Gilles Michaux

Differential physiological effects during tonic painful hand immersion tests using hot and ice water

The cold pressor test (CPT) is an empirically validated test commonly used in research on stress, pain and cardiovascular reactivity. Surprisingly, the equivalent test with water heated to noxious temperatures (hot water immersion test, HIT) has not been thoroughly investigated. The aim of the present study was to characterize the physiological effects and psychophysics of both tests and to analyze whether the autonomic responses are mainly induced by baroreflexes or a consequence of the pain experience itself. The study consisted of a single session including one CPT (4 ± 0.2 °C) and one HIT (47 ± 0.5 °C; cut‐off point 5 min) trial performed on 30 healthy drug free volunteers aged 19–57 (median 24) yrs. The sequence of both trials was alternated and participants were randomly assigned to sequence order and parallelized with respect to gender. Physiological parameters (cardiovascular, respiratory and electrodermal activity) and subjective pain intensity were continuously monitored. In addition, pain detection and tolerance thresholds as well as pain unpleasantness were assessed. Both tests were comparable with regard to the time course and intensity of subjective pain. However, a significantly higher increase of blood pressure could be observed during the CPT when compared to the HIT. The HIT appears less confounded with thermoregulatory baroreflex activity and therefore seems to be a more appropriate model for tonic pain.

Increased basal mechanical pain sensitivity but decreased perceptual wind-up in a human model of relative hypocortisolism

&NA; Clinical data have accumulated showing that relative hypocortisolism, which may be regarded as a neuroendocrinological correlate of chronic stress, may be a characteristic of some functional pain syndromes. However, it has not been clarified yet whether deregulations of the hypothalamus–pituitary–adrenal (HPA) axis may directly alter pain perception and thus be causally involved in the pathophysiology of these disorders. To test this hypothesis, we performed a randomized placebo‐controlled crossover trial in N = 20 healthy drug‐free volunteers (median age 24 yrs) and analyzed the effects of metyrapone‐induced hypocortisolism on quantitatively assessed basal mechanical pain sensitivity (1.5–13 m/s impact stimuli), perceptual wind‐up (9 m/s impact stimuli at 1 Hz) and temporal summation of pain elicited by inter‐digital web pinching (IWP; 10 N pressure stimuli for 2 min). Experimentally induced hypocortisolism significantly decreased pain detection thresholds and augmented temporal summation of IWP‐induced pain (p < .05). The latter effect was dependent on the relative reduction in cortisol levels, and seemed to rely on a potentiated sensitization and not merely on the observed changes in basal pain sensitivity. Perceptual wind‐up by contrast was reduced when cortisol synthesis was blocked (p < .05). This result is reminiscent of findings from animal studies showing a reversal of NMDA receptor activation by glucocorticoid receptor antagonists in neuropathic pain models. Our results speak in favor of a potential causal role of HPA axis alterations in pain chronicity.

Experimental characterization of the effects of acute stresslike doses of hydrocortisone in human neurogenic hyperalgesia models

Summary A moderate dose of hydrocortisone reduced capsaicin‐induced secondary hyperalgesia, but not pain to pinprick suggesting an antihyperalgesic action of glucocorticoids consistent with protection against maladaptive pain plasticity. Abstract Relative hypothalamic‐pituitary‐adrenal axis dysfunction has been described as a common feature of several dysfunctional pain syndromes, and its end hormone cortisol may thus constitute a protective factor against the development of chronic pain. We investigated the potential influence of experimentally induced stresslike hypercortisolism on the induction of neurogenic hyperalgesia using 2 human surrogate models: secondary hyperalgesia after intradermal capsaicin injection into the volar forearm, and perceptual windup in normal skin. In a double‐blind, placebo‐controlled, randomized, crossover study, a psychophysical study was performed in 10 healthy subjects (median age 23 years) examining the effects of 40 mg orally administered hydrocortisone. Numeric pain ratings were assessed for punctate pinprick and light touch stimuli applied to the zone of secondary hyperalgesia adjacent to the capsaicin injection and to the contralateral control side. In addition, visual analog ratings were assessed for repetitive pinprick stimulation of the noninjected arm. Hydrocortisone significantly attenuated the late phase of capsaicin‐induced pain by nearly 50%, and hyperalgesia to pinprick stimuli by 33% (both P < .05). Baseline mechanical pain and dynamic mechanical allodynia remained unaltered. Temporal summation (windup) to mechanical pain stimuli and electrically induced windup of second pain (tested in an independent cohort of 10 other subjects) were also unchanged. The selective effects of hydrocortisone on pinprick hyperalgesia but not pinprick pain suggest an antihyperalgesic rather than analgesic effect. The findings suggest that hypothalamic‐pituitary‐adrenal axis reactivity might be an important mechanism in resilience to dysfunctional pain syndromes.

