PET radiotracers for molecular imaging of serotonin 5-HT1A receptors.

Serotonin and its various receptors are involved in numerous brain functions and neuropsychiatric disorders. The 5-HT1A family is the best characterized subtype of the fourteen currently known 5-HT receptors. The 5-HT1A receptor is closely involved in the pathogenesis of anxiety, depression, epilepsy and eating disorders and therefore is an important target for drug therapy. The development in the 1980s of molecules specifically targeting this receptor was followed by the rapid development of corresponding PET neuroimaging. Because this receptor represents a crucial target in neuroscience, a large number of radioligands have been developed by academic and industry centers for visualization and quantification, first in living animals and ultimately in humans. After a brief account of some of the structural and functional characteristics of brain 5-HT1A receptors, this review focuses on the main lines of evolution opened up by preclinical and clinical 5-HT1A PET radiopharmaceuticals, illustrating the potential value of PET for clinical research and drug development.

Mechanical allodynia in neuropathic pain. Where are the brain representations located? A positron emission tomography (PET) study.

BACKGROUND: Brain areas involved in nociception have been repeatedly investigated. Therefore, brain responses to physiological pain conditions are well identified. The same is not true for allodynic pain in patients with neuropathic pain since the cortical reorganizations that are involved in the conversion of non-noxious stimuli into painful sensations still remain unknown. METHODS: The present positron emission tomography (PET) study enrolled 19 patients with dynamic mechanical allodynia to brushing or to cold rubbing of the skin. PET activations during allodynic stimulation were compared to those obtained with the same innocuous stimulation applied outside the neuropathic pain area (control). In a second comparison, they were compared with responses to a noxious heat stimulation applied outside the neuropathic pain area (experimental pain). RESULTS: Common responses to allodynia and control stimulations were found in contralateral SI, SII and insula and in ipsilateral cerebellum. Not surprisingly, heat pain condition was associated with activations in contralateral prefrontal and SII cortices and, bilaterally, in the anterior insular cortices. Distinctive cortical responses between control and allodynic conditions were restricted to one activation within the contralateral anterior insula, a region also activated by experimental heat pain. CONCLUSIONS: The insular subdivision was inappropriately activated considering the innocuous nature of the stimulus, but adequately activated with regard to pain-evoked sensation. Subcortically, the hypothesis of reorganization at any level of the somatosensory and pain pathways underlying such insular activity was supported by the observed shift of thalamic activation from a lateral-posterior to an anterior-medial position.

[Fluorine-18 in radiopharmacy]. / Le fluor 18 en radiopharmacie.

Positron emission tomography (PET) is a recent and expanding functional nuclear imaging technique. Its extensive development is related to the radiophysical properties fluorine 18 (18F) (weak energy of positron, sufficiently long physical half-life) and to the simple production and labeling procedures for 18F. [18F]fluorodesoxyglucose was the first licensed radiopharmaceutical in France in 1998. [18F]fluoroDOPA was registered in 2006. Introduction of automated chemistry modules enable development of new fluorinated tracers.

Motor urgency is mediated by the contralateral cerebellum in Parkinson's disease.

BACKGROUND: In patients with Parkinson's disease (PD), motor performance may be dramatically improved in urgent and stressful situations. OBJECTIVE: The aim of this PET H(2)(15)O study was to determine the changes in brain activation pattern related to this unconscious increase in motor speed observed in the context of urgency in patients with PD. METHODS: Eight right-handed patients with PD, who had been off medication for at least 12 hours, without tremor, were enrolled. A reaching task with the right hand was performed under three conditions: self-initiated (SI), externally cued (EC) and externally cued-urgent (ECu). RESULTS: (1) Self-initiated movements (SI-EC) revealed activations in the prefrontal cortex bilaterally, the right lateral premotor cortex, anterior cingulate cortex and cerebellum, and the left primary motor cortex and thalamus; (2) Externally driven responses (EC-SI) did not involve any statistically detectable activation; (3) Urgent situations (ECu-EC) engaged the left cerebellum. Compared with a control group previously studied, the cerebellar activation was greater in patients with PD. CONCLUSIONS: This study demonstrates that the increase in movement speed in urgent situations in patients with PD is associated with the recruitment of the left (contralateral) cerebellum. This structure is a key node of the accessory motor circuitry typically recruited by patients with PD to compensate for basal ganglia dysfunction and by healthy subjects to increase movement velocity in urgent motor contexts.

