classification of the types of pain, mention some particular experimental models of pain, analyze the respective physiological mechanisms acting in such models, and also discussed some advantages and limitations of different experimental approaches used in these models.

A choreography of intracellular Ca2+ and extracellular ATP to refine auditory nociceptors before hearing.

Our hearing ability is exquisite in terms of sensitivity, dynamic range, and frequency discrimination. However, this acuity comes at the price of high vulnerability to a range of adverse influences—including sustained loud sounds. One may therefore expect that the ear is equipped with an alert system that can help prevent hearing damage, akin to the nociceptive sensory system that safeguards us from undergoing tissue injury. Here, Ceriani et al reveal a complex signaling interplay of sensory and non‐sensory cells that helps setting up such a system in development.

Long term reliability of nociceptive withdrawal reflex thresholds

BackgroundThe nociceptive withdrawal reflex (NWR) is a polysynaptic spinal reflex protecting the body from harmful stimuli. Two different methods to assess its’ threshold (NWR-T) have been part of clinical trials concerning the evaluation of the nociceptive system in the human body. NWR-T’s are gathered by stimulation at the sole of the foot and over the sural pathway. Consequently, EMG analyzes the muscle activity over the biceps femoris and tibialis anterior muscle. Past studies favor stimulation at the sole of the foot. New methodThe two methods were compared concerning retest-reliability and subjective pain ratings. The retest-reliability was tested over a period of 21 days using an up-down staircase method. Reliability was evaluated with a Bland Altman agreement analysis. Subjective pain ratings were evaluated with a numeric rating scale (NRS). ResultsNWR-T assessment was successful for all subjects. The EMG muscle activity had larger reflex amplitudes for measurements of the tibialis anterior muscle. NWR-T values showed greater variability than NRS values. Comparison with existing methodThe retest-reliability over a period of 21 days showed stable NWR-T results for both stimulation sites, but superior reliability was gathered with stimulation at the sole of the foot. Subjects rated stimulation over the sural pathway as more painful. ConclusionsThe NWR-T upholds reliable measurements over a longer period of time and seems to be a stable measure for pain condition. Reliability estimations, EMG recordings, and subject’s rating show stimulation at the sole of the foot could be the better choice.

Prenatal Effects of Fluoxetine on Adaptive Behavior and the Cognitive Domain in Male Rats During the Prepubertal Period of Development

The effects of injections of the selective serotonin reuptake inhibitor fluoxetine or physiological saline to rats during pregnancy (from day 9 to day 20) on behavioral parameters of the tonic pain system, anxiety levels, depression, and cognitive measures were studied in male offspring during the prepubertal period of development. The results demonstrated decreases in body weight in neonatal and 25-day-old males. Improvements in spatial learning ability were seen, though there were no changes in measures of psychoemotional behavior in males in the prepubertal period of development. Comparison of the effects of prenatal administration of fluoxetine and physiological saline on the functional activity of the nociceptive system showed that the serotonin reuptake inhibitor eliminated the effect of invasive stress due to the injection. Chronic injections of the antidepressant fluoxetine during pregnancy did not increase pain sensitivity in male offspring.

Priming of Adult Incision Response by Early-Life Injury: Neonatal Microglial Inhibition Has Persistent But Sexually Dimorphic Effects in Adult Rats.