Internal validity of inter-digital web pinching as a model for perceptual diffuse noxious inhibitory controls-induced hypoalgesia in healthy humans.

Hot and ice‐water immersions are commonly used for heterotopic noxious counter‐stimulation (HNCS) in investigations on endogenous pain modulation. However, coincident sympathetic thermoregulatory activity does not allow to differentiate between perceptual hypoalgesia related to baroreflex sensitivity (BRS) or diffuse noxious inhibitory controls (DNIC). The present study analysed the internal validity of another supposedly less confounded tonic pain model (inter‐digital web pinching; IWP) regarding its potential as DNIC trigger.

Beep Tones Attenuate Pain following Pavlovian Conditioning of an Endogenous Pain Control Mechanism

Heterotopic noxious counter-stimulation (HNCS) is commonly used to study endogenous pain control systems. The resulting pain inhibition is primarily based on spinal cord-brainstem loops. Recently, functional imaging studies have shown that limbic structures like the anterior cingulate cortex and amygdala are also implicated. Since these structures are involved in learning processes, it is possible that the HNCS-induced pain inhibition may depend on specific cues from the environment that have been associated with pain reduction through associative learning. We investigated the influence of Pavlovian conditioning on HNCS-induced pain inhibition in 32 healthy subjects by using a differential conditioning paradigm in which two different acoustic stimuli were either repeatedly paired or unpaired with HNCS. Series of noxious electrical pulse trains delivered to the non-dominant foot served as test stimuli. Diffuse noxious inhibitory control (DNIC)-like effects were induced by concurrent application of tonic HNCS (immersion of the contralateral hand in ice water). Subjective pain intensity and pain unpleasantness ratings and electromyographic recordings of the facial corrugator muscle and the nocifensive RIII flexion reflex were used to measure changes in pain sensitivity. HNCS induced significant pain and reflex inhibitions. In the post-conditioning phase, only the paired auditory cue was able to significantly reduce pain perceptions and corrugator muscle activity. No conditioned effect could be observed in RIII reflex responses. Our results indicate that the functional state of endogenous pain control systems may depend on associative learning processes that, like in the present study, may lead to an attenuation of pain perception. Similar albeit opposite conditioning of pain control mechanisms may significantly be involved in the exacerbation and chronification of pain states.

Comments on “Recommendations on terminology and practice of psychophysical DNIC testing” by Yarnitsky et al., 14 (4), 339

We were highly pleased to notice the attempt of an ad hoc forum of researchers at the latest EFIC congress to find a consensual universal terminology for experimental models of diffuse noxious inhibitory controls (DNIC) in order to coalesce the corresponding observations and data on this phenomenon, which relates to descending surround inhibition activated by heterotopic noxious stimuli, into a coherent whole (Yarnitsky et al., 2010). However, we believe that the proposed term for the stimulus used to induce DNIC-like changes in pain perception, namely ‘conditioning stimulus’, might be greatly confusing, since it corresponds to the widely used technical term reserved for denoting the conditioning stimulus used in respondent (syn. Pavlovian) conditioning experiments (see Moore (2002) for instance). Although, Yarnitsky and colleagues (2010) do not put forward an abbreviation, the most obvious one would be ‘CS’, which again is the generally accepted and textbookish abbreviation for the conditioning or conditioned stimulus in psychological terminology of associative learning. More to the point, the proposed nomenclature leads to further confusion between both concepts, when investigating respondent conditioning of DNIC-like phenomena (cf. Erpelding et al., 2009), where you would have to speak of the ‘conditioned/conditioning stimulus’ – an issue certainly not intended by the forum. We totally agree with the authors that ‘heterotopic noxious conditioning stimulation’ (HNCS) is predominantly used in the literature (as indexed in PubMed). Nonetheless, scientific terminology should not necessarily be based on common acceptation, but first and foremost on cogency and accuracy. We suggest that the suffix ‘counter-’ would be more appropriate than ‘conditioning’, and still being useable with the commonly used abbreviation HNCS. Using the term ‘counterirritation’ (CI), on the other hand, would avoid any confusion with ‘‘classical” conditioning and thus constitute the better alternative from a definitional point of view. Interestingly, counterirritation was also the term chosen in the seminal paper on DNIC by LeBars and co-workers (1979) stating that ‘‘. . . under the terms of counterirritation or ‘‘hyperstimulation analgesia” . . . are designated various phenomena the common feature of which is that painful stimuli applied to one area of the body are at the origin of analgesic effects observed on other areas.” In the title of their commentary, Yarnitsky et al. (2010) employ the term DNIC, but in the text they set out to define HNCS. This seems conceptually unclear and is beset with taxonomical problems, since DNIC and HNCS are overlapping yet not homogenous constructs, in the sense that HNCS is considered to be a potential trigger of DNIC in the reticular formation but not a sine qua non of DNIC activation – at least in animals (cf. Monconduit et al.,