A distinct [18F]MPPF PET profile in amnestic mild cognitive impairment compared to mild Alzheimer's disease.

To date, two positron emission tomography (PET) studies have explored 5-HT(1A) receptor density in the hippocampus of Alzheimer's disease (AD) patients. They showed early changes of 5-HT(1A) receptors in this brain region, known to have a dense serotonergic innervation. These studies only reported measurements in hippocampus. In the present PET study, we used an antagonist of 5-HT(1A) receptors, the [(18)F]MPPF (1) to explore 5-HT(1A) receptor density in the whole brain of AD patients at a mild stage of dementia and amnestic mild cognitive impairment (aMCI) patients compared to a control population; (2) to explore more precisely the 5-HT(1A) receptor density in the limbic brain regions of AD patients and aMCI patients compared to controls. Voxel-based analyses were performed to assess differences in the [(18)F]MPPF binding potential (BP) between AD patients and aMCI patients compared to controls. Analyses of whole-brain [(18)F]MPPF BP showed a global decrease in AD brains in contrast with a global increase in aMCI brains. In AD brains, a significant decrease of BP was detected in hippocampus and parahippocampal gyrus, whereas a significant increase of BP was observed in the inferior occipital gyrus in aMCI brains. These whole brain results are in accordance to hippocampal data reported in a previous study, showing an increase of [(18)F]MPPF binding in the aMCI group contrasting with a decrease in the AD group. Altogether, these results suggest the implication of a compensatory mechanism illustrated by an up regulation of serotonergic metabolism at the aMCI stage before a breakdown of this mechanism at the AD stage. This difference of serotonergic receptor labeling allows to distinguish the groups of aMCI patients from mild AD patients with specific [(18)F]MPPF PET profiles for each patient group.

Formation of diacetyl and acetoin by Lactococcus lactis via aspartate catabolism.

AIMS: To verify whether diacetyl can be produced by Lactococcus lactis via amino acid catabolism, and to investigate the impact of the pH on the conversion. METHODS AND RESULTS: Resting cells of L. lactis were incubated in reaction media at different pH values, containing L-aspartic acid or L-alanine as a substrate. After incubation, the amino acid and metabolites were analysed by HPLC and GC/MS. At pH 5 about 75% of aspartic acid and only 40% of alanine was degraded to pyruvate via a transamination step that requires the presence of alpha-ketoglutarate in the medium, but diacetyl was only produced from aspartic acid. Three per cent of pyruvate was transformed to acetolactate of which 50% was converted into diacetyl. At pH 5 x 5 and above the pyruvate conversion into acetolactate was less efficient than at pH 5, and acetolactate was mainly decarboxylated to acetoin. CONCLUSIONS: Acetoin and diacetyl can be formed as a result of aspartate or alanine catabolism by L. lactis in the presence of alpha-ketoglutarate in the medium. SIGNIFICANCE AND IMPACT OF THE STUDY: Lactic acid bacteria exhibiting both glutamate dehydrogenase activity and high aspartate aminotransferase activity are expected to be good diacetyl producers during cheese ripening at pH close to 5.

Up-regulation of hippocampal serotonin metabolism in mild cognitive impairment.

OBJECTIVE: Recent studies have suggested modifications of serotonin cerebral metabolism and of 5-HT(1A) receptors density in Alzheimer disease (AD). This study aims at exploring hippocampus 5-HT(1A) receptor density in patients at the amnesic mild cognitive impairment (aMCI) and mild AD dementia stages. METHODS: With use of PET with a selective 5-HT(1A) antagonist, 2'-methoxyphenyl-(N-2'-pyridinyl)-p-[(18)F]fluoro-benzamidoethylpiperazine ([(18)F]MPPF), the hippocampus 5-HT(1A) binding potential (BP) was quantified in 10 patients with mild AD, in 11 patients with aMCI, and in 21 aged paired control subjects. To take into account hippocampal atrophy, a partial volume correction was applied to the [(18)F]MPPF data, leading to the calculation of a corrected BP (BP(c)). Comparison of hippocampus BP over populations was performed using Kruskal-Wallis rank analysis. RESULTS: Hippocampus serotonergic receptor binding distinguishes patients from controls and patients with aMCI from patients with AD. In aMCI patients, the mean hippocampus BP(c) was 59% higher than the controls' (p < 0.005), and it was conversely 35% lower in patients with mild AD (p < 0.01). The difference in BP(c) values between patients with aMCI and mild AD was large, resulting in a p value of <0.0005. These differences were not related to hippocampus atrophy. CONCLUSION: A compensatory mechanism illustrated by an up-regulation of serotonergic metabolism has been shown at the stage of amnesic mild cognitive impairment (aMCI) in contrast with a dramatic decrease at later stages of Alzheimer disease (AD). This difference of hippocampus serotonergic receptor labeling allows distinguishing of patients with aMCI from those with mild AD. Exploring 5-HT(1A) receptors with 2'-methoxyphenyl-(N-2'-pyridinyl)-p-(18)F-fluoro-benzamidoethylpiperazine PET seems to be of interest for better understanding pathophysiologic changes at early stages of AD.