Neonatal hindpaw incision primes developing spinal nociceptive circuitry, resulting in enhanced hyperalgesia following reinjury in adulthood. Spinal microglia contribute to this persistent effect, and microglial inhibition at the time of adult reincision blocks the enhanced hyperalgesia. Here, we pharmacologically inhibited microglial function with systemic minocycline or intrathecal SB203580 at the time of neonatal incision and evaluated sex-dependent differences following adult reincision. Incision in adult male and female rats induced equivalent hyperalgesia and spinal dorsal horn expression of genes associated with microglial proliferation (Emr1) and transformation to a reactive phenotype (Irf8). In control adults with prior neonatal incision, the enhanced degree and duration of incision-induced hyperalgesia and spinal microglial responses to reincision were equivalent in males and females. However, microglial inhibition at the time of the neonatal incision revealed sex-dependent effects: the persistent mechanical and thermal hyperalgesia following reincision in adulthood was prevented in males but unaffected in females. Similarly, reincision induced Emr1 and Irf8 gene expression was downregulated in males, but not in females, following neonatal incision with minocycline. To evaluate the distribution of reincision hyperalgesia, prior neonatal incision was performed at different body sites. Hyperalgesia was maximal when the same paw was reincised, and was increased following prior incision at ipsilateral, but not contralateral, sites, supporting a segmentally restricted spinal mechanism. These data highlight the contribution of spinal microglial mechanisms to persistent effects of early-life injury in males, and sex-dependent differences in the ability of microglial inhibition to prevent the transition to a persistent pain state span developmental stages.SIGNIFICANCE STATEMENT Following the same surgery, some patients develop persistent pain. Contributory mechanisms are not fully understood, but early-life experience and sex/gender may influence the transition to chronic pain. Surgery and painful procedural interventions in vulnerable preterm neonates are associated with long-term alterations in somatosensory function and pain that differ in males and females. Surgical injury in neonatal rodents primes the developing nociceptive system and enhances reinjury response in adulthood. Neuroimmune interactions are critical mediators of persistent pain, but sex-dependent differences in spinal neuroglial signaling influence the efficacy of microglial inhibitors following adult injury. Neonatal microglial inhibition has beneficial long-term effects on reinjury response in adult males only, emphasizing the importance of evaluating sex-dependent differences at all ages in preclinical studies.

Clinical efficacy feasibility of osteopathic correction for patients with primary algomenorrhea

Introduction.From 30 to 92 % of reproductive age women suffer from menstrual pain (algomenorrhea). The effectiveness of drug treatment of this suffering does not exceed 50–70 %. Moreover, it is temporary and accompanied by a high incidence of side effects. Dysfunction of the autonomic nervous system is the basis of the algomenorrhea pathogenesis; it is resulting from chronic exposure to psychogenic factor and adaptive mechanisms decrease in thalamus and hypothalamus which is leading to the nociceptive system excitation. Currently, there are scientifi c studies showing the effectiveness of osteopathic correction of autonomic dysfunction that can eliminate menstrual pain.Goal of research— to justify the osteopathic treatment effectiveness for patients with primary algomenorrhea.Materials and methods.The study included 30 women aged from 15 to 29 years who applied to the gynecological offi ce, diagnosed with primary algomenorrhea and a disease period of 3 to 16 years. They were randomly divided into 2 groups: experimental and control, of 15 people each. The patients of experimental group received osteopathic treatment, the patients of control group received drug therapy only. Osteopathic status was determined in all patients before and after treatment. Pain intensity was assessed by using a visual analogue scale (VAS), the direction of autonomic dysfunction — by using the Kerdo index and the severity of autonomic dysfunction — according to the Wayne questionnaire.Results.Dura mater RBN S (93 % of patients) and RBN in the visceral chest region (70 %) were specifi c regional somatic dysfunctions. The remaining regional somatic dysfunctions were common less than in 50 % of patients. Specifi c local somatic dysfunctions (LD) in patients with algomenorrhea were uterus LD (73 %) and mediastinum LD (70 %). Due to osteopathic treatment, the number of regional and local somatic dysfunctions was decreased in the experimental group. Autonomic dysfunction severity and pain syndrome intensity were decreased as well.Conclusion.The results of the study allow us to recommend osteopathic treatment for patients with primary algomenorrhea.