204 RESPONDENT CONDITIONING OF ENDOGENOUS PAIN MODULATION IN HUMANS

and an inhibition of ON neuron activity in the RVM. By using double immunofluorescence techniques, we found that TRPV1and m-opioid receptors are co-expressed in several neurons of the VLPAG. Conclusions: These findings suggest that m-receptors activation not only acts on inhibitory neurons to disinhibit PAG output neurons, but also interacts with TRPV1 activation at increasing glutamate release into the RVM, possibly by acting directly on PAG output neurons projecting to the RVM.

210 INTERNAL VALIDITY AND MODALITY SPECIFICITY OF INTERDIGITAL WEB PINCHING AS A MODEL FOR PERCEPTUAL DNIC-INDUCED HYPOALGESIA IN MAN

Serotonin is a major component of the inflammatory chemical milieu and contributes to the pain of tissue injury via an action on multiple receptor subtypes. Buspirone, is a partial 5-HT1 A receptor agonist buspirone which is widely used for treating anxiety. Sumatriptan is a 5HT 1B/1D serotonin receptor agonist use used to treat severe migraine headaches. The aim of the present study was to establish the effects of two 5HT1 serotonine receptor subtype agonists in cutaneous and visceral pain models in mice. Material and method: The experiment was carried out, with white male mice (20–25g), distributed into 3 groups of 7 animals each, treated intraperitoneally as follows: Group I: saline solution 0.3ml (Control); Group II (BUS): buspirone 8mg/kbw; Group III (SUM): sumatriptan 30mg/kbw. The nociceptive cutaneous testing was performed using hot plate assay. The model of visceral pain consists of inflammatory cystitis after intraperitoneal injection of cyclophosphamide (200mg/kbw). Data were statistically analyzed using SPSS program. Results: Buspirone significantly increased the response latency in the mouse hot plate test and markedly decreased the nociceptive behavioral manifestations in experimental chemical cystitis model. Sumatriptan increased pain threshold in the model of thermal noxious stimulation, but do not influence painful behavioral manifestations in the visceral pain test. Conclusions: Using the mouse model of acute pain hot plate analgesia meter, we found antinociceptive properties of both buspirone and sumatriptan. Buspirone is antinociceptor, while sumatriptan possesses no analgesic properties, in visceral pain model. 212 BOTH VISCERAL AND SOMATIC ENDOGENOUS PAIN MODULATION ARE ABNORMAL IN IRRITABLE BOWEL SYNDROME (IBS) PATIENTS: A META-ANALYSIS ACROSS DIFFERENT RACES C. Wilder-Smith *. Brain-Gut Research Group, Bern, Switzerland; Dept Medicine, National University Singapore, Singapore, Singapore Recent psychophysical and brain fMRI studies have shown abnormal endogenous visceral or somatic pain modulation in smaller numbers of IBS patients of different races. In this meta-analysis visceral and somatic pain modulation, specifically diffuse noxious inhibitory controls (DNIC), were compared across different races in a large number of IBS and healthy subjects. DNIC was examined by heterotopic stimulation using rectal distension (visceral DNIC) or electrical hand stimulation (somatic DNIC) applied alone and together with cold foot stimulation as the conditioning stimulation. DNIC is the change in primary pain during simultaneous application of the conditioning pain. Stimulation intensities were between 50–70 on 0–100 VAS. Mean somatic and visceral DNIC (95%CI) were similar in the 84 IBS patients (decrease in primary pain intensity −0.5 (−5.4–4.4) and −2.6 (−5.9–1.0), resp.) and in the 69 matched healthy controls (−13.4 (−18–−9) and −8.6 (−15–−3), resp., but different between IBS and controls (p < 0.0001). The pooled change in visceral and somatic pain due to DNIC was −6% (−13–1) in IBS and −22% (−28– −17) in controls (p < 0.0001). 