Functional anatomy of the therapeutic effects of prism adaptation on left neglect.

OBJECTIVE: To investigate the anatomic substrates underlying the beneficial effect of prism adaptation in five patients with persistent left neglect following right stroke. METHODS: In a functional imaging PET study, we used a covariation analysis to examine linear changes of regional cerebral blood flow over sessions as a function of left neglect improvement. RESULTS: The network of significant brain regions associated with improvement of left neglect performance produced by prism adaptation involved the right cerebellum, the left thalamus, the left temporo-occipital cortex, the left medial temporal cortex, and the right posterior parietal cortex. CONCLUSION: Our results suggest that the realignment of visuomotor coordinates is processed by the cerebellum and that low level sensorimotor adaptation actively modulates cerebral areas, albeit now relying on intact cerebellocerebral connections. Hence, our data support the hypothesis that the beneficial effect of prism adaptation on the clinical presentation of left neglect derives from modulation of cortical regions implicated in spatial cognition.

[11C]-Methionine PET: dysembryoplastic neuroepithelial tumours compared with other epileptogenic brain neoplasms.

BACKGROUND AND OBJECTIVES: Brain tumours responsible for longstanding partial epilepsy are characterised by a high prevalence of dysembryoplastic neuroepithelial tumour (DNT), whose natural evolution is much more benign than that of gliomas. The preoperative diagnosis of DNT, which is not yet feasible on the basis of available clinical and imaging data, would help optimise the therapeutic strategy for this type of tumour. This study tested whether [(11)C]-methionine positron emission tomography (MET-PET) could help to distinguish DNTs from other epileptogenic brain tumours. METHODS: Prospective study of 27 patients with partial epilepsy of at least six months duration related to a non-rapidly progressing brain tumour on magnetic resonance imaging (MRI). A structured visual analysis, which distinguished between normal, moderately abnormal, or markedly abnormal tumour methionine uptake, as well as various regions of interest and semiquantitative measurements were conducted. RESULTS: Pathological results showed 11 DNTs (41%), 5 gangliogliomas (18%), and 11 gliomas (41%). MET-PET visual findings significantly differed between the various tumour types (p<0.0002), regardless of gadolinium enhancement on MRI, and were confirmed by semiquantitative analysis (p<0.001 for all calculated ratios). All gliomas and gangliogliomas were associated with moderately or markedly increased tumour methionine uptake, whereas 7/11 DNTs had a normal methionine uptake, including all six located in the mesiotemporal structures. No DNT presented with a marked MET-PET abnormality. CONCLUSION: Normal MET-PET findings in patient with an epileptogenic and non-rapidly progressing brain tumour are suggestive of DNT, whereas a markedly increased tumour methionine uptake makes this diagnosis unlikely.

High and low grade oligodendrogliomas (ODG): correlation of amino-acid and glucose uptakes using PET and histological classifications.