Tension-type headache

Tension-type headache is the most common primary headache disorder. The life-time prevalence of tension-type headache in general population is between 30 to 78%. Tension-type has the tremendous socio-economic impact on the individual and the society. Unfortunately, it is the least studied primary headache. The pathophysiology of this headache disorder is not fully understood. The diagnosis of tension-type headache is based on the history, and general and neurological examinations. Abnormalities in peripheral and central nociceptive nervous systems in combination with environmental and genetic factors may play a role in the pathophysiology of tension-type headache. The pharmacotherapy of episodic tension-type headache is non-specific and includes simple analgesics and nonsteroidal anti-inflammatory drugs. Tricyclic antidepressants are the mainstay in the prophylactic treatment of chronic tension-type headache.

PC-FACS

PC-FACS

Unimodal and crossmodal extinction of nociceptive stimuli in healthy volunteers

Nociception, the physiological mechanisms specifically processing information about noxious and potentially painful stimuli, has the double function to warn about potential body damages (interoception) and about the cause of such potential damages (exteroception). The exteroceptive function is thought to rely on multisensory integration between somatic and extra-somatic stimuli, provided that extra-somatic stimuli occur near the stimulated body area. To corroborate this hypothesis, we succeeded to show in healthy volunteers that the perception of nociceptive stimuli applied on one hand can be extinguished, as compared to single presentation, by the simultaneous application of nociceptive stimuli on the opposite hand, as well as by the presentation of visual stimuli near the opposite hand. On the contrary, visual stimuli presented near the same stimulated hand facilitated the perception of nociceptive stimuli. This nociceptive extinction phenomenon indicates that the perception of noxious events does not merely rely on the specific activation of the nociceptive system, but also depends on other sensory experiences about the body and the space around it.

Crosstalk between NF\u03baB-dependent astrocytic CXCL1 and neuron CXCR2 plays a role in descending pain facilitation

BackgroundDespite accumulating evidence on the role of glial cells and their associated chemicals in mechanisms of pain, few studies have addressed the potential role of chemokines in the descending facilitation of chronic pain. We aimed to study the hypothesis that CXCL1/CXCR2 axis in the periaqueductal gray (PAG), a co-restructure of the descending nociceptive system, is involved in descending pain facilitation.MethodsIntramedullary injection of Walker 256 mammary gland carcinoma cells of adult female Sprague Dawley rats was used to establish a bone cancer pain (BCP) model. RT-PCR, Western blot, and immunohistochemistry were performed to detect pNfkb, Cxcl1, and Cxcr2 and their protein expression in the ventrolateral PAG (vlPAG). Immunohistochemical co-staining with NeuN, GFAP, and CD11 were used to examine the cellular location of pNFκB, CXCL1, and CXCR2. The effects of NFκB and CXCR2 antagonists and CXCL1 neutralizing antibody on pain hypersensitivity were evaluated by behavioral testing.ResultsBCP induced cortical bone damage and persistent mechanical allodynia and increased the expression of pNFκB, CXCL1, and CXCR2 in vlPAG. The induced phosphorylation of NFκB was co-localized with GFAP and NeuN, but not with CD11. Micro-injection of BAY11-7082 attenuated BCP and reduced CXCL1 increase in the spinal cord. The expression level of CXCL1 in vlPAG showed co-localization with GFAP, but not with CD11 and NeuN. Micro-administration of CXCL1 neutralizing antibody from 6 to 9 days after inoculation attenuated mechanical allodynia. Furthermore, vlPAG application of CXCL1 elicited pain hypersensitivity in normal rats. Interestingly, CXCR2 was upregulated in vlPAG neurons (not with CD11 and GFAP) after BCP. CXCR2 antagonist SB225002 completely blocked the CXCL1-induced mechanical allodynia and attenuated BCP-induced pain hypersensitivity.ConclusionThe NFκB-dependent CXCL1-CXCR2 signaling cascade played a role in glial-neuron interactions and in descending facilitation of BCP.