54% of IBS patients versus 9% of controls showed pain facilitation instead of the expected inhibition (p < 0.0001). The magnitude of DNIC was influenced by race (white > asian > black, p < 0.001). Both visceral and somatic pain modulation were highly abnormal across all races in this large group of IBS patients, implying a generalised dysfunction of sensory modulation. There are significant racial differences in endogenous pain modulation. Facilitation during heterotopic stimulation is infrequent in controls and is therefore quite specific for IBS. 213 NEURONAL PENTRAXIN 1 CONTRIBUTES TO THE DESCENDING MODULATION OF NEUROPATHIC PAIN A. Zapata *, R. Schepers, B. Gehrke, E. Oh, R. Trullas, T. Shippenberg. National Institute on Drug Abuse, Baltimore, United States; Institut d’Investigacions Biomediques de Barcelona, CSIC/IDIBAPS, Barcelona, Spain Background and Aims: The neuronal pentraxin family of proteins promotes synaptic clustering of AMPA glutamate receptors and synaptic plasticity. Increased glutamatergic signaling in the rostral ventromedial medulla (RVM), a brainstem region important for the descending modulation of nociception, is implicated in the maintenance of neuropathic pain. We have investigated the involvement of neuronal pentraxin 1 (NP1) in a neuropathic pain model in rodents. Methods: We have used gene knock-out techniques and viralmediated silencing/over-expression of NP1 in the RVM in vivo to address the involvement of this protein in the spared nerve injury (SNI) model of neuropathic pain in rodents. Mechanical allodynia (Von Frey filaments) and hyperalgesia (pin prick test) was evaluated in the sural nerve territory of both paws. Results:Mechanical allodynia associated with SNI is reduced in NP1 knock-out mice. Consistent with the role of the RVM in descending facilitation of nerve injury-evoked pain, rescuing NP1 expression therein abolishes the phenotype of knock-out mice. Silencing NP1 in the RVM of rats prior to nerve injury prevents the development of allodynia and hyperalgesia. Furthermore, when silencing occurs after SNI, the expression of allodynia and hyperalgesia is reversed. Modulation of NP1 expression did not change basal nociception in the ipsilateral paw nor alter mechanical thresholds in the contralateral paw after injury. Conclusions: These data demonstrate a specific role of NP1 in the pathogenesis of neuropathic pain and suggest that targeting this protein may provide a novel treatment for persistent pain arising from diverse etiologies. 214 THE EFFECT OF PERSONALITY ON CENTRAL PAIN PROCESSING C. Berna *, A. Reinecke, E.A. Holmes, G.M. Goodwin, I. Tracey. Department of Psychiatry, University of Oxford, Oxford, United Kingdom; Centre for Functional Magnetic Imaging of the Brain (FMRIB), Departments of Clinical Neurology and Anaesthetics, University of Oxford, Oxford, United Kingdom Background and Aims: Neuroticism is a personality trait, predisposing to depression and associated with negative outcomes

Psychology in Luxembourg

Tracing back to the early stages of scientific psychology in Luxembourg, past and recent developments in the academic and applied fields of psychology are chronicled for one of the smallest member states of the European Union. In addition, the institutionalization of psychology with regard to professional associations and in the context of the newly created University of Luxembourg is depicted. Based on survey data, the major occupational fields and the present situation of professional psychologists are described. Reflections concerning the future perspective of psychology as an academic discipline as well as a profession and an overview of the legal regulations concerning psychology in Luxembourg complete the report.