Classification and treatment strategy of oligodendrogliomas (ODG) remain controversial. Imaging relies essentially on contrast enhancement using CT or MRI. The aim of our study was to use positron emission tomography (PET) using [18F]-flurodeoxyglucose (FDG) and [11C]-L-methyl-methionine (MET) to evaluate metabolic characteristics of ODG. We studied 19 patients with proven ODG, comparing standardized uptake values (SUV) and maximal tumor/contralateral normal tissues ratios (T/N). Imaging findings were compared with WHO, Smith and Daumas-Duport classifications. Uptake of FDG was decreased only in 8 patients, independently of grading, while MET uptake was always increased. MET uptake was significantly higher for high grade tumors grouped according to Smith or Daumas-Duport classifications, while no significant difference in MET uptake was found when using WHO classification. A different correlation was found between FDG and MET uptakes in normal tissues and high grade tumors. A trend for improved progression free survival was found for tumors that lacked contrast enhancement on MRI or those showing low FDG or MET uptake. In conclusion, MET appeared more sensitive than FDG to detect proliferation in ODG. The preferential protein metabolism, already noticeable for low-grade tumor, correlated with glucose metabolism and helped to separate, in vivo, high and low grade tumors.

Toward brain imaging of serotonin 5-HT1A autoreceptor internalization.

Enhancing cerebral serotonin (5-hydroxytryptamine, 5-HT) neurotransmission is a common property of antidepressant treatments and the basis for their efficacy. 5-HT1A receptors located on the cell body and dendrites of 5-HT neurons (autoreceptors) play a key role in this regard. Because they normally mediate an inhibition of neuronal firing, their desensitization is a prerequisite to the delayed enhancement of 5-HT neurotransmission upon treatment with monoamine oxidase (MAOI) inhibitors or specific serotonin reuptake inhibitors (SSRI). Using beta-sensitive microprobes in vivo, we measured a significant decrease (-30%) in binding sites for the 5-HT1A PET radioligand [18F]MPPF associated with an equivalent reduction (-34%) in the cell surface density of 5-HT1A receptor immunoreactivity (internalization), in the nucleus raphe dorsalis (autoreceptors), but not hippocampus (heteroreceptors), of rats given a single dose of the specific 5-HT1A receptor agonist, 8-OH-DPAT (0.5 mg/kg, iv). This effect was completely blocked by pretreatment with the selective 5-HT1A antagonist WAY 100635. Having ruled out that this decreased density of [18F]MPPF binding in the nucleus raphe dorsalis of 8-OH-DPAT-treated rats resulted from a local blood flow effect, we obtained autoradiographic evidence indicating that the total amount of specific binding of [18F]MPPF in tissue sections was unaffected by the 8-OH-DPAT treatment in either NRD or hippocampus. It was therefore concluded that the internalization of 5-HT1A autoreceptors accounted for the decreased binding in vivo of [18F]MPPF in the nucleus raphe dorsalis of rats treated with 8-OH-DPAT. Thus, PET imaging might provide a mean to measure 5-HT1A receptor internalization in human brain and thus assess responsiveness to antidepressant treatment.

Chronic subthalamic nucleus stimulation and striatal D2 dopamine receptors in Parkinson's disease--A [(11)C]-raclopride PET study.

CONTEXT: Subthalamic nucleus (STN) stimulation mechanism of action remains a matter for debate. In animals, an increased striatal dopamine (DA) release due to STN stimulation has been reported. OBJECTIVE: To determine in Parkinson's disease (PD) patients using positron emission tomography (PET) and [11C]-Raclopride, whether STN stimulation induces a striatal DA release. METHODS: Nine PD patients with bilateral STN stimulation were enrolled and underwent two [11C]-Raclopride PET scans. The scans were randomly performed in off and on stimulation conditions. Striatal [11C]-Raclopride binding potential (BP) was calculated using regions of interest and statistical parametric mapping. RESULTS: For PD patients, the mean [(11C]-Raclopride BP (+/- SD) were, in Off stimulation condition: 1.7 +/- 0.3 for the right caudate nucleus, 1.8 +/- 0.4 for the left caudate nucleus, 2.6 +/- 0.5 for the right putamenand 2.6 +/- 0.5 for the left putamen. In On stimulation condition: 1.7 +/- 0.4 for the right caudate nucleus, 1.9 +/- 0.5 for the left caudate nucleus, 2.8 +/- 0.7 for the right putamen and 2.7 +/- 0.8 for the left putamen. No significant difference of BP related to the stimulation was noted. CONCLUSION: STN stimulation does not produce significant variations of striatal DA release as assessed by PET and [11C]-Raclopride.

Positron emission tomography in epileptogenic hypothalamic hamartomas.