Built in "osteo-innate-immunological machinery" in nociceptive system

Built in "osteo-innate-immunological machinery" in nociceptive system

Modern view of the pathogenetic mechanisms of the limbic system role in the forming of pain syndromes in pharmacoresistant facial sympathalgia

The present work was devoted to pharmacoresistant facial sympathalgia which held one of the frequent places among other neuropatic acute and chronic pain syndromes; they usually characterized by long-term clinical course and severe pain which is resistant to conducted conservative therapy by several pharmaceutical drugs. In this paper the general modern data about the etiopathogenetic mechanisms and the role of limbic system, its other anatomical and physiological parts in the genesis and forming of pain paroxysms in facial sympathalgia were presented. Pharmacoresistant facial sympathalgia differs from the other pain syndromes with more similar and typical localization, the severity of clinical manifestations, the presence of neurological deficit, long-recurrent clinical course, resistance to various treatment methods, both therapeutic and neurosurgical, and different somatic complications. At the autonomic response disturbances, epileptic or paroxysmal focus plays the leading disorganizing role, located mainly in the medial structures of the limbic-reticular complex. It has been established, that the limited convulsive activity in various structures of the limbic-reticular complex is the pathogenesis basis of non-epileptic or painful paroxysms, which does not reach of the formation of morpho-functional epileptic system because of influence of various stabilizing factors. Also it was discussed that in the pathogenetic mechanisms any changes in the functional state of the pain-sensing nociceptive and antinociceptive systems and leading neurotransmitters have played the certain role in pharmacologically resistant facial sympathalgia where glutamate and aspartate are being modulators of the convulsive and neuroplastic brain activity, directly and indirectly participating in the formation of processes of excitation and pain threshold, different neurotoxic processes.

Anti‐nerve growth factor monoclonal antibodies for the control of pain in dogs and cats

Nerve growth factor (NGF) is essential for the survival of sensory and sympathetic neurons during development. However, in the adult, NGF and its interaction with tropomyosin receptor kinase A receptor (TrkA) has been found to play a critical role in nociception and nervous system plasticity in pain conditions. Thus, various monoclonal antibody (mAb) therapies targeting this pathway have been investigated in the development of new pharmacotherapies for chronic pain. Although none of the mAbs against NGF are yet approved for use in humans, they look very promising for the effective control of pain. Recently, species-specific anti-NGF mAbs for the management of osteoarthritis (OA)-associated pain in dogs and cats has been developed, and early clinical trials have been conducted. Anti-NGF therapy looks to be both very effective and very promising as a novel therapy against chronic pain in dogs and cats. This review outlines the mechanism of action of NGF, the role of NGF in osteoarthritis, research in rodent OA models and the current status of the development of anti-NGF mAbs in humans. Furthermore, we describe and discuss the recent development of species-specific anti-NGF mAbs for the treatment of OA-associated pain in veterinary medicine.

Analgesic and anti-edemic properties of etifoxine in models of inflammatory sensitization

Inflammatory processes are critical promoting factors of chronic pain states, mostly by inducing peripheral and central sensitization of the nociceptive system. These processes are associated with a massive increase in glutamatergic transmission, sometimes facilitated by spinal disinhibition. In this study, we used etifoxine, a non-benzodiazepine anxiolytic known to amplify inhibition mediated by gamma-aminobutyric acid type A (GABAA) receptors in pain processing regions, either directly (through allosteric modulation) or indirectly (through the synthesis of endogenous neurosteroids). We used different models of local inflammation to evaluate the possible direct action of etifoxine on analgesia and edema. Pain symptom and edema measurements were performed after intraplantar carrageenan injection or after topical ear inflammation. We found that etifoxine treatment was associated with reduced plantar surface temperature 24 h after intraplantar carrageenan injection. In this model, etifoxine also alleviated thermal hot and mechanical hyperalgesia. A similar finding was observed while analyzing pain symptoms in the late phase of the formalin test. In a model of ear inflammation, etifoxine appeared to have a moderate anti-edemic effect after topical application. This slight action of etifoxine on the limitation of inflammatory processes could be mediated in part by cyclo-oxygenase 1 activity inhibition. Etifoxine appears as a promising therapeutic tool contributing to the limitation of inflammatory pain symptoms. Since etifoxine is already prescribed as an anxiolytic in several countries, it could be a good candidate for the prevention of inflammatory-driven edema and hyperalgesia, although the precise mechanism of action relative to its anti-inflammatory potential remains to be elucidated.