Whether the intrinsic epileptogenicity of hypothalamic hamartomas (HH) is responsible for the entire clinical spectrum of epileptic, neuropsychological and behavioural disorders associated with HH, remains an open issue, in as much as morphologically similar HH can be associated with dramatically different seizure types and cognitive outcomes. The aim of this study was to investigate brain glucose metabolism in patients with epileptogenic HH, in an attempt to identify signs of focal cortical and subcortical dysfunction which might correlate with other clinical data. We have studied five patients with epileptogenic HH using [18F]-fluoro-desoxyglucose and positron emission tomography (FDG-PET). All our patients also underwent an optimal MRI and a video-EEG monitoring, as well as an intra-cranial EEG recording in one of them. The anatomical distribution of FDG-PET abnormalities was compared to that of interictal and ictal electroclinical findings. All five patients demonstrated focal hypometabolism, ipsilateral to the predominant EEG abnormalities and side of HH. Hypometabolic areas greatly varied between patients, but were grossly concordant with the cortical regions suspected to participate in the ictal discharges in each individual. Epileptogenic hypothalamic hamartomas are usually associated with focal cortical hypometabolism in regions which might participate in the overall HH-driven epileptic network. Whether these cortical abnormalities only reflect the propagation of ictal discharges, or a potentially independent seizure onset zone remains unknown.

The potential of the beta-Microprobe, an intracerebral radiosensitive probe, to monitor the [(18)F]MPPF binding in the rat dorsal raphe nucleus.

The aim of this study was to demonstrate the ability of a recently developed beta(+)-range sensitive intracerebral probe (beta-Microprobe) to measure the binding kinetics of [(18)F]MPPF, a well-documented 5-HT(1A) serotoninergic receptor ligand, in the dorsal raphe nucleus (DRN) of the anaesthetised rat. This midbrain nucleus presents a high concentration of 5-HT(1A) receptors known to be implicated in the effects of antidepressants. The difficulty confronting this study lay in the fact that the dimensions of the DRN are smaller than the detection volume of the beta-Microprobe. In the first part of the study, we studied the feasibility of this measurement from a theoretical point of view by autoradiography and a Monte Carlo simulation. We determined the optimal beta-Microprobe location close to the DRN and verified that this configuration allowed accurate determination of [(18)F]MPPF specific binding in the nucleus. In the second part of our study, we measured the in vivo time-concentration curves of [(18)F]MPPF binding in the DRN in comparison with the cerebellum. The specificity of [(18)F]MPPF binding in the DRN was confirmed by its displacement after non-labelled 5-HT(1A)antagonist injection (MPPF or WAY-100635). Moreover, we verified the feasibility of using beta-Microprobe monitoring and simultaneous validation by microdialysis to study the effect of an increase in extracellular serotonin, induced by fenfluramine injection, on [(18)F]MPPF binding in the DRN. Our theoretical simulations, confirmed by our experimental results, demonstrate the ability of this new device to monitor in vivo the binding of [(18)F]MPPF in the DRN of anaesthetised rodents.

[Nociceptors and mediators in acute inflammatory pain]. / Nocicepteurs et médiateurs dans la douleur aiguë inflammatoire.

OBJECTIVE: To bring together the most recent data concerning the physiology of nociceptors at a time when there has been significant progress in the understanding of these. DATA SOURCES: References were obtained from computerised bibliographic data banks (Medline and others) and the authors' personal documents. DATA SYNTHESIS: Nociceptive impulses are generated at the periphery in unmyelinated fibres called nociceptors, the responses of which depend on the tissue environment. Numerous mediators can activate, sensitise or "wake up" nociceptor: kinins (bradykinin, kallidin and their metabolites), pro-inflammatory cytokines (TNF alpha, IL-6, IL-1 beta, IL-8), anti-inflammatory cytokines (IL-4, IL-6, IL-10, IL-12, IL-13), prostanoids (PGE2, PGI2), lipo-oxygenases (leucotrienes such LTB4 or 15-HETE), the "central mediators of the immune response" (NF-kappa B), growth factors such as neurotrophins (NGF, BDNF, NT-3 and NT-4/5), peptides (substance P, CGRP, Neurokinin A), nitric oxide, histamine, serotonin, proteases, excitatory amino acids, adrenergic amines and opioids. The release of neuromediators by primary afferent fibres in the spinal cord may be summarised by successively considering calcium channels, presynaptic receptors, excitatory amino acids and peptides. CONCLUSION: Sensitisation phenomena are not exclusively peripheral but also central in origin and these are interlinked.

Animal models of nociception.

The study of pain in awake animals raises ethical, philosophical, and technical problems. We review the ethical standards for studying pain in animals and emphasize that there are scientific as well as moral reasons for keeping to them. Philosophically, there is the problem that pain cannot be monitored directly in animals but can only be estimated by examining their responses to nociceptive stimuli; however, such responses do not necessarily mean that there is a concomitant sensation. The types of nociceptive stimuli (electrical, thermal, mechanical, or chemical) that have been used in different pain models are reviewed with the conclusion that none is ideal, although chemical stimuli probably most closely mimic acute clinical pain. The monitored reactions are almost always motor responses ranging from spinal reflexes to complex behaviors. Most have the weakness that they may be associated with, or modulated by, other physiological functions. The main tests are critically reviewed in terms of their sensitivity, specificity, and predictiveness. Weaknesses are highlighted, including 1) that in most tests responses are monitored around a nociceptive threshold, whereas clinical pain is almost always more severe; 2) differences in the fashion whereby responses are evoked from healthy and inflamed tissues; and 3) problems in assessing threshold responses to stimuli, which continue to increase in intensity. It is concluded that although the neural basis of the most used tests is poorly understood, their use will be more profitable if pain is considered within, rather than apart from, the body's homeostatic mechanisms.

Effects of sufentanil and NMDA antagonists on a C-fibre reflex in the rat.

The effects of intravenous sufentanil and pre-administration of N-methyl-D-aspartate (NMDA) receptor antagonists were tested on a reflex triggered by C-fibre activation. The reflex was elicited by electrical stimulation of the sural nerve and recorded from the ipsilateral biceps femoris muscle in halothane anaesthetized rats either (1) with an intact neuraxis or (2) in which the brain had previously been transected at the level of the obex. All four doses of sufentanil (0.33, 0.6, 1 and 2 microg kg(-1)) elicited a depression of the reflex in a dose-dependent manner. However, following the expected depression, all doses of sufentanil elicited both facilitation of the reflex and tonic inter-stimulus discharges. The C-fibre reflex was not modified following intravenous ketamine (1 mg kg(-1)) or (+)-HA966 (5 or 10 mg kg(-1)) but, when administered 5 min before sufentanil, these drugs enhanced both the extent and the duration of the depression and strongly reduced the facilitations. In the obex-transected rats, the depressive effect of 1 microg kg(-1) sufentanil increased, while the facilitation of the C-fibre reflex and the tonic inter-stimulus discharges disappeared. Pre-administration of 10 mg kg(-1) (+)-HA966 reinforced and prolonged the depressive effect of sufentanil. These results extend previous studies suggesting the involvement of NMDA receptors in the spinal transmission of nociceptive signals. They illustrate the potential of spinal NMDA receptor blockade to both enhance the analgesic, and prevent the pro-nociceptive, effects of sufentanil.

[Acute pain measurement in animals. Part 1]. / Evaluation de la douleur aiguë chez l'animal d'expérience. Première partie.

OBJECTIVE: To describe tests of nociception which appear in the "pre-clinical" literature. DATA SOURCES: References obtained by computerized bibliographic research (Medline) and the authors' personal data. DATA SYNTHESIS: Ethical problems arising from the study of the pain in awake animals, problems arising from the choice of stimulus and stimulus parameters and the quantification of responses are presented. Pain in animals can be estimated only by examining their reactions, but at the same time, the existence of a reaction does not necessarily mean that there is a concomitant sensation. A description of the signs of pain in mammals is proposed. A noxious stimulus can be defined by its physical nature, its site of application and what has previously happened to the tissues at this site. Electrical stimulation short-circuits the process of transduction at free nerve endings and is not specific; however it has the advantage that it can be applied suddenly and briefly and thus results in synchronised signals in the relevant primary afferent fibres which can be differentiated into A delta and C fibres. Heat selectively stimulates thermoreceptors and nociceptors, but the low calorific power of conventional stimulators restricts their usefulness. Radiant sources have the disadvantage of emitting waves in the visible and the adjacent infrared spectra, for which the skin is a poor absorber and good reflector. Thermodes have the disadvantage of activating mechanoreceptors and thermoreceptors simultaneously; furthermore, their capacity for transferring heat depends on the quality of contact with skin and thus on the pressure with which they are applied. These problems can be overcome by using CO2 lasers but even today, the cost of these is a major disadvantage. Chemical stimuli differ from those mentioned above by the progressive onset of their effectiveness, their duration of action and the fact that they are of an inescapable nature. Experimental models employing chemical stimuli are undoubtedly the most similar to acute clinical pain. A wide spectrum of reactions are observed in nociceptive tests, but in almost every case they involve motor responses. After defining the ideal characteristics of a nociceptive test, tests based on the use of short duration and longer duration stimuli are presented. In tests of phasic pain, reactions are evoked by thermal (tail-flick test, hot-plate test), mechanical or electrical (flinch-jump test, vocalisation test) stimuli. Tests of tonic pain employ injections of algogenic agents intradermally (formalin test) or intraperitoneally (writhing test) or even the dilation of hollow organs. All these tests will be critically appraised in a subsequent paper [1]. CONCLUSION: The tail-flick and hot-plate tests are the most used, but there is an increasing recourse to the formalin test and tests involving foot withdrawal after mechanical stimulation.