Analgesic activity of 4-amino-5-methyl-4H-1,2,4-triazol-3-thiones

Significance. Nowadays non-steroidal anti-inflammatory drugs have found a wide application in treatment of medical conditions. Despite the clinical effectiveness of non-steroidal anti-inflammatory drugs, their administration is followed by a set of side effects. With aim to reveal the substances with a potency of altering pain threshold in animals, the action of 4-amino-5-methyl-4 H -1,2,4-triazol-3-thiones on the nociceptive system in conditions of thermal irritation of rats’ extremities was studied. Aim. Study of the analgesic activity of 4-amino-5-methyl-4 H -1,2,4-triazol-3-thiones. Materials and methods. Analgesic activity of the synthesized compounds was evaluated in terms of the set of experiments conducted on white rats of 180-240 g weight. The primary pain threshold after the administration of the substances was assessed using a “hot plate” test, involving a metal plate heated at 55 o C as an irritator. The time of the corresponding response (paw licking, jumping out, squeaking) was measured in seconds. Analgesic activity was assessed by observations of the alterations of pain threshold of the group of studied animals to whom the substances of research were administrated, comparing results with the control group and expressing them in percent. Results. According to the results, it was concluded that the compound of 4-(3,4-dimethoxebenzylidenamino)-5-methyl-4 H -1,2,4-triazol-3-thione was the most potent, which reduced the sensitivity to thermal irritation of extremities in the group of animals by 127.78%; that said, its activity is higher than that for the reference drug Analgin, which was also evaluated in a “hot plate” test. It was established that substance (IV) was slightly more active than the reference drug Analgin, demonstrating 121.11% of analgesic activity. Processing of the experimental data revealed some dependencies between the chemical structure and pharmacological activity of the substances of research. Conclusion. The obtained results demonstrate that analgesic activity is existent among the set of 1,2,4-triazole derivatives, which mandates a deeper research of the effectiveness and safety of the most active compounds among the studied compounds.

The study of analgesic effect of 5-(furan-2-yl, 2-methylfuran-3-yl)-4-amino-1,2,4-triazole-3-thion derivatives

Introduction . The nucleus of 1,2,4-triazole is the subject of close attention from a wide range of scientists because of numerous unique properties. Analyzing literary sources, it should be noted that there is a large amount of information devoted to the study of analgesic activity of 1,2,4-triazole derivatives. Consequently, the search for new promising molecules among derivatives of 1,2,4-triazole, which may later be used as objects for the creation of potential analgesic agents, remains relevant, has theoretical and practical significance. The purpose of our work was to investigate the analgesic activity of 14 new derivatives of 5-(furan-2-yl, 2-methylfuran-3-yl)-4-amino-1,2,4-triazole-3-thiols, in some cases, to trace the relationship between the activity of compounds and their structure. Materials and methods . Studying of new derivatives of 5-(furan-2-yl, 2-methylfuran-3-yl)-4-amino-1,2,4-triazole-3-thion on the central component of the nociceptive system was carried out on the model of “acetic acid convulsions” according to a well-known technique. Experimental part . The Analgin and the test substances were administered intraperitoneally in the form of an aqueous suspension. Control group of rats was administered with isotonic sodium chloride solution. The studied compounds and isotonic sodium chloride solution were administered at a dose of 1/10 of LD 50 . Results . Among the compounds that were studied only some of them were close to the results of Analgin, other compounds showed lower activity. But among the 14 substances that were studied, some regularities have been noticed which can be applied for further purposeful synthesis of new molecules. Conclusions . For the first time, analgesic activity was studied for new 5-(furan-2-yl, 2-methylfuran-3-yl)-4-amino-1,2,4-triazole-3-thione. It was found that most compounds exhibit moderate activity. The pronounced analgesic effect, which approximated to the reference drug, is attributed to the sodium salt of 2-((5-furan-2-yl)-4-amino-1,2,4-triazole-3-ylthio)acetate and methylammonium 2-((5-furan-2-yl)-4-amino-1,2,4-triazole-3-ylthio)acetate. Some dependences of the substituents influence on the parameters of analgesic activity were established.