[Critical analysis of animal models of acute pain. II]. / Analyse critique des modèles animaux de douleur aiguë. Seconde partie.

OBJECTIVE: To analyse models of acute pain in experimental animals. DATA SOURCES: References were obtained from computerised bibliographic data banks (Medline and others) and the authors' personal documents. DATA SYNTHESIS: The majority of tests permit only a measurement of threshold, whereas clinical pain is almost always prolonged. The relationships between tests of acute pain and motor activity are reviewed from a number of standpoints; in particular we consider the influence, which postural adjustments of the animal may exert on motor responses in the limbs and the significance of flexor and extensor reflexes. In analysing the problem of the sensitivity of tests, we raise the following questions: 1) what type(s) of fibres underlie the observed responses and might these be different depending on whether one is stimulating a healthy or an inflamed tissue; 2) what significance do measurements of "latency" have when a stimulus is increasing; 3) how valid are the methods of analysing the results? The influence of species and the genetic line used in tests and the specificity and predictivity of tests are considered. Finally, we review those factors, which may distort behavioural measurements in animals, notably--pharmacokinetics, interactions between heterotopic stimuli, environmental factors and related psychophysiological/psychological considerations (subjective "undesirable" phenomena, learning phenomena). We pay particular attention to related physiological functions (thermoregulation, vasomotricity, blood pressure). These considerations lead us to re-position nociception within a much larger homeostatic framework which in addition to pain, includes phenomena such as anxiety and vegetative functions. They also suggest that we should define an "effective stimulus" as one, which activates nociceptive nerve terminals after a physical stimulus, has passed through a "peripheral lens" which regulates its intensity for reasons, which are physical, albeit of biological origin. Finally they remind us that the "system of pain" forms part of a whole set of subsystems--sensory, motor, vegetative, emotional, motivational--which scientific method, being reductionist by nature, cannot study in its entirety. However one must consider results of nociceptive tests within this general context. CONCLUSION: It is only by taking the approach described in this review, that fundamental and clinical research can interact usefully.

Stage-dependent changes in the modulation of spinal nociceptive neuronal activity during the course of inflammation.

Spinal and supraspinal controls can tonically or phasically modulate the output of spinal nociceptive neurons. Alterations of these modulatory systems have been described during the acute stage of inflammation. In the present study in the rat, tonic descending controls were assessed during acute (24--48 h) and chronic (3--4 weeks) stages of monoarthritis of the ankle. The electrophysiological properties of spinal convergent neurons with ankle input were compared before and after spinalization. In a parallel series of experiments, spinal convergent neurons were recorded from the normal side in order to assess the propriospinal and supraspinal inhibitory controls triggered by nociceptive stimulation of the inflamed ankle. Tonic descending inhibition of convergent neurons with input from the inflamed ankle was enhanced during the acute stage and then decreased during the chronic stage of monoarthritis. Contralateral-induced inhibitions exhibited a similar temporal evolution. Time-dependent changes in the spinal transmission of nociceptive signals were shown by removing descending modulation in animals with monoarthritis; sensitization of spinal neurons with input from the inflamed ankle was demonstrated during the acute stage of monoarthritis, whereas a crossed transmission between inflamed and normal sides was observed during the chronic stage of the disease. These results show that dynamic and stage-dependent modifications of descending controls tend to dampen the central changes associated with inflammation.