Multimodal General Anesthesia: Theory and Practice.

Balanced general anesthesia, the most common management strategy used in anesthesia care, entails the administration of different drugs together to create the anesthetic state. Anesthesiologists developed this approach to avoid sole reliance on ether for general anesthesia maintenance. Balanced general anesthesia uses less of each drug than if the drug were administered alone, thereby increasing the likelihood of its desired effects and reducing the likelihood of its side effects. To manage nociception intraoperatively and pain postoperatively, the current practice of balanced general anesthesia relies almost exclusively on opioids. While opioids are the most effective antinociceptive agents, they have undesirable side effects. Moreover, overreliance on opioids has contributed to the opioid epidemic in the United States. Spurred by concern of opioid overuse, balanced general anesthesia strategies are now using more agents to create the anesthetic state. Under these approaches, called “multimodal general anesthesia,” the additional drugs may include agents with specific central nervous system targets such as dexmedetomidine and ones with less specific targets, such as magnesium. It is postulated that use of more agents at smaller doses further maximizes desired effects while minimizing side effects. Although this approach appears to maximize the benefit-to-side effect ratio, no rational strategy has been provided for choosing the drug combinations. Nociception induced by surgery is the primary reason for placing a patient in a state of general anesthesia. Hence, any rational strategy should focus on nociception control intraoperatively and pain control postoperatively. In this Special Article, we review the anatomy and physiology of the nociceptive and arousal circuits, and the mechanisms through which commonly used anesthetics and anesthetic adjuncts act in these systems. We propose a rational strategy for multimodal general anesthesia predicated on choosing a combination of agents that act at different targets in the nociceptive system to control nociception intraoperatively and pain postoperatively. Because these agents also decrease arousal, the doses of hypnotics and/or inhaled ethers needed to control unconsciousness are reduced. Effective use of this strategy requires simultaneous monitoring of antinociception and level of unconsciousness. We illustrate the application of this strategy by summarizing anesthetic management for 4 representative surgeries.

Evidence for a spinal involvement in temporal pain contrast enhancement

Spatiotemporal filtering and amplification of sensory information at multiple levels during the generation of perceptual representations is a fundamental processing principle of the nervous system. While for the visual and auditory system temporal filtering of sensory signals has been noticed for a long time, respective contrast mechanisms within the nociceptive system became only recently subject of investigations, mainly in the context of offset analgesia (OA) subsequent to noxious stimulus decreases. In the present study we corroborate in a first experiment the assumption that offset analgesia involves a central component by showing that an OA-like effect accounting for 74% of a corresponding OA reference can be evoked by decomposing the stimulus offset into two separate box-car stimuli applied within the same dermatome but to separate populations of primary afferent neurons. In order to draw conclusions about the levels of the CNS at which temporal filtering of nociceptive information takes place during OA we investigate in a second experiment neuronal activity in the spinal cord during a painful thermal stimulus offset employing high-resolution fMRI in healthy volunteers. Pain-related BOLD responses in the spinal cord were significantly reduced during OA and their time course followed widely behavioral hypoalgesia, but not the thermal stimulation profile. In summary, the results suggest that temporal pain contrast enhancement during OA comprises a central mechanism and this mechanism becomes already effective at the level of the spinal